Tag: Dopamine

What is Dopamine Supersensitivity Psychosis?

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Introduction

Dopamine supersensitivity psychosis is a hypothesis that attempts to explain the phenomenon in which psychosis (e.g. having hallucinations, which can mean hearing or seeing things that other people do not see or hear) occurs despite treatment with escalating doses of antipsychotics. Dopamine supersensitivity may be caused by the dopamine receptor D2 antagonising effect of antipsychotics, causing a compensatory increase in D2 receptors within the brain that sensitizes neurons to endogenous release of the neurotransmitter dopamine. Because psychosis is thought to be mediated—at least in part—by the activity of dopamine at D2 receptors, the activity of dopamine in the presence of supersensitivity may paradoxically give rise to worsening psychotic symptoms despite antipsychotic treatment at a given dose. This phenomenon may co-occur with tardive dyskinesia, a rare movement disorder that may also be due to dopamine supersensitivity.

Brief History

When supersensitivity psychosis was explored in 1978, a featured concern was increasing resistance to medication, requiring higher doses or not responding to higher doses. Some articles use the term tardive psychosis to reference to this specific concept. However, articles have disputed its validity. The condition has been discovered in very few people. Palmstierna asserts that tardive psychosis is a combination of “several different and not necessarily correlated phenomena related to neuroleptic treatment of schizophrenia.”

Mechanism

Dopamine supersensitivity psychosis may occur due to upregulation of dopamine 2 receptors (D2). The D2 receptor is the primary target of almost all antipsychotics, which oppose the action of the neurotransmitter dopamine at this receptor. The antagonising or “blockade” of D2 by antipsychotics may cause neurons, a type of cell within the brain, to undergo compensatory changes to make up for the loss of activity at D2 receptors. The D2 signalling pathway within neurons is complex, and involves multiple enzymes and other secondary messengers. It may be the case that, in response to antipsychotics, neurons increase the production of D2 receptors (upregulation), thereby sensitizing the neuron to dopamine. However, this is likely an oversimplification, as—despite differences in sensitivity to dopamine of around 3-fold in people that have taken antipsychotics chronically, there is a disproportionately low increase in the amount of D2 receptors in the brain in these people (around 1.4-fold in the striatum of the brain in people with schizophrenia). Other hypotheses include increases in the “active” D2 receptors (termed D2High) relative to the “inactive” conformation (D2Low).

The result is dopamine supersensitivity. It is thought that the psychotic symptoms within schizophrenia are primarily due to overactive dopamine activity in the mesolimbic area of the brain. Therefore, dopamine supersensitivity may reduce the effect of antipsychotics and increase the brain’s response to endogenous dopamine, leading to worsening psychosis.

Tardive dyskinesia, a type of rare movement disorder that can be caused by antipsychotics, may also be caused by dopamine receptor sensitization. This may explain why, for people with tardive dyskinesia, increasing the dose of the antipsychotic may temporarily improve symptoms.

Diagnosis

The original criteria for dopamine supersensitivity psychosis were the following:

A. Continuous use of antipsychotics for at least 3 months.
B. One of the following:

  1. Rebound psychosis within 6 weeks of a change (e.g. dose reduction, or antipsychotic switching) in an oral antipsychotic regimen or 3 months for long-acting injectable antipsychotics
  2. Tolerance to antipsychotic effects (requiring escalating doses, even beyond what has controlled symptoms in the past)
  3. Presence of tardive dyskinesia (which should occur when antipsychotics are withdrawn, and improve or disappear when antipsychotics are restarted)

Differential Diagnosis

It may sometimes be impossible to distinguish dopamine supersensitivity psychosis from psychosis that occurs “naturally” in the course of a primary psychotic disorder like schizophrenia, including cases in which the person was not taking their antipsychotic medication. Even in the presence of an alternative aetiology, or when it is impossible to determine the precise aetiology for a psychotic episode, it is possible that dopamine supersensitivity psychosis can play a role in the presentation. Recognising the possible role of dopamine supersensitivity psychosis in a psychotic episode has implications for how to best manage someone’s antipsychotic therapy.

Society and Culture

Dopamine supersensitivity is often dismissed as an inconsequential factor in the progression of psychotic disorders by psychiatrists in the medical literature. The dopamine supersensitivity hypothesis was discussed by investigative journalist and author Robert Whitaker in his book Anatomy of an Epidemic, published in 2010.

Research

As of 2017, much of the evidence for dopamine supersensitivity psychosis comes from studies performed in animals. There is still a need for robust, human research.

In a cohort study of people taking chronic antipsychotic therapy with either schizophrenia or schizoaffective disorder that presented for psychiatric care due to a relapse of their psychotic symptoms without a clear precipitating cause (e.g. new or worsening substance abuse, evidence of nonadherence to antipsychotics), 39% of the sample met the authors’ checklist for dopamine supersensitivity psychosis. The people that met the criteria were more likely than others to have worse symptoms when their psychosis returned (relapsed), have residual psychotic symptoms, had overall worse health outcomes at 6-month follow-ups, and were more likely to live in residential care.

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What is a Serotonin-Norepinephrine-Dopamine Reuptake Inhibitor?

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Introduction

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.

Other SNDRIs were developed as potential antidepressants and treatments for other disorders, such as obesity, cocaine addiction, attention-deficit hyperactivity disorder (ADHD), and chronic pain. They are an extension of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) whereby the addition of dopaminergic action is thought to have the possibility of heightening therapeutic benefit. However, increased side effects and abuse potential are potential concerns of these agents relative to their SSRI and SNRI counterparts.

The SNDRIs are similar to non-selective monoamine oxidase inhibitors (MAOIs) such as phenelzine and tranylcypromine in that they increase the action of all three of the major monoamine neurotransmitters. They are also similar to serotonin–norepinephrine–dopamine releasing agents (SNDRAs) like MDMA (“ecstasy”) and α-ethyltryptamine (αET) for the same reason, although they act via a different mechanism and have differing physiological and qualitative effects.

Although their primary mechanisms of action are as NMDA receptor antagonists, ketamine and phencyclidine are also SNDRIs and are similarly encountered as drugs of abuse.

Indications

Depression

Major depressive disorder (MDD) is the foremost reason supporting the need for development of an SNDRI. According to the World Health Organization, depression is the leading cause of disability and the 4th leading contributor to the global burden of disease in 2000. By the year 2020, depression is projected to reach 2nd place in the ranking of DALYs (disability-adjusted life year).

About 16% of the population is estimated to be affected by major depression, and another 1% is affected by bipolar disorder, one or more times throughout an individual’s lifetime. The presence of the common symptoms of these disorders are collectively called ‘depressive syndrome’ and includes a long-lasting depressed mood, feelings of guilt, anxiety, and recurrent thoughts of death and suicide. Other symptoms including poor concentration, a disturbance of sleep rhythms (insomnia or hypersomnia), and severe fatigue may also occur. Individual patients present differing subsets of symptoms, which may change over the course of the disease highlighting its multifaceted and heterogeneous nature. Depression is often highly comorbid with other diseases, e.g. cardiovascular disease (myocardial infarction, stroke), diabetes, cancer, Depressed subjects are prone to smoking, substance abuse, eating disorders, obesity, high blood pressure, pathological gambling and internet addiction, and on average have a 15 to 30 year shorter lifetime compared with the general population.

Major depression can strike at virtually any time of life as a function of genetic and developmental pre-disposition in interaction with adverse life-events. Although common in the elderly, over the course of the last century, the average age for a first episode has fallen to ~30 years. However, depressive states (with subtly different characteristics) are now frequently identified in adolescents and even children. The differential diagnosis (and management) of depression in young populations requires considerable care and experience; for example, apparent depression in teenagers may later transpire to represent a prodromal phase of schizophrenia.

The ability to work, familial relationships, social integration, and self-care are all severely disrupted.

The genetic contribution has been estimated as 40-50%. However, combinations of multiple genetic factors may be involved because a defect in a single gene usually fails to induce the multifaceted symptoms of depression.

Pharmacotherapy

There remains a need for more efficacious antidepressant agents. Although two-thirds of patients will ultimately respond to antidepressant treatment, one-third of patients respond to placebo, and remission is frequently sub-maximal (residual symptoms). In addition to post-treatment relapse, depressive symptoms can even recur in the course of long-term therapy (tachyphylaxis). Also, currently available antidepressants all elicit undesirable side-effects, and new agents should be divested of the distressing side-effects of both first and second-generation antidepressants.

Another serious drawback of all antidepressants is the requirement for long-term administration prior to maximal therapeutic efficacy. Although some patients show a partial response within 1–2 weeks, in general one must reckon with a delay of 3–6 weeks before full efficacy is attained. In general, this delay to onset of action is attributed to a spectrum of long-term adaptive changes. These include receptor desensitization, alterations in intracellular transduction cascades and gene expression, the induction of neurogenesis, and modifications in synaptic architecture and signalling.

Depression has been associated with impaired neurotransmission of serotonergic (5-HT), noradrenergic (NE), and dopaminergic (DA) pathways, although most pharmacologic treatment strategies directly enhance only 5-HT and NE neurotransmission. In some patients with depression, DA-related disturbances improve upon treatment with antidepressants, it is presumed by acting on serotonergic or noradrenergic circuits, which then affect DA function. However, most antidepressant treatments do not directly enhance DA neurotransmission, which may contribute to residual symptoms, including impaired motivation, concentration, and pleasure.

Preclinical and clinical research indicates that drugs inhibiting the reuptake of all three of these neurotransmitters can produce a more rapid onset of action and greater efficacy than traditional antidepressants.

DA may promote neurotrophic processes in the adult hippocampus, as 5-HT and NA do. It is thus possible that the stimulation of multiple signalling pathways resulting from the elevation of all three monoamines may account, in part, for an accelerated and/or greater antidepressant response.

Dense connections exist between monoaminergic neurons. Dopaminergic neurotransmission regulates the activity of 5-HT and NE in the dorsal raphe nucleus (DR) and locus coeruleus (LC), respectively. In turn, the ventral tegmental area (VTA) is sensitive to 5-HT and NE release.

In the case of SSRIs, the promiscuity among transporters means that there may be more than a single type of neurotransmitter to consider (e.g. 5-HT, DA, NE, etc.) as mediating the therapeutic actions of a given medication. MATs are able to transport monoamines other than their “native” neurotransmitter. It was advised to consider the role of the organic cation transporters (OCT) and the plasma membrane monoamine transporter (PMAT).

To examine the role of monoamine transporters in models of depression DAT, NET, and SERT knockout (KO) mice and wild-type littermates were studied in the forced swim test (FST), the tail suspension test, and for sucrose consumption. The effects of DAT KO in animal models of depression are larger than those produced by NET or SERT KO, and unlikely to be simply the result of the confounding effects of locomotor hyperactivity; thus, these data support re-evaluation of the role that DAT expression could play in depression and the potential antidepressant effects of DAT blockade.

The SSRIs were intended to be highly selective at binding to their molecular targets. However it may be an oversimplification, or at least controversial in thinking that complex psychiatric (and neurological) diseases are easily solved by such a monotherapy. While it may be inferred that dysfunction of 5-HT circuits is likely to be a part of the problem, it is only one of many such neurotransmitters whose signalling can be affected by suitably designed medicines attempting to alter the course of the disease state.

Most common CNS disorders are highly polygenic in nature; that is, they are controlled by complex interactions between numerous gene products. As such, these conditions do not exhibit the single gene defect basis that is so attractive for the development of highly-specific drugs largely free of major undesirable side-effects (“the magic bullet”). Second, the exact nature of the interactions that occur between the numerous gene products typically involved in CNS disorders remain elusive, and the biological mechanisms underlying mental illnesses are poorly understood.

Clozapine is an example of a drug used in the treatment of certain CNS disorders, such as schizophrenia, that has superior efficacy precisely because of its broad-spectrum mode of action. Likewise, in cancer chemotherapeutics, it has been recognized that drugs active at more than one target have a higher probability of being efficacious.

In addition, the nonselective MAOIs and the TCA SNRIs are widely believed to have an efficacy that is superior to the SSRIs normally picked as the first-line choice of agents for/in the treatment of MDD and related disorders. The reason for this is based on the fact that SSRIs are safer than nonselective MAOIs and TCAs. This is both in terms of there being less mortality in the event of overdose, but also less risk in terms of dietary restrictions (in the case of the nonselective MAOIs), hepatotoxicity (MAOIs) or cardiotoxicity (TCAs).

Applications other than Depression

  • Alcoholism (c.f. DOV 102,677)
  • Cocaine addiction (e.g., indatraline)
  • Obesity (e.g., amitifadine, tesofensine)
  • Attention-deficit hyperactivity disorder (ADHD) (c.f. NS-2359, EB-1020)
  • Chronic pain (c.f. bicifadine)
  • Parkinson’s disease

List of SNDRIs

Approved Pharmaceuticals

  • Mazindol (Mazanor, Sanorex) – anorectic; 50 nM for SERT, 18 nM for NET, 45 nM for DAT
  • Nefazodone (Serzone, Nefadar, Dutonin) – antidepressant; non-selective; 200 nM at SERT, 360 nM at NET, 360 nM at DAT
  • Nefopam (Ki SER/NE/DA = 29/33/531nM)

Sibutramine (Meridia) is a withdrawn anorectic that is an SNDRI in vitro with values of 298 nM at SERT, 5451 at NET, 943 nM at DAT. However, it appears to act as a prodrug in vivo to metabolites that are considerably more potent and possess different ratios of monoamine reuptake inhibition in comparison, and in accordance, sibutramine behaves contrarily as an SNRI (73% and 54% for norepinephrine and serotonin reuptake inhibition, respectively) in human volunteers with only very weak and probably inconsequential inhibition of dopamine reuptake (16%).

Venlafaxine (Effexor) is sometimes referred to as an SNDRI, but is extremely imbalanced with values of 82 nM for SERT, 2480 nM for NET, and 7647 nM for DAT, with a ratio of 1:30:93. It may weakly inhibit the reuptake of dopamine at high doses.

Coincidental

  • Esketamine (Ketanest S) – anesthetic; S-enantiomer of ketamine; weak SNDRI action likely contributes to effects and abuse potential
  • Ketamine (Ketalar) – anesthetic and dissociative drug of abuse; weak SNDRI action likely contributes to effects and abuse potential
  • Phencyclidine (Sernyl) – discontinued anesthetic and dissociative psychostimulant drug of abuse; SNDRI action likely contributes to effects and abuse potential
  • Tripelennamine (Pyribenzamine) – antihistamine; weak SNDRI; sometimes abused for this reason
  • Mepiprazole

Undergoing Clinical Trials

  • Ansofaxine (LY03005/LPM570065). Completed Phase 2 & 3 trials. FDA accepted NDA application.
  • Centanafadine (EB-1020) – see here for details 1 to 6 to 14 ratio for NDS. Completed Phase 3 trials for ADHD.
  • OPC-64005 – In phase 2 trials (2022)
  • Lu AA37096 – see here (SNDRI and 5-HT6 modulator).
  • NS-2360 – principle metabolite of tesofensine.
  • Tesofensine (NS-2330) (2001) In trials for obesity.

Failed Clinical Trials

  • Bicifadine (DOV-220,075) (1981)
  • BMS-866,949
  • Brasofensine (NS-2214, BMS-204,756) (1995)
  • Diclofensine (Ro 8–4650) (1982)
  • DOV-216,303 (2004)
  • EXP-561 (1965)
  • Liafensine (BMS-820,836)
  • NS-2359 (GSK-372,475)
  • RG-7166 (2009–2012)
  • SEP-227,162
  • SEP-228,425
  • SEP-432 aka SEP-228432, CID:58954867
  • Amitifadine (DOV-21,947, EB-1010) (2003)
  • Dasotraline (SEP-225,289)
  • Lu AA34893 – see here (SNDRI and 5-HT2A, α1, and 5-HT6 modulator)
  • Tedatioxetine (Lu AA24530) – SNDRI and 5-HT2C, 5-HT3, 5-HT2A, and α1 modulator

Designer Drugs

  • 3-Methyl-PCPy
  • Naphyrone (O-2482, naphthylpyrovalerone, NRG-1) (2006)
  • 5-APB

Research Compounds (No Record of having been taken by Humans)

  • 3,4-Diphenylquinuclidine HCl salt: [72811-36-0].
  • 3,4-Diphenylpiperidines (a panoply of analogs was disclosed by French Hoechst) Ref: Patents: The 3′,4′-Dichloro lactam was the most powerful psychostimulant tested. Its SAR can be compared to a similar French Hoechst compound called Lomevactone.
  • MDL 47,832 [52423-89-9] Patent: SAR is similar to RG-7166 & Amitifadine. For SAR study see under Osanetant.
  • 3,3-Diphenylcyclobutanamine (1978)
  • AK Dutta: D-161 (2008) D-473 [1632000-05-5] & D-578.
  • DOV-102,677 (2006–2011)
  • Fezolamine (Win-41,528-2)
  • GlaxoSmithKline (Italia): GSK1360707F (2010): CID:46866510:
  • HP-505
  • Lundbeck group: Indatraline (1985), Lu-AA42202 & CID:11515108 [874296-10-3].
  • JNJ-7925476 (2008; first appeared in 1987), Mcn 5707 [96795-88-9] & Mcn-5292 [105234-89-7].
  • Kozikowski group: DMNPC (2000), JZ-IV-10 (2005) & JZAD-IV-22 (2010)
  • Lilly group: LR-5182 (maybe only NDRI) (1978) CID:9903806:
    • CID:11335177, CID:9867350, CID:11234430
  • HM Deutsch group: Methylnaphthidate (HDMP-28) (2001)
  • MI-4 MI-4 is the same compound as Ro-25-6981 [169274-78-6]. This is NMDA antagonist.
  • Benzazepine derivatives: SKF-83,959 (2013) & Nor-Trepipam [20569-49-7]
  • Various phenyltropanes, such as WF-23, dichloropane, and RTI-55
  • NeuroSearch group: NS9775, NS18283. & 4-Benzhydryl-1,2,3,6-tetrahydropyridine [1186529-81-6].
    • CID:54673194 (S/N/D = 0.26/6.0/4.8nM)
    • CID:9921901 [387869-25-2], 3-(3,4-Dichlorophenyl)-tropan-2-ene (S/N/D = 4.7/26/79nM)
  • Liming Shao (Sepracor/Sunovion). 3’,4’-Dichlorotramadol, CID:53321058 (S/N/D = 19/04/01nM
    • CID:66809062: CID:46870521 CID:10151573 CID:46701015
  • Takeda group, CID:44629033 (S/N/D = 11/14/190nM)
  • Trudell group: HK3-263 (S/N/D = 0.3/20/16nM)
  • Pfizer group CP-607366 & CP-939689.
    • Desmethylsertraline – active metabolite of sertraline; 76 nM for SERT, 420 nM for NET, 440 nM for DAT
    • 3,4-Dichlorotametraline (trans-(1R,4S)-sertraline) (1980)
  • Venlafaxine analogues, LPM580098 & LPM580153. And TP1 later reassigned name to PA01.
    • PRC (Carlier) group: PRC200-SS (2008), PRC050, and PRC025.
  • Albany Molecular Research group (Bruce Molino) AMR-2 (DAT 3.1nM, SERT 8.3nM, NET 3.0nM)
    • CID:49765424 (S)-enantiomer: [1254941-82-6]:
  • SK Group: CID:44555333 & CID:49866033
  • Boots UK: BTS 74,398, SPD-473 citrate: [161190-26-7]
  • Pridefine
  • SMe1EC2M3
  • SIPI5357 (CID:52939791)
  • 23j-S (S/N/D = 83/3.8/160nM)
  • Tetrazoles (ROK)
  • 10dl (CID:118713802) (S/N/D 7.6/45.2/330nM)
  • 2at (CID:118706539)
  • THIQ Derivatives: AN12 (CID:10380161): CID:9839278
  • 2j (CID:66572162) (S/N/D = 411/71/159nM)
  • 6aq (CID:70676472) (S/N/D 44/10/32nM)
  • Naphthyl milnacipran analog (2007), CID:17748230 (S/N/D = 18/05/140nM).

Herbals

  • The coca flour contains cocaine – natural alkaloid and drug of abuse
  • Ginkgo biloba extract (EGb761) – “The norepinephrine (NET), the serotonin (SERT), the dopamine (DAT) uptake transporters and MAO activity are inhibited by EGb761 in vitro”
  • St John’s Wort – natural product and over-the-counter herbal antidepressant
    • Hyperforin
    • Adhyperforin
    • Uliginosin B – IC50 DA = 90 nM, 5-HT = 252 nM, NE = 280 nM
  • Oregano extract.
  • Although not specifically a SNDRI, Rosmarinus officinalis is one of the trimonoamine modulator (TMM) that affect SER/CAs.
  • Hederagenin

Toxicological

Toxicological screening is important to ensure safety of the drug molecules. In this regard, the p m-dichloro phenyl analog of venlafaxine was dropped from further development after its potential mutagenicity was called into question.[158] The mutagenicity of this compound is still doubtful though. It was dropped for other reasons likely related to speed at which it could be released onto the market relative to the more developed compound venlafaxine. More recently, the carcinogenicity of PRC200-SS was likewise reported.

(+)-CPCA (“nocaine”) is the 3R,4S piperidine stereoisomer of (phenyltropane based) RTI-31. It is non addictive, although this might be due to it being a NDRI, not a SNDRI. The β-naphthyl analog of “Nocaine” is a SNDRI though in the case of both the SS and RR enantiomers. Consider the piperidine analogs of brasofensine and tesofensine. These were prepared by NeuroSearch (In Denmark) by the chemists Peter Moldt (2002), and Frank Wätjen (2004–2009). There are four separate isomers to consider (SS, RR, S/R and R/S). This is because there are two chiral carbon sites of asymmetry (means 2 to the power of n isomers to consider where n is the number of chiral carbons). They are therefore a diastereo(iso)meric pair of racemers. With a racemic pair of diastereomers, there is still the question of syn (cis) or anti (trans). In the case of the phenyltropanes, although there are four chiral carbons, there are only eight possible isomers to consider. This is based on the fact that the compound is bicyclic and therefore does not adhere to the equation given above.

It is complicated to explain which isomers are desired. For example, although Alan P. Kozikowski showed that R/S nocaine is less addictive than SS Nocaine, studies on variously substituted phenyltropanes by F. Ivy Carroll et at. revealed that the ββ isomers were less likely to cause convulsions, tremor and death than the corresponding trans isomers (more specifically, what is meant is the 1R,2R,3S isomers). While it does still have to be conceded that RTI-55 caused death at a dosage of 100 mg/kg, it’s therapeutic index of safety is still much better than the corresponding trans isomers because it is more potent compound.

In discussing cocaine and related compounds such as amphetamines, it is clear that these psychostimulants cause increased blood pressure, decreased appetite (and hence weight loss), increased locomotor activity (LMA) etc. In the United States, cocaine overdose is one of the leading causes of ER admissions each year due to drug overdose. People are at increased risk of heart attack and stroke and also present with an array of psychiatric symptoms including anxiety & paranoia etc. On removal of the 2C tropane bridge and on going from RTI-31 to the simpler SS and RS Nocaine it was seen that these compounds still possessed activity as NDRIs but were not powerful psychostimulants. Hence, this might be viewed as a strategy for increasing the safety of the compounds and would also be preferable to use in patients who are not looking to achieve weight loss.

In light of the above paragraph, another way of reducing the psychomotor stimulant and addictive qualities of phenyltropane stimulants is in picking one that is relatively serotonergic. This strategy was employed with success for RTI-112.

Another thing that is important and should be mentioned is the risk for serotonin syndrome when incorporating the element of 5-HT transporter inhibition into a compound that is already fully active as a NDRI (or vice versa). The reasons for serotonin syndrome are complicated and not fully understood.

Addiction

Drug addiction may be regarded as a disease of the brain reward system. This system, closely related to the system of emotional arousal, is located predominantly in the limbic structures of the brain. Its existence was proved by demonstration of the “pleasure centres,” that were discovered as the location from which electrical self-stimulation is readily evoked. The main neurotransmitter involved in the reward is dopamine, but other monoamines and acetylcholine may also participate. The anatomical core of the reward system are dopaminergic neurons of the ventral tegmentum that project to the nucleus accumbens, amygdala, prefrontal cortex and other forebrain structures.

There are several groups of substances that activate the reward system and they may produce addiction, which in humans is a chronic, recurrent disease, characterized by absolute dominance of drug-seeking behaviour.

According to various studies, the relative likelihood of rodents and non-human primates self-administering various psychostimulants that modulate monoaminergic neurotransmission is lessened as the dopaminergic compounds become more serotonergic.

The above finding has been found for amphetamine and some of its variously substituted analogues including PAL-287 etc.

RTI-112 is another good example of the compound becoming less likely to be self-administered by the test subject in the case of a dopaminergic compound that also has a marked affinity for the serotonin transporter.

WIN 35428, RTI-31, RTI-51 and RTI-55 were all compared and it was found that there was a negative correlation between the size of the halogen atom and the rate of self-administration (on moving across the series). Rate of onset was held partly accountable for this, although increasing the potency of the compounds for the serotonin transporter also played a role.

Further evidence that 5-HT dampens the reinforcing actions of dopaminergic medications comes from the co-administration of psychostimulants with SSRIs, and the phen/fen combination was also shown to have limited abuse potential relative to administration of phentermine only.

NET blockade is unlikely to play a major role in mediating addictive behaviour. This finding is based on the premise that desipramine is not self-administered, and also the fact that the NRI atomoxetine was not reinforcing. However, it was still shown to facilitate dopaminergic neurotransmission in certain brain regions such as in the core of the PFC.

Relation to Cocaine

Cocaine is a short-acting SNDRI that also exerts auxiliary pharmacological actions on other receptors. Cocaine is a relatively “balanced” inhibitor, although facilitation of dopaminergic neurotransmission is what has been linked to the reinforcing and addictive effects. In addition, cocaine has some serious limitations in terms of its cardiotoxicity due to its local anaesthetic activity. Thousands of cocaine users are admitted to emergency units in the USA every year because of this; thus, development of safer substitute medications for cocaine abuse could potentially have significant benefits for public health.

Many of the SNDRIs currently being developed have varying degrees of similarity to cocaine in terms of their chemical structure. There has been speculation over whether the new SNDRIs will have an abuse potential like cocaine does. However, for pharmacotherapeutical treatment of cocaine addiction it is advantageous if a substitute medication is at least weakly reinforcing because this can serve to retain addicts in treatment programmes:

… limited reinforcing properties in the context of treatment programs may be advantageous, contributing to improved patient compliance and enhanced medication effectiveness.

However, not all SNDRIs are reliably self-administered by animals. Examples include:

  • PRC200-SS was not reliably self-administered.
  • RTI-112 was not self-administered because at low doses the compound preferentially occupies the SERT and not the DAT.
  • Tesofensine was also not reliably self-administered by human stimulant addicts.
  • The nocaine analogue JZAD-IV-22 only partly substituted for cocaine in animals, but produced none of the psychomotor activation of cocaine, which is a trait marker for stimulant addiction.

Legality

Cocaine is a controlled drug (Class A in the UK; Schedule II in the USA); it has not been entirely outlawed in most countries, as despite having some “abuse potential” it is recognised that it does have medical uses.

Brasofensine was made “class A” in the UK under the MDA (misuse of drugs act). The semi-synthetic procedure for making BF uses cocaine as the starting material.

Naphyrone first appeared in 2006 as one of quite a large number of analogues of pyrovalerone designed by the well-known medicinal chemist P. Meltzer et al. When the designer drugs mephedrone and methylone became banned in the United Kingdom, vendors of these chemicals needed to find a suitable replacement. Mephedrone and methylone affect the same chemicals in the brain as a SNDRI, although they are thought to act as monoamine releasers and not act through the reuptake inhibitor mechanism of activity. A short time later, mephedrone and methylone were banned (which had become quite popular by the time they became illegal), naphyrone appeared under the trade name NRG-1. NRG-1 was promptly illegalised, although it is not known if its use resulted in any hospitalisations or deaths.

Role of Monoamine Neurotransmitters

Monoamine Hypothesis

The original monoamine hypothesis postulates that depression is caused by a deficiency or imbalances in the monoamine neurotransmitters (5-HT, NE, and DA). This has been the central topic of depression research for approximately the last 50 years; it has since evolved into the notion that depression arises through alterations in target neurons (specifically, the dendrites) in monoamine pathways.

When reserpine (an alkaloid with uses in the treatment of hypertension and psychosis) was first introduced to the West from India in 1953, the drug was unexpectedly shown to produce depression-like symptoms. Further testing was able to reveal that reserpine causes a depletion of monoamine concentrations in the brain. Reserpine’s effect on monoamine concentrations results from blockade of the vesicular monoamine transporter, leading to their increased catabolism by monoamine oxidase. However, not everyone has been convinced by claims that reserpine is depressogenic, some authors (David Healy in particular) have even claimed that it is antidepressant.

Tetrabenazine, a similar agent to reserpine, which also depletes catecholamine stores, and to a lesser degree 5-HT, was shown to induce depression in many patients.

Iproniazid, an inhibitor of MAO, was noted to elevate mood in depressed patients in the early 1950s, and soon thereafter was shown to lead to an increase in NA and 5-HT.

Hertting et al. demonstrated that the first TCA, imipramine, inhibited cellular uptake of NA in peripheral tissues. Moreover, both antidepressant agents were demonstrated to prevent reserpine-induced sedation. Likewise, administration of DOPA to laboratory animals was shown to reverse reserpine induced sedation; a finding reproduced in humans. Amphetamine, which releases NA from vesicles and prevents re-uptake was also used in the treatment of depression at the time with varying success.

In 1965 Schildkraut formulated the catecholamine theory of depression. This was subsequently the most widely cited article in the American Journal of Psychiatry. The theory stated that “some, if not all, depressions are associated with an absolute or relative deficiency of catecholamines, in particular noradrenaline (NA), at functionally important adrenergic receptor sites in the brain. However, elation may be associated with an excess of such amines.”

Shortly after Schildkraut’s catecholamine hypothesis was published, Coppen proposed that 5-HT, rather than NA, was the more important neurotransmitter in depression. This was based on similar evidence to that which produced the NA theory as reserpine, imipramine, and iproniazid affect the 5-HT system, in addition to the noradrenergic system. It was also supported by work demonstrating that if catecholamine levels were depleted by up to 20% but 5-HT neurotransmission remained unaltered there was no sedation in animals. Alongside this, the main observation promoting the 5-HT theory was that administration of a MAOI in conjunction with tryptophan (precursor of 5-HT) elevated mood in control patients and potentiated the antidepressant effect of MAOI. Set against this, combination of an MAOI with DOPA did not produce a therapeutic benefit.

Inserting a chlorine atom into imipramine leads to clomipramine, a drug that is much more SERT selective than the parent compound.

Clomipramine was a predecessor to the development of the more recent SSRIs. There was, in fact, a time prior to the SSRIs when selective NRIs were being considered (c.f. talopram and melitracen). In fact, it is also believed that the selective NRI nisoxetine was discovered prior to the invention of fluoxetine. However, the selective NRIs did not get promoted in the same way as did the SSRIs, possibly due to an increased risk of suicide. This was accounted for on the basis of the energising effect that these agents have. Moreover, NRIs have the additional adverse safety risk of hypertension that is not seen for SSRIs. Nevertheless, NRIs have still found uses.

Further support for the monoamine hypothesis came from monoamine depletion studies:

  • Alpha-methyl-p-tyrosine (AMPT) is a tyrosine hydroxylase enzyme inhibitor that serves to inhibit catecholamine synthesis. AMPT led to a resurgence of depressive symptoms in patients improved by the NE reuptake inhibitor (NRI) desipramine, but not by the SSRI fluoxetine. The mood changes induced by AMPT may be mediated by decreases in norepinephrine, while changes in selective attention and motivation may be mediated by dopamine.
  • Dietary depletion of the DA precursors phenylalanine and tyrosine does not result in the relapse of formerly depressed patients off their medication.
  • Administration of fenclonine (para-chlorophenylalanine) is able to bring about a depletion of 5-HT. The mechanism of action for this is via tryptophan hydroxylase inhibition. In the 1970s administration of parachlorophenylalanine produced a relapse in depressive symptoms of treated patients, but it is considered too toxic for use today.
  • Although depletion of tryptophan — the rate-limiting factor of serotonin synthesis — does not influence the mood of healthy volunteers and untreated patients with depression, it does produce a rapid relapse of depressive symptoms in about 50% of remitted patients who are being, or have recently been treated with serotonin selective antidepressants.

Dopaminergic

There appears to be a pattern of symptoms that are currently inadequately addressed by serotonergic antidepressants – loss of pleasure (anhedonia), reduced motivation, loss of interest, fatigue and loss of energy, motor retardation, apathy and hypersomnia. Addition of a pro-dopaminergic component into a serotonin based therapy would be expected to address some of these short-comings.

Several lines of evidence suggest that an attenuated function of the dopaminergic system may play an important role in depression:

  • Mood disorders are highly prevalent in pathologies characterized by a deficit in central DA transmission such as Parkinson’s disease (PD). The prevalence of depression can reach up to 50% of individuals with PD.
  • Patients taking strong dopaminergic antagonists such as those used in the treatment of psychosis are more likely than the general population to develop symptoms of depression.
  • Data from clinical studies have shown that DA agonists, such as bromocriptine, pramipexole and ropinirole, exhibit antidepressant properties.
  • Amineptine, a TCA-derivative that predominantly inhibits DA re-uptake and has minimal noradrenergic and serotonergic activity has also been shown to possess antidepressant activity. A number of studies have suggested that amineptine has similar efficacy to the TCAs, MAOIs and SSRIs. However, amineptine is no longer available as a treatment for depression due to reports of an abuse potential.
  • The B-subtype selective MAOI selegiline (a drug developed for the treatment of PD) has now been approved for the treatment of depression in the form of a transdermal patch (Emsam). For some reason, there have been numerous reports of users taking this drug in conjunction with β-phenethylamine.
  • Taking psychostimulants for the alleviation of depression is well proven strategy, although in a clinical setting the use of such drugs is usually prohibited because of their strong addiction propensity.
  • When users withdraw from psychostimulant drugs of abuse (in particular, amphetamine), they experience symptoms of depression. This is likely because the brain enters into a hypodopaminergic state, although there might be a role for noradrenaline also.

For these drugs to be reinforcing, they must block more than 50% of the DAT within a relatively short time period (<15 minutes from administration) and clear the brain rapidly to enable fast repeated administration.

In addition to mood, they may also improve cognitive performance, although this remains to be demonstrated in humans.

The rate of clearance from the body is faster for ritalin than it is for regular amphetamine.

Noradrenergic

The decreased levels of NA proposed by Schildkraut, suggested that there would be a compensatory upregulation of β-adrenoceptors. Despite inconsistent findings supporting this, more consistent evidence demonstrates that chronic treatment with antidepressants and electroconvulsive therapy (ECT) decrease β-adrenoceptor density in the rat forebrain. This led to the theory that β-adrenoceptor downregulation was required for clinical antidepressant efficacy. However, some of the newly developed antidepressants do not alter, or even increase β-adrenoceptor density.

Another adrenoceptor implicated in depression is the presynaptic α2-adrenoceptor. Chronic desipramine treatment in rats decreased the sensitivity of α2-adrenoceptors, a finding supported by the fact that clonidine administration caused a significant increase in growth hormone (an indirect measure of α2-adrenoceptor activity) although platelet studies proved inconsistent. This supersensitivity of α2-adrenoceptor was postulated to decrease locus coeruleus (the main projection site of NA in the central nervous system, CNS) NA activity leading to depression.

In addition to enhancing NA release, α2-adrenoceptor antagonism also increases serotonergic neurotransmission due to blockade of α2-adrenoceptors present on 5-HT nerve terminals.

Serotonergic

5-Hydroxytryptamine (5-HT or serotonin) is an important cell-to-cell signalling molecule found in all animal phyla. In mammals, substantial concentrations of 5-HT are present in the central and peripheral nervous systems, gastrointestinal tract and cardiovascular system. 5-HT is capable of exerting a wide variety of biological effects by interacting with specific membrane-bound receptors, and at least 13 distinct 5-HT receptor subtypes have been cloned and characterised. With the exception of the 5-HT3 receptor subtype, which is a transmitter-gated ion channel, 5-HT receptors are members of the 7-transmembrane G protein-coupled receptor superfamily. In humans, the serotonergic system is implicated in various physiological processes such as sleep-wake cycles, maintenance of mood, control of food intake and regulation of blood pressure. In accordance with this, drugs that affect 5-HT-containing cells or 5-HT receptors are effective treatments for numerous indications, including depression, anxiety, obesity, nausea, and migraine.

Because serotonin and the related hormone melatonin are involved in promoting sleep, they counterbalance the wake-promoting action of increased catecholaminergic neurotransmission. This is accounted for by the lethargic feel that some SSRIs can produce, although TCAs and antipsychotics can also cause lethargy albeit through different mechanisms.

Appetite suppression is related to 5-HT2C receptor activation as for example was reported for PAL-287 recently.

Activation of the 5-HT2C receptor has been described as “panicogen” by users of ligands for this receptor (e.g., mCPP). Antagonism of the 5-HT2C receptor is known to augment dopaminergic output. Although SSRIs with 5-HT2C antagonist actions were recommended for the treatment of depression, 5-HT2C receptor agonists were suggested for treating cocaine addiction since this would be anti-addictive. Nevertheless, the 5-HT2C is known to be rapidly downregulated upon repeated administration of an agonist agent, and is actually antagonized.

Azapirone-type drugs (e.g. buspirone), which act as 5-HT1A receptor agonists and partial agonists have been developed as anxiolytic agents that are not associated with the dependence and side-effect profile of the benzodiazepines. The hippocampal neurogenesis produced by various types of antidepressants, likewise, is thought to be mediated by 5-HT1A receptors. Systemic administration of a 5-HT1A agonist also induces growth hormone and adrenocorticotropic hormone (ACTH) release through actions in the hypothalamus.

Current Antidepressants

Most antidepressants on the market today target the monoaminergic system.

SSRIs

The most commonly prescribed class of antidepressants in the USA today are the selective serotonin reuptake inhibitors (SSRIs). These drugs inhibit the uptake of the neurotransmitter 5-HT by blocking the SERT, thus increasing its synaptic concentration, and have shown to be efficacious in the treatment of depression, however sexual dysfunction and weight gain are two very common side-effects that result in discontinuation of treatment.

Although many patients benefit from SSRIs, it is estimated that approximately 50% of depressive individuals do not respond adequately to these agents. Even in remitters, a relapse is often observed following drug discontinuation. The major limitation of SSRIs concerns their delay of action. It appears that the clinical efficacy of SSRIs becomes evident only after a few weeks.

SSRIs can be combined with a host of other drugs including bupropion, α2 adrenergic antagonists (e.g. yohimbine) as well as some of the atypical antipsychotics. The augmentation agents are said to behave synergistically with the SSRI although these are clearly of less value than taking a single compound that contains all of the necessary pharmacophoric elements relative to the consumption of a mixture of different compounds. It is not entirely known what the reason for this is, although ease of dosing is likely to be a considerable factor. In addition, single compounds are more likely to be approved by the FDA (US Food and Drug Administration) than are drugs that contain greater than one pharmaceutical ingredient (polytherapies).

A number of SRIs were under development that had auxiliary interactions with other receptors. Particularly notable were agents behaving as co-joint SSRIs with additional antagonist activity at 5-HT1A receptors. 5-HT1A receptors are located presynaptically as well as post-synaptically. It is the presynaptic receptors that are believed to function as autoreceptors (cf. studies done with pindolol). These agents were shown to elicit a more robust augmentation in the % elevation of extracellular 5-HT relative to baseline than was the case for SSRIs as measured by in vivo microdialysis.

NRIs

Norepinephrine reuptake inhibitors (NRIs) such as reboxetine prevent the reuptake of norepinephrine, providing a different mechanism of action to treat depression. However reboxetine is no more effective than the SSRIs in treating depression. In addition, atomoxetine has found use in the treatment of ADHD as a non-addictive alternative to Ritalin. The chemical structure of atomoxetine is closely related to that of fluoxetine (an SSRI) and also duloxetine (SNRI).

NDRIs

Bupropion is a commonly prescribed antidepressant that acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It prevents the reuptake of NA and DA (weakly) by blocking the corresponding transporters, leading to increased noradrenergic and dopaminergic neurotransmission. This drug does not cause sexual dysfunction or weight gain like the SSRIs but has a higher incidence of nausea. Methylphenidate is a much more reliable example of an NDRI (the action that it displays on the DAT usually getting preferential treatment). Methylphenidate is used in the treatment of ADHD; its use in treating depression is not known to have been reported, but it is presumed owing to its psychomotor activating effects and it functioning as a positive reinforcer. There are also reports of methylphenidate being used in the treatment of psychostimulant addiction, in particular cocaine addiction, since the addictive actions of this drug are believed to be mediated by the dopamine neurotransmitter.

SNRIs

Serotonin–norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor), its active metabolite desvenlafaxine (Pristiq), and duloxetine (Cymbalta) prevent the reuptake of both serotonin and norepinephrine, however their efficacy appears to be only marginally greater than the SSRIs.

Sibutramine is the name of an SNRI based appetite suppressant with use in the treatment of obesity. This was explored in the treatment of depression, but was shown not to be effective.

Both sibutramine and venlafaxine are phenethylamine-based. At high doses, both venlafaxine and sibutramine will start producing dopaminergic effects. The inhibition of DA reuptake is unlikely to be relevant at clinically approved doses.

MAOIs

Monoamine oxidase inhibitors (MAOIs) were the first antidepressants to be introduced. They were discovered entirely by serendipity. Iproniazide (the first MAOI) was originally developed as an antitubercular agent but was then unexpectedly found to display antidepressant activity.

Isoniazid also displayed activity as an antidepressant, even though it is not a MAOI. This led some people to question whether it is some property of the hydrazine, which is responsible for mediating the antidepressant effect, even going as far as to state that the MAOI activity could be a secondary side-effect. However, with the discovery of tranylcypromine (the first non-hydrazine MAOI), it was shown that MAOI is thought to underlie the antidepressant bioactivity of these agents. Etryptamine is another example of a non-hydrazine MAOI that was introduced.

The MAOIs work by inhibiting the monoamine oxidase enzymes that, as the name suggests, break down the monoamine neurotransmitters. This leads to increased concentrations of most of the monoamine neurotransmitters in the human brain, serotonin, norepinephrine, dopamine and melatonin. The fact that they are more efficacious than the newer generation antidepressants is what leads scientists to develop newer antidepressants that target a greater range of neurotransmitters. The problem with MAOIs is that they have many potentially dangerous side-effects such as hypotension, and there is a risk of food and drug interactions that can result in potentially fatal serotonin syndrome or a hypertensive crisis. Although selective MAOIs can reduce, if not eliminate these risks, their efficacy tends to be lower.

MAOIs may preferentially treat TCA-resistant depression, especially in patients with features such as fatigue, volition inhibition, motor retardation and hypersomnia. This may be a function of the ability of MAOIs to increase synaptic levels of DA in addition to 5-HT and NE. The MAOIs also seem to be effective in the treatment of fatigue associated with fibromyalgia (FM) or chronic fatigue syndrome (CFS).

Although a substantial number of MAOIs were approved in the 1960s, many of these were taken off the market as rapidly as they were introduced. The reason for this is that they were hepatotoxic and could cause jaundice.

TCAs

The first tricyclic antidepressant (TCA), imipramine (Tofranil), was derived from the antipsychotic drug chlorpromazine, which was developed as a useful antihistaminergic agent with possible use as a hypnotic sedative. Imipramine is an iminodibenzyl (dibenzazepine).

The TCAs such as imipramine and amitriptyline typically prevent the reuptake of serotonin or norepinephine.

It is the histaminiergic (H1), muscarinic acetylcholinergic (M1), and alpha adrenergic (α1) blockade that is responsible for the side-effects of TCAs. These include somnolence and lethargy, anticholinergic side-effects, and hypotension. Due to the narrow gap between their ability to block the biogenic amine uptake pumps versus the inhibition of fast sodium channels, even a modest overdose of one of the TCAs could be lethal. TCAs were, for 25 years, the leading cause of death from overdoses in many countries. Patients being treated with antidepressants are prone to attempt suicide and one method they use is to take an overdose of their medications.

Another example of a TCA is amineptine which is the only one believed to function as a DRI. It is no longer available.

Failure of SNDRIs for Depression

SNDRIs have been under investigation for the treatment of major depressive disorder for a number of years but, as of 2015, have failed to meet effectiveness expectations in clinical trials. In addition, the augmentation of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor with lisdexamfetamine, a norepinephrine–dopamine releasing agent, recently failed to separate from placebo in phase III clinical trials of individuals with treatment-resistant depression, and clinical development was subsequently discontinued. These occurrences have shed doubt on the potential benefit of dopaminergic augmentation of conventional serotonergic and noradrenergic antidepressant therapy. As such, scepticism has been cast on the promise of the remaining SNDRIs that are still being trialled, such as ansofaxine (currently in phase II trials), in the treatment of depression. Nefazodone a weak SNDRI has been successful in treating major depressive disorder which makes it unique.

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What is a Serotonin-Dopamine Releasing Agent?

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Introduction

A serotonin–dopamine releasing agent (SDRA) is a type of drug which induces the release of serotonin and dopamine in the body and/or brain.

A closely related type of drug is a serotonin–dopamine reuptake inhibitor (SDRI).

Examples of SDRAs

A number of tryptamine derivatives have been found to act as SDRAs. One such agent is 5-chloro-αMT (PAL-542), which has been reported as having about 64-fold selectivity for dopamine release over norepinephrine release and about 3-fold selectivity for serotonin release over dopamine release, making it a highly selective and well-balanced SDRA. Another agent is 5-fluoro-αET (PAL-545), which has about 35-fold selectivity for dopamine release over norepinephrine release and about 4-fold selectivity for serotonin release over dopamine release. Though selective for inducing the release of serotonin and dopamine over norepinephrine, these agents are not selective monoamine releasers; they have all also been found to be potent agonists of the 5-HT2A receptor, and may act as agonists of other serotonin receptors as well.

UWA-101 is an SDRI that, based on its chemical structure, may also have a great efficacy as a releasing agent of serotonin and dopamine.

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What is a Serotonin-Norepinephrine-Dopamine Releasing Agent?

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Introduction

A serotonin–norepinephrine–dopamine releasing agent (SNDRA), also known as a triple releasing agent (TRA), is a type of drug which induces the release of serotonin, norepinephrine/epinephrine, and dopamine in the brain and body. SNDRAs produce euphoriant, entactogen, and psychostimulant effects, and are almost exclusively encountered as recreational drugs.

A closely related type of drug is a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI).

Stahl uses the term “Trimonoaminergic Modulators” (TMM) in his work.

Examples of SNDRAs

Examples of SNDRAs include specific amphetamines such as MDMA, MDA, 4-methylamphetamine, methamphetamine (in high doses), certain substituted benzofurans such as 5-APB and 6-APB, naphthylisopropylamine; cathinones such as mephedrone and methylone; tryptamines such as αMT and αET; along with agents of other chemical classes such as 4,4′-DMAR, and 5-IAI. αET and αMT are of special notability among SNDRAs in that those tryptamines were once used as pharmaceutical drugs, specifically as antidepressants, but were withdrawn shortly after introduction in the 1960s due to problems with toxicity and recreational use. Such tryptamines were originally thought to act as monoamine oxidase inhibitors (MAOIs) before the signature monoamine-releasing actions were elucidated. Many years after being withdrawn, αET was also determined to produce serotonergic neurotoxicity, similarly to MDMA and various other SNDRAs; the same is very likely true for αMT as well, although it has not specifically been assessed.

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What is a Dopamine Releasing Agent?

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Introduction

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain (refer to Monoamine Releasing Agent). No selective DRAs are currently known. Many releasing agents of both dopamine and norepinephrine (norepinephrine–dopamine releasing agents, or NDRAs) and of serotonin, norepinephrine, and dopamine are known (serotonin-norepinephrine-dopamine releasing agents, or SNDRAs), however. Serotonin–dopamine releasing agents are much rarer and are not selective for monoamine release. Examples of NDRAs include amphetamine and methamphetamine, and an example of an SNDRA is MDMA. The most selective dopamine releaser is 4-methylaminorex, but it also has considerable activity as a norepinephrine releaser. These drugs are frequently used for recreational purposes and encountered as drugs of abuse.

A closely related type of drug is a dopamine reuptake inhibitor (DRI). Various selective DRIs are known, in contrast to the case of DRAs. It is particularly of note that the mechanism of action at the dopamine transporter (DAT) for dopamine releasers/substrates is entropy-driven (i.e. hydrophobic), whereas for dopamine re-uptake inhibitors it is enthalpy-driven (i.e. conformational change).

There is some, albeit mixed, in vitro evidence that the antidepressant and modestly selective DRI amineptine may in addition to inhibiting the reuptake of dopamine selectively induce the presynaptic release of dopamine without affecting that of norepinephrine or serotonin.

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What are Dopaminergic Pathways?

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Introduction

Dopaminergic pathways (dopamine pathways, dopaminergic projections) in the human brain are involved in both physiological and behavioural processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine control. Each pathway is a set of projection neurons, consisting of individual dopaminergic neurons.

The four major dopaminergic pathways are the mesolimbic pathway, the mesocortical pathway, the nigrostriatal pathway, and the tuberoinfundibular pathway. The mesolimbic pathway and the mesocortical pathway form the mesocorticolimbic system. Two other dopaminergic pathways to be considered are the hypothalamospinal tract and the incertohypothalamic pathway.

Parkinson’s disease, attention deficit hyperactivity disorder (ADHD), substance use disorders (addiction), and restless legs syndrome (RLS) can be attributed to dysfunction in specific dopaminergic pathways.

The dopamine neurons of the dopaminergic pathways synthesize and release the neurotransmitter dopamine. Enzymes tyrosine hydroxylase and dopa decarboxylase are required for dopamine synthesis. These enzymes are both produced in the cell bodies of dopamine neurons. Dopamine is stored in the cytoplasm and vesicles in axon terminals. Dopamine release from vesicles is triggered by action potential propagation-induced membrane depolarisation. The axons of dopamine neurons extend the entire length of their designated pathway.

Pathways

Major

Six of the dopaminergic pathways are listed in the table below.

Pathway NameDescriptionAssociated ProcessesAssociated Disorders
Mesocorticolimbic
system (Mesolimbic
pathway)		1. The mesolimbic pathway transmits dopamine from the ventral tegmental area (VTA), which is located in the midbrain, to the ventral striatum, which includes both the nucleus accumbens and olfactory tubercle.
2. The “meso” prefix in the word “mesolimbic” refers to the midbrain, or “middle brain”, since “meso” means “middle” in Greek.		1. Reward-related cognition
a. Incentive salience (“wanting”)
b. Pleasure (“liking”) response from certain stimuli
c. Positive reinforcement
2. Aversion-related cognition		1. ADHD
2. Addiction
3. Schizophrenia
Mesocorticolimbic
system (Mesocortical
pathway)		1. The mesocortical pathway transmits dopamine from the VTA to the prefrontal cortex.
2. The “meso” prefix in “mesocortical” refers to the VTA, which is located in the midbrain, and “cortical” refers to the cortex.		1. Executive functions1. ADHD
2. Addiction
3. Schizophrenia
Nigrostriatal pathway1. The nigrostriatal pathway transmits dopaminergic neurons from the zona compacta of the substantia nigra to the caudate nucleus and putamen.
2. The substantia nigra is located in the midbrain, while both the caudate nucleus and putamen are located in the dorsal striatum.		1. Motor function
2. Reward-related cognition
3. Associative learning		1. Addiction
2. Chorea
3. Huntington’s disease
4. Schizophrenia
5. ADHD
6. Tourette’s Syndrome
7. Parkinson’s disease
Tuberoinfundibular pathway1. The tuberoinfundibular pathway transmits dopamine from the hypothalamus to the pituitary gland.
2. This pathway controls the secretion of certain hormones, including prolactin, from the pituitary gland.
3. “Infundibular” in the word “tuberoinfundibular” refers to the cup or infundibulum, out of which the pituitary gland develops.		1. Regulation of prolactin secretion1. Hyperprolactinaemia
Hypothalamospinal tract1. This pathway influences locomotor networks in the brainstem and spinal cord.1. Motor function1. Restless leg syndrome
Incertohypothalamic pathway1. This pathway from the zona incerta influences the hypothalamus and locomotor centres in the brainstem.1. Visceral and sensorimotor activities1. Tremor

Minor

  • Hypothalamospinal
    • Hypothalamus → Spinal cord
  • Incertohypothalamic
    • Zona incerta → Hypothalamus
    • Zona incerta → Brainstem VTA → Amygdala (mesoamygdaloid pathway)
  • VTA → Hippocampus
  • VTA → Cingulate cortex
  • VTA → Olfactory bulb
  • SNc → Subthalamic nucleus

Function

Mesocorticolimbic system

The mesocorticolimbic system (mesocorticolimbic circuit) refers to both the mesocortical and mesolimbic pathways. Both pathways originate at the ventral tegmental area (VTA). Through separate connections to the prefrontal cortex (mesocortical) and ventral striatum (mesolimbic), the mesocorticolimbic projection has a significant role in learning, motivation, reward, memory and movement. Dopamine receptor subtypes, D1 and D2 have been shown to have complementary functions in the mesocorticolimbic projection, facilitating learning in response to both positive and negative feedback. Both pathways of the mesocorticolimbic system are associated with ADHD, schizophrenia and addiction.

Mesocortical Pathway

The mesocortical pathway projects from the ventral tegmental area to the prefrontal cortex (VTA → Prefrontal cortex). This pathway is involved in cognition and the regulation of executive functions (e.g. attention, working memory, inhibitory control, planning, etc.) Dysregulation of the neurons in this pathway has been connected to ADHD.

Mesolimbic Pathway

Referred to as the reward pathway, mesolimbic pathway projects from the ventral tegmental area to the ventral striatum ( VTA → Ventral striatum (nucleus accumbens and olfactory tubercle). When a reward is anticipated, the firing rate of dopamine neurons in the mesolimbic pathway increases. The mesolimbic pathway is involved with incentive salience, motivation, reinforcement learning, fear and other cognitive processes. In animal studies, depletion of dopamine in this pathway, or lesions at its site of origin, decrease the extent to which an animal is willing to go to obtain a reward (e.g. the number of lever presses for nicotine or time searching for food). Research is ongoing to determine the role of the mesolimbic pathway in the perception of pleasure.

Nigrostriatal Pathway

The nigrostriatal pathway is involved in behaviours relating to movement and motivation. The transmission of dopaminergic neurons to the dorsal striatum particularly plays a role in reward and motivation while movement is influenced by the transmission of dopaminergic neurons to the substantia nigra. The nigrostriatal pathway is associated with conditions such as Huntington’s disease, Parkinson’s disease, ADHD, Schizophrenia, and Tourette’s Syndrome. Huntington’s disease, Parkinson’s disease, and Tourette’s Syndrome are conditions affected by motor functioning while schizophrenia and ADHD are affected by reward and motivation functioning. This pathway also regulates associated learning such as classical conditioning and operant conditioning.

Tuberoinfundibular Pathway

The tuberoinfundibular pathway transmits dopamine the hypothalamus to the pituitary gland. This pathway also regulates the secretion of prolactin from the pituitary gland, which is responsible for breast milk production in females. Hyperprolactinemia is an associated condition caused by an excessive amount of prolactin production that is common in pregnant women.

Cortico-Basal Ganglia-Thalamo-Cortical Loop

The dopaminergic pathways that project from the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) into the striatum (i.e. the nigrostriatal and mesolimbic pathways, respectively) form one component of a sequence of pathways known as the cortico-basal ganglia-thalamo-cortical loop. The nigrostriatal component of the loop consists of the SNc, giving rise to both inhibitory and excitatory pathways that run from the striatum into the globus pallidus, before carrying on to the thalamus, or into the subthalamic nucleus before heading into the thalamus. The dopaminergic neurons in this circuit increase the magnitude of phasic firing in response to positive reward error, that is when the reward exceeds the expected reward. These neurons do not decrease phasic firing during a negative reward prediction (less reward than expected), leading to hypothesis that serotonergic, rather than dopaminergic neurons encode reward loss (source?). Dopamine phasic activity also increases during cues that signal negative events, however dopaminergic neuron stimulation still induces place preference, indicating its main role in evaluating a positive stimulus. From these findings, two hypotheses have developed, as to the role of the basal ganglia and nigrostiatal dopamine circuits in action selection. The first model suggests a “critic” which encodes value, and an actor which encodes responses to stimuli based on perceived value. However, the second model proposes that the actions do not originate in the basal ganglia, and instead originate in the cortex and are selected by the basal ganglia. This model proposes that the direct pathway controls appropriate behaviour and the indirect suppresses actions not suitable for the situation. This model proposes that tonic dopaminergic firing increases the activity of the direct pathway, causing a bias towards executing actions faster.

These models of the basal ganglia are thought to be relevant to the study of OCD, ADHD, Tourette syndrome, Parkinson’s disease, schizophrenia, and addiction. For example, Parkinson’s disease is hypothesized to be a result of excessive inhibitory pathway activity, which explains the slow movement and cognitive deficits, while Tourettes is proposed to be a result of excessive excitatory activity resulting in the tics characteristic of Tourettes.

Regulation

The ventral tegmental area and substantia nigra pars compacta receive inputs from other neurotransmitters systems, including glutaminergic inputs, GABAergic inputs, cholinergic inputs, and inputs from other monoaminergic nuclei. The VTA contains 5-HT1A receptors that exert a biphasic effects on firing, with low doses of 5-HT1A receptor agonists eliciting an increase in firing rate, and higher doses suppressing activity. The 5-HT2A receptors expressed on dopaminergic neurons increase activity, while 5-HT2C receptors elicit a decrease in activity. The mesolimbic pathway, which projects from the VTA to the nucleus accumbens, is also regulated by muscarinic acetylcholine receptors. In particular, the activation of muscarinic acetylcholine receptor M2 and muscarinic acetylcholine receptor M4 inhibits dopamine release, while muscarinic acetylcholine receptor M1 activation increases dopamine release. GABAergic inputs from the striatum decrease dopaminergic neuronal activity, and glutaminergic inputs from many cortical and subcortical areas increase the firing rate of dopaminergic neurons. Endocannabinoids also appear to have a modulatory effect on dopamine release from neurons that project out of the VTA and SNc. Noradrenergic inputs deriving from the locus coeruleus have excitatory and inhibitory effects on the dopaminergic neurons that project out of the VTA and SNc. The excitatory orexinergic inputs to the VTA originate in the lateral hypothalamus and may regulate the baseline firing of VTA dopaminergic neurons.

Inputs to the Ventral Tegmental Area (VTA) and Substantia Nigra Pars Compacta (SNc)

NeurotransmitterOriginType of Connection
Glutamate1. pedunculopontine nucleus
2. subthalamic nucleus
3. laterodorsal tegmental nucleus
4. stria terminalis
5. superior colliculus
6. lateral hypothalamus
7. preoptic area
8. periaqueductal gray
9. raphe nuclei		1. Excitatory projections into the VTA and SNc
GABA1. rostromedial tegmental nucleus
2. striatum
3. local GABAergic inputs		1. Inhibitory projections into the VTA and SNc
Serotonin1. raphe nuclei1. Modulatory effect, depending on receptor subtype
2. Produces a biphasic effect on VTA neurons
Norepineprhine1. locus coeruleus
2. other noradrenergic nuclei		1. Modulatory effect, depending on receptor subtype
2. The excitatory and inhibitory effects of the LC on the VTA and SNc are time-dependent
Endocannabinoids1. VTA dopamine neurons[note 1 & 2]
2. SNc dopamine neurons[note 1 & 2]		1. Excitatory effect on dopaminergic neurons from inhibiting GABAergic inputs
2. Inhibitory effect on dopaminergic neurons from inhibiting glutamatergic inputs
3. May interact with orexins via CB1–OX1 receptor heterodimers to regulate neuronal firing
Acetylcholine1. pedunculopontine nucleus
2. laterodorsal tegmental nuclei		1. Modulatory effect, depending on receptor subtype
Orexin1. lateral hypothalamus1. Excitatory effect on dopaminergic neurons via signalling through orexin receptors (OX1 and OX2)
2. Increases both tonic and phasic firing of dopaminergic neurons in the VTA
3. May interact with endocannabinoids via CB1–OX1 receptor heterodimers to regulate neuronal firing

Notes

  1. At a chemical synapse, neurotransmitters are normally released from the presynaptic axon terminal and signal through receptors that are located on the dendrites of the postsynaptic neuron; however, in retrograde neurotransmission, the dendrites of the postsynaptic neuron release neurotransmitters that signal through receptors that are located on the axon terminal of the presynaptic neuron.
  2. Endocannabinoids signal between neurons through retrograde neurotransmission at synapses; consequently, the dopaminergic neurons that project out of the VTA and SNc release endocannabinoids from their dendrites onto the axon terminals of their inhibitory GABAergic and excitatory glutamatergic inputs to inhibit their effects on dopamine neuronal firing.

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What is a Dopamine Transporter?

Published on by Andrew Marshall10 Comments

Introduction

The dopamine transporter (DAT) also (sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in the human by the SLC6A3 gene, (also known as DAT1), that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

DAT is implicated in a number of dopamine-related disorders, including attention deficit hyperactivity disorder, bipolar disorder, clinical depression, eating disorders, and substance use disorders. The gene that encodes the DAT protein is located on chromosome 5, consists of 15 coding exons, and is roughly 64 kbp long. Evidence for the associations between DAT and dopamine related disorders has come from a type of genetic polymorphism, known as a variable number tandem repeat, in the SLC6A3 gene, which influences the amount of protein expressed.

Function

DAT is an integral membrane protein that removes dopamine from the synaptic cleft and deposits it into surrounding cells, thus terminating the signal of the neurotransmitter. Dopamine underlies several aspects of cognition, including reward, and DAT facilitates regulation of that signal.

Mechanism

DAT is a symporter that moves dopamine across the cell membrane by coupling the movement to the energetically-favourable movement of sodium ions moving from high to low concentration into the cell. DAT function requires the sequential binding and co-transport of two Na+ ions and one Cl− ion with the dopamine substrate. The driving force for DAT-mediated dopamine reuptake is the ion concentration gradient generated by the plasma membrane Na+/K+ ATPase.

In the most widely accepted model for monoamine transporter function, sodium ions must bind to the extracellular domain of the transporter before dopamine can bind. Once dopamine binds, the protein undergoes a conformational change, which allows both sodium and dopamine to unbind on the intracellular side of the membrane.

Studies using electrophysiology and radioactive-labelled dopamine have confirmed that the dopamine transporter is similar to other monoamine transporters in that one molecule of neurotransmitter can be transported across the membrane with one or two sodium ions. Chloride ions are also needed to prevent a build-up of positive charge. These studies have also shown that transport rate and direction is totally dependent on the sodium gradient.

Because of the tight coupling of the membrane potential and the sodium gradient, activity-induced changes in membrane polarity can dramatically influence transport rates. In addition, the transporter may contribute to dopamine release when the neuron depolarises.

DAT–Cav Coupling

Preliminary evidence suggests that the dopamine transporter couples to L-type voltage-gated calcium channels (particularly Cav1.2 and Cav1.3), which are expressed in virtually all dopamine neurons. As a result of DAT–Cav coupling, DAT substrates that produce depolarising currents through the transporter are able to open calcium channels that are coupled to the transporter, resulting in a calcium influx in dopamine neurons. This calcium influx is believed to induce CAMKII-mediated phosphorylation of the dopamine transporter as a downstream effect; since DAT phosphorylation by CAMKII results in dopamine efflux in vivo, activation of transporter-coupled calcium channels is a potential mechanism by which certain drugs (e.g. amphetamine) trigger neurotransmitter release.

Protein Structure

The initial determination of the membrane topology of DAT was based upon hydrophobic sequence analysis and sequence similarities with the GABA transporter. These methods predicted twelve transmembrane domains (TMD) with a large extracellular loop between the third and fourth TMDs. Further characterisation of this protein used proteases, which digest proteins into smaller fragments, and glycosylation, which occurs only on extracellular loops, and largely verified the initial predictions of membrane topology. The exact structure of the Drosophila melanogaster dopamine transporter (dDAT) was elucidated in 2013 by X-ray crystallography.

Location and Distribution

Regional distribution of DAT has been found in areas of the brain with established dopaminergic circuitry, including the nigrostriatal, mesolimbic, and mesocortical pathways. The nuclei that make up these pathways have distinct patterns of expression. Gene expression patterns in the adult mouse show high expression in the substantia nigra pars compacta.

DAT in the mesocortical pathway, labelled with radioactive antibodies, was found to be enriched in dendrites and cell bodies of neurons in the substantia nigra pars compacta and ventral tegmental area. This pattern makes sense for a protein that regulates dopamine levels in the synapse.

Staining in the striatum and nucleus accumbens of the mesolimbic pathway was dense and heterogeneous. In the striatum, DAT is localized in the plasma membrane of axon terminals. Double immunocytochemistry demonstrated DAT colocalisation with two other markers of nigrostriatal terminals, tyrosine hydroxylase and D2 dopamine receptors. The latter was thus demonstrated to be an autoreceptor on cells that release dopamine. TAAR1 is a presynaptic intracellular receptor that is also colocalised with DAT and which has the opposite effect of the D2 autoreceptor when activated; i.e. it internalises dopamine transporters and induces efflux through reversed transporter function via PKA and PKC signalling.

Surprisingly, DAT was not identified within any synaptic active zones. These results suggest that striatal dopamine reuptake may occur outside of synaptic specializations once dopamine diffuses from the synaptic cleft.

In the substantia nigra, DAT is localised to axonal and dendritic (i.e. pre- and post-synaptic) plasma membranes.

Within the perikarya of pars compacta neurons, DAT was localised primarily to rough and smooth endoplasmic reticulum, Golgi complex, and multivesicular bodies, identifying probable sites of synthesis, modification, transport, and degradation.

Genetics and Regulation

The gene for DAT, known as DAT1, is located on chromosome 5p15. The protein encoding region of the gene is over 64 kb long and comprises 15 coding segments or exons. This gene has a variable number tandem repeat (VNTR) at the 3’ end (rs28363170) and another in the intron 8 region. Differences in the VNTR have been shown to affect the basal level of expression of the transporter; consequently, researchers have looked for associations with dopamine-related disorders.

Nurr1, a nuclear receptor that regulates many dopamine-related genes, can bind the promoter region of this gene and induce expression. This promoter may also be the target of the transcription factor Sp-1.

While transcription factors control which cells express DAT, functional regulation of this protein is largely accomplished by kinases. MAPK, CAMKII, PKA, and PKC can modulate the rate at which the transporter moves dopamine or cause the internalisation of DAT. Co-localised TAAR1 is an important regulator of the dopamine transporter that, when activated, phosphorylates DAT through protein kinase A (PKA) and protein kinase C (PKC) signalling. Phosphorylation by either protein kinase can result in DAT internalisation (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux). Dopamine autoreceptors also regulate DAT by directly opposing the effect of TAAR1 activation.

The human dopamine transporter (hDAT) contains a high affinity extracellular zinc binding site which, upon zinc binding, inhibits dopamine reuptake and amplifies amphetamine-induced dopamine efflux in vitro. In contrast, the human serotonin transporter (hSERT) and human norepinephrine transporter (hNET) do not contain zinc binding sites. Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of attention deficit hyperactivity disorder.

Biological Role and Disorders

The rate at which DAT removes dopamine from the synapse can have a profound effect on the amount of dopamine in the cell. This is best evidenced by the severe cognitive deficits, motor abnormalities, and hyperactivity of mice with no dopamine transporters. These characteristics have striking similarities to the symptoms of ADHD.

Differences in the functional VNTR have been identified as risk factors for bipolar disorder and ADHD. Data has emerged that suggests there is also an association with stronger withdrawal symptoms from alcoholism, although this is a point of controversy. An allele of the DAT gene with normal protein levels is associated with non-smoking behaviour and ease of quitting. Additionally, male adolescents particularly those in high-risk families (ones marked by a disengaged mother and absence of maternal affection) who carry the 10-allele VNTR repeat show a statistically significant affinity for antisocial peers.

Increased activity of DAT is associated with several different disorders, including clinical depression.

Mutations in DAT have been shown to cause dopamine transporter deficiency syndrome, an autosomal recessive movement disorder characterised by progressively worsening dystonia and parkinsonism.

Pharmacology

The dopamine transporter is the target of substrates, dopamine releasers, transport inhibitors and allosteric modulators.

Cocaine blocks DAT by binding directly to the transporter and reducing the rate of transport. In contrast, amphetamine enters the presynaptic neuron directly through the neuronal membrane or through DAT, competing for reuptake with dopamine. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine binds to TAAR1, it reduces the firing rate of the postsynaptic neuron and triggers protein kinase A and protein kinase C signalling, resulting in DAT phosphorylation. Phosphorylated DAT then either operates in reverse or withdraws into the presynaptic neuron and ceases transport. When amphetamine enters the synaptic vesicles through VMAT2, dopamine is released into the cytosol. Amphetamine also produces dopamine efflux through a second TAAR1-independent mechanism involving CAMKIIα-mediated phosphorylation of the transporter, which putatively arises from the activation of DAT-coupled L-type calcium channels by amphetamine.

The dopaminergic mechanisms of each drug are believed to underlie the pleasurable feelings elicited by these substances.

Interactions

Dopamine transporter has been shown to interact with:

  • Alpha-synuclein
  • PICK1
  • TGFB1I1

Apart from these innate protein-protein interactions, recent studies demonstrated that viral proteins such as HIV-1 Tat protein interacts with the DAT and this binding may alter the dopamine homeostasis in HIV positive individuals which is a contributing factor for the HIV-associated neurocognitive disorders.

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What is a Dopamine Reuptake Inhibitor?

Published on by Andrew Marshall4 Comments

Introduction

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

DRIs are used in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy for their psychostimulant effects, and in the treatment of obesity and binge eating disorder for their appetite suppressant effects. They are sometimes used as antidepressants in the treatment of mood disorders, but their use as antidepressants is limited given that strong DRIs have a high abuse potential and legal restrictions on their use. Lack of dopamine reuptake and the increase in extracellular levels of dopamine have been linked to increased susceptibility to addictive behavior given increase in dopaminergic neurotransmission. The dopaminergic pathways are considered to be strong reward centers. Many DRIs such as cocaine are drugs of abuse due to the rewarding effects evoked by elevated synaptic concentrations of dopamine in the brain.

Brief History

Until the 1950s, dopamine was thought to only contribute to the biosynthesis of norepinephrine and epinephrine. It was not until dopamine was found in the brain in similar levels as norepinephrine that the possibility was considered that its biological role might be other than the synthesis of the catecholamines.

Pharmacotherapeutic Uses

The following drugs have DRI action and have been or are used clinically specifically for this property: amineptine, dexmethylphenidate, difemetorex, fencamfamine, lefetamine, levophacetoperane, medifoxamine, mesocarb, methylphenidate, nomifensine, pipradrol, prolintane, and pyrovalerone.

The following drugs are or have been used clinically and possess only weak DRI action, which may or may not be clinically-relevant: adrafinil, armodafinil, bupropion, mazindol, modafinil, nefazodone, sertraline, and sibutramine.

The following drugs are or have been clinically used but only coincidentally have DRI properties: benzatropine, diphenylpyraline, etybenzatropine, ketamine, nefopam, pethidine (meperidine), and tripelennamine.

The following are a selection of some particularly notably abused DRIs: cocaine, ketamine, MDPV, naphyrone, and phencyclidine (PCP). Amphetamines, including amphetamine, methamphetamine, MDMA, cathinone, methcathinone, mephedrone, and methylone, are all DRIs as well, but are distinct in that they also behave, potentially more potently, as dopamine releasing agents (DRAs) (due to Yerkes–Dodson’s law, ‘more potently stimulated’ may not equal more optimally functionally stimulated). There are very distinct differences in the mode of action between dopamine releasers/substrates & dopamine re-uptake inhibitors; the former are functionally entropy-driven (i.e. relating to hydrophobicity) and the latter are enthalpy-driven (i.e. relating conformational change). Reuptake inhibitors such as cocaine induce hyperpolarization of cloned human DAT upon oocytes that are naturally found on neurons, whereas releasing agents induce de-polarization of the neuron membrane.

The wakefulness-promoting agent modafinil and its analogues (e.g. adrafinil, armodafinil) have been approved to treat narcolepsy and shift work sleep disorder. These act as weak (micromolar) DRIs, but this effect does not correlate with wakefulness-promoting effects, suggesting the effect is too weak to be of clinical significance. The conclusion is these drugs promote wakefulness via some other mechanism.

DRIs have been explored as potential antiaddictive agents in the context of replacement therapy strategies, analogous to nicotine replacement for treating tobacco addiction and methadone replacement in the case of opioid addiction. DRIs have been explored as treatment for cocaine addiction, and have shown to alleviate cravings and self-administration.

Monoamine reuptake inhibitors, including DRIs, have shown effectiveness as therapy for excessive food intake and appetite control for obese patients. Though such pharmacotherapy is still available, the majority of stimulant anorectics marketed for this purpose have been withdrawn or discontinued due to adverse side effects such as hypertension, valvulopathy, and drug dependence.

List of DRIs

Only DRIs which are selective for the DAT over the other monoamine transporters (MATs) are listed below. For a list of DRIs that act at multiple MATs, see other monoamine reuptake inhibitor pages such as NDRI and SNDRI.

Selective Dopamine Reuptake Inhibitors

  • 4-Hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone
  • Altropane (O-587)
  • Amfonelic acid (WIN 25978)
  • Amineptine (has a reasonable degree of selectivity for dopamine over norepinephrine reuptake inhibition)
  • BTCP (GK-13), same acronym as for breakthrough cancer pain.
  • 3C-PEP
  • DBL-583
  • Difluoropine (O-620)
  • GBR-12783
  • GBR-12935
  • GBR-13069
  • GBR-13098
  • GYKI-52895
  • Iometopane (β-CIT, RTI-55)
  • Ethylphenidate (more selective for DA vs NE reuptake inhibition compared to methylphenidate, but still has a marked effect on both)
  • Modafinil (relatively weak but very selective for the dopamine transporter, with little to no effect on the norepinephrine or serotonin transporters)
  • Armodafinil (R-enantiomer of modafinil; somewhat more potent at inhibiting DAT than racemic modafinil, with equally negligible action on NET and SERT)
  • RTI-229
  • Vanoxerine (GBR-12909)

DRIs with Substantial Activity at Other Sites

  • Adrafinil (weak, possibly stressful on liver)
  • Amantadine (also a weak NMDA receptor antagonist)
  • Benztropine (also muscarinic antagonist)
  • Bupropion (also a more potent NRI and likely NRA due to bupropion’s major metabolite hydroxybupropion)
  • Cocaine
  • Fluorenol (extremely weak)
  • Medifoxamine (relatively weak)
  • Metaphit (irreversible; depletes dopamine)
  • Methylphenidate (has a mild degree of selectivity for dopamine over norepinephrine reuptake inhibition, although it significantly affects both)
  • Nomifensine (Dual selective norepinephrine–dopamine reuptake inhibitor (NDRI) is a drug used for the treatment of clinical depression, attention deficit hyperactivity disorder (ADHD), narcolepsy, and the management of Parkinson’s disease.
  • Phenylpiracetam
  • Isopropylphenidate
  • Rimcazole
  • Venlafaxine (weak)
  • Solriamfetol (also norepinephrine reuptake inhibitor)

Other DRIs

  • Chaenomeles speciosa (Flowering quince)
  • Oroxylin A (found in Oroxylum indicum and Scutellaria baicalensis (Skullcap))

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What is a Monoamine Reuptake Inhibitor?

Published on by Andrew Marshall5 Comments

Introduction

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

Uses

The majority of currently approved antidepressants act predominantly or exclusively as MRIs, including the selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and almost all of the tricyclic antidepressants (TCAs). Many psychostimulants used either in the treatment of ADHD or as appetite suppressants in the treatment of obesity also behave as MRIs, although notably amphetamine (and methamphetamine), which do act to some extent as monoamine reuptake inhibitors, exerts their effects primarily as releasing agents. Additionally, psychostimulants acting as MRIs that affect dopamine such as cocaine and methylphenidate are often abused as recreational drugs. As a result, many of them have become controlled substances, which in turn has resulted in the clandestine synthesis of a vast array of designer drugs for the purpose of bypassing drug laws; a prime example of such is the mixed monoamine reuptake inhibitor and releasing agent mephedrone.

Types of MRIs

There are a variety of different kinds of MRIs, of which include the following:

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What is a Serotonin-Dopamine Reuptake Inhibitor?

Published on by Andrew Marshall2 Comments

Introduction

A serotonin–dopamine reuptake inhibitor (SDRI) is a type of drug which acts as a reuptake inhibitor of the monoamine neurotransmitters serotonin and dopamine by blocking the actions of the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of serotonin and dopamine, and, therefore, an increase in serotonergic and dopaminergic neurotransmission.

A closely related type of drug is a serotonin–dopamine releasing agent (SDRA).

Comparison to SNDRIs

Relative to serotonin–norepinephrine–dopamine reuptake inhibitors (SNDRIs), which also inhibit the reuptake of norepinephrine in addition to serotonin and dopamine, SDRIs might be expected to have a reduced incidence of certain side effects, namely insomnia, appetite loss, anxiety, and heart rate and blood pressure changes.

Examples of SDRIs

Unlike the case of other combination monoamine reuptake inhibitors such as serotonin–norepinephrine reuptake inhibitors (SNRIs) and norepinephrine–dopamine reuptake inhibitors (NDRIs), on account of the very similar chemical structures of their substrates, it is exceptionally difficult to tease apart affinity for the DAT from the norepinephrine transporter (NET) and inhibit the reuptake of dopamine alone. As a result, selective dopamine reuptake inhibitors (DRIs) are rare, and comparably, SDRIs are even more so.

Pharmaceutical Drugs

Medifoxamine (Cledial, Gerdaxyl) is an antidepressant that appears to act as an SDRI as well as a 5-HT2 receptor antagonist. Sibutramine (Reductil, Meridia, Siredia, Sibutrex) is a withdrawn anorectic that itself as a molecule in vitro is an SNDRI but preferentially an SDRI, with 18.3- and 5.8-fold preference for inhibiting the reuptake of serotonin and dopamine over norepinephrine, respectively. However, the metabolites of sibutramine are substantially more potent and possess different ratios of monoamine reuptake inhibition in comparison, and sibutramine appears to be acting in vivo mainly as a prodrug to them; accordingly, it was found to act as an SNRI (73% and 54% for norepinephrine and serotonin reuptake inhibition, respectively) in human volunteers with only very weak inhibition of dopamine reuptake (16%).

Sertraline

Sertraline (Zoloft) is a selective serotonin reuptake inhibitor (SSRI), but, uniquely among most antidepressants, it shows relatively high (nanomolar) affinity for the DAT as well. As such, it has been suggested that clinically it may weakly inhibit the reuptake of dopamine, particularly at high dosages. For this reason, sertraline has sometimes been described as an SDRI. This is relevant as dopamine is thought to be involved in the pathophysiology of depression, and increased dopaminergic signaling by sertraline in addition to serotonin may have additional benefits against depression.

Tatsumi et al. (1997) found Ki values of sertraline at the SERT, DAT, and NET of 0.29, 25, and 420 nM, respectively. The selectivity of sertraline for the SERT over the DAT was 86-fold. In any case, of the wide assortment of antidepressants assessed in the study, sertraline showed the highest affinity of them all for the DAT, even higher than the norepinephrine–dopamine reuptake inhibitors (NDRIs) nomifensine (Ki = 56 nM) and bupropion (Ki = 520 nM). Sertraline is also said to have similar affinity for the DAT as the NDRI methylphenidate. It is notable that tametraline (CP-24,441), a very close analogue of sertraline and the compound from which sertraline was originally derived, is an NDRI that was never marketed.

Single doses of 50 to 200 mg sertraline have been found to result in peak plasma concentrations of 20 to 55 ng/mL (65–180 nM), while chronic treatment with 200 mg/day sertraline, the maximum recommended dosage, has been found to result in maximal plasma levels of 118 to 166 ng/mL (385–542 nM). However, sertraline is highly protein-bound in plasma, with a bound fraction of 98.5%. Hence, only 1.5% is free and theoretically bioactive. Based on this percentage, free concentrations of sertraline would be 2.49 ng/mL (8.13 nM) at the very most, which is only about one-third of the Ki value that Tatsumi et al. found with sertraline at the DAT. A very high dosage of sertraline of 400 mg/day has been found to produce peak plasma concentrations of about 250 ng/mL (816 nM). This can be estimated to result in a free concentration of 3.75 ng/mL (12.2 nM), which is still only about half of the Ki of sertraline for the DAT.

As such, it seems unlikely that sertraline would produce much inhibition of dopamine reuptake even at clinically used dosages well in excess of the recommended maximum clinical dosage. This is in accordance with its 86-fold selectivity for the SERT over the DAT and hence the fact that nearly 100-fold higher levels of sertraline would be necessary to also inhibit dopamine reuptake. In accordance, while sertraline has very low abuse potential and may even be aversive at clinical dosages, a case report of sertraline abuse described dopaminergic-like effects such as euphoria, mental overactivity, and hallucinations only at a dosage 56 times the normal maximum and 224 times the normal minimum. For these reasons, significant inhibition of dopamine reuptake by sertraline at clinical dosages is controversial, and occupation by sertraline of the DAT is thought by many experts to not be clinically relevant.

Research Chemicals

Two SDRIs that are known in research at present are RTI-83 and UWA-101, though other related compounds are also known. Based on its chemical structure, UWA-101 may actually also possess some activity as a releasing agent, and if so, unlike RTI-83, it would not be an SDRI in the purest sense and would also be an SDRA. Manning et al. presented two high-affinity MAT-ligands with good binding selectivity for SERT and DAT, namely the 4-indolyl and 1-naphthyl arylalkylamines ent-16b (Ki 0.82, 3.8, 4840 nM for SERT, DAT, NET) and ent-13b respectively. AN-788 (NSD-788) is another SDRI, and has been under development for the treatment of depressive and anxiety disorders.

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