Monoamine Receptors Research Articles

Stereochemistry of phase-1 metabolites of mephedrone determines their effectiveness as releasers at the serotonin transporter

Mephedrone (4-methyl-N-methylcathinone) is a psychostimulant that promotes release of monoamines via the high affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). Metabolic breakdown of mephedrone results in bioactive metabolites that act as substrate-type releasers at monoamine transporters and stereospecific metabolism of mephedrone has been reported. This study compared the effects of the enantiomers of the phase-1 metabolites nor-mephedrone, 4-hydroxytolyl-mephedrone (4-OH-mephedrone) and dihydro-mephedrone on (i) DAT, NET and SERT mediated substrate fluxes, (ii) determined their binding affinities towards a battery of monoamine receptors and (iii) examined the relative abundance of the enantiomers in human urine.Each of the enantiomers tested inhibited uptake mediated by DAT, NET and SERT. No marked differences were detected at DAT and NET. However, at SERT, the S-enantiomers of nor-mephedrone and 4-OH-mephedrone were several times more potent than the corresponding R-enantiomers. Moreover, the R-enantiomers were markedly less effective as releasers at SERT. S-nor-mephedrone displayed moderate affinities towards human alpha1A, human 5-HT2A and rat and mouse trace amine-associated receptor 1.These results demonstrate that stereochemistry dictates the pharmacodynamics of the phase-1 metabolites of mephedrone at SERT, but not at DAT and NET, which manifests in marked differences in their relative potencies, i.e. DAT/SERT ratios. Chiral analysis of urine samples demonstrated that nor-mephedrone predominantly exists as the S-enantiomer. Given the asymmetric abundance of the enantiomers in biological samples, these findings may add to our understanding of the subjective effects of administered mephedrone, which indicate pronounced effects on the serotonergic system.

Risk for antipsychotic-induced extrapyramidal symptoms: a focus on monoamine receptors on peripheral blood lymphocytes

Single image super-resolution (SR) aims to estimate a high-resolution (HR) image from only one observed low-resolution (LR) image. It is a severely ill-posed problem that needs image priors to ensure a reliable HR estimation. Since different priors usually emphasize different aspects of image characteristics, it’s a big challenge to impose a balanced-and-overall image property constraint on single image SR. In this paper, we cast single image SR into a maximum a posteriori optimization problem and combine two types of complementary priors to answer this challenge. One prior is a novel local gradient field prior derived from example-based gradient field estimation (EGFE) that focuses on recovering the sharpness of gradient profiles. It is good at enhancing the edge sharpness and restoring fine texture details. Whereas the other is a powerful non-local low rank prior implemented in a weighted adaptive p-norm model (WANM). By imposing lp penalties adaptive to regional saliency and weighted constraints, the WANM prior performs well in preserving edge smoothness and suppressing image noise and reconstruction artifacts. An improved Split Bregman Iteration method that adaptively attenuates the regularization strength is further developed to solve the proposed EGFE-WANM SR problem. Comprehensive experiments are conducted and the results show that the proposed EGFE-WANM SR method outperforms many state-of-the-art methods in both objective evaluations and subjective visual comparisons.

Pharmacological characterization of the LSD analog N-ethyl-N-cyclopropyl lysergamide (ECPLA).

The lysergamide lysergic acid diethylamide (LSD) is a prototypical classical hallucinogen with remarkably high potency. LSD remains a popular recreational drug but is also becoming an important research tool for medical and neuroscience studies. Recently, several lysergamides that are close structural analogs of LSD have been sold as recreational drugs, which suggests that further studies are needed to explore the pharmacological properties of these compounds. In this present investigation, another LSD congener, N-ethyl-N-cyclopropyl lysergamide (ECPLA), which to date has not been marketed as a recreational substance, was evaluated for its pharmacological features relative to those previously reported for LSD. The experiments focused on interactions with the 5-HT2A receptor, which is responsible for mediating the psychedelic effects of LSD and other hallucinogens. Competitive binding assays were performed to measure the affinity of ECPLA for 27 monoamine receptors. The ability of ECPLA to activate human 5-HT2 receptor subtypes was assessed using calcium mobilization assays. Head twitch response (HTR) studies were conducted in C57BL/6J mice to determine whether ECPLA activates 5-HT2A receptors in vivo. Two other N-alkyl substituted lysergamides, N-methyl-N-isopropyl lysergamide (MIPLA) and N-methyl-N-propyl lysergamide (LAMPA), were also tested in the HTR paradigm for comparative purposes. ECPLA has high affinity for most serotonin receptors, α2-adrenoceptors, and D2-like dopamine receptors. Additionally, ECPLA was found to be a potent, highly efficacious 5-HT2A agonist for Gq-mediated calcium flux. Treatment with ECPLA induced head twitches in mice with a median effective dose (ED50) of 317.2nmol/kg (IP), which is ~ 40% of the potency observed previously for LSD. LAMPA (ED50 = 358.3nmol/kg) was virtually equipotent with ECPLA in the HTR paradigm whereas MIPLA (ED50 = 421.7nmol/kg) was slightly less potent than ECPLA. These findings demonstrate that the pharmacological properties of ECPLA, MIPLA, and LAMPA are reminiscent of LSD and other lysergamide hallucinogens.

The Role of Cannabis within an Emerging Perspective on Schizophrenia.

Background: Approximately 0.5% of the population is diagnosed with some form of schizophrenia, under the prevailing view that the pathology is best treated using pharmaceutical medications that act on monoamine receptors. Methods: We briefly review evidence on the impact of environmental forces, particularly the effect of autoimmune activity, in the expression of schizophrenic profiles and the role of Cannabis therapy for regulating immunological functioning. Results: A review of the literature shows that phytocannabinoid consumption may be a safe and effective treatment option for schizophrenia as a primary or adjunctive therapy. Conclusions: Emerging research suggests that Cannabis can be used as a treatment for schizophrenia within a broader etiological perspective that focuses on environmental, autoimmune, and neuroinflammatory causes of the disorder, offering a fresh start and newfound hope for those suffering from this debilitating and poorly understood disease.

Regulation of monoamine transporters and receptors by lipid microdomains: implications for depression.

Lipid microdomains ("rafts") are dynamic, nanoscale regions of the plasma membrane enriched in cholesterol and glycosphingolipids, that possess distinctive physicochemical properties including higher order than the surrounding membrane. Lipid microdomain integrity is thought to affect neurotransmitter signaling by regulating membrane-bound protein signaling. Among the proteins potentially affected are monoaminergic receptors and transporters. As dysfunction of monoaminergic neurotransmission is implicated in major depressive disorder and other neuropsychiatric conditions, interactions with lipid microdomains may be of clinical importance. This systematic review evaluates what is known about the molecular relationships of monoamine transporter and receptor regulation to lipid microdomains. The PubMed/MeSH database was searched for original studies published in English through August 2017 concerning relationships between lipid microdomains and serotonin, dopamine and norepinephrine transporters and receptors. Fifty-seven publications were identified and assessed. Strong evidence implicates lipid microdomains in the regulation of serotonin and norepinephrine transporters; serotonin 1A, 2A, 3A, and 7A receptors; and dopamine D1 and β2 adrenergic receptors. Results were conflicting or more complex regarding lipid microdomain associations with the dopamine transporter, D2, D3, and D5 receptors; and negative with respect to β1 adrenergic receptors. Indirect evidence suggests that antidepressants, lipid-lowering drugs, and polyunsaturated fatty acids may exert effects on depression and suicide by altering the lipid milieu, thereby affecting monoaminergic transporter and receptor signaling. The lipid composition of membrane subdomains is involved in localization and trafficking of specific monoaminergic receptors and transporters. Elucidating precise mechanisms whereby lipid microdomains modulate monoamine neurotransmission in clinical contexts can have critical implications for pharmacotherapeutic targeting.

The psychostimulant (±)-cis-4,4′-dimethylaminorex (4,4′-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters

(±)-cis-4,4′-Dimethylaminorex (4,4′-DMAR) is a new psychoactive substance (NPS) that has been associated with 31 fatalities and other adverse events in Europe between June 2013 and February 2014. We used in vitro uptake inhibition and transporter release assays to determine the effects of 4,4′-DMAR on human high-affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). In addition, we assessed its binding affinities to monoamine receptors and transporters. Furthermore, we investigated the interaction of 4,4′-DMAR with the vesicular monoamine transporter 2 (VMAT2) in rat phaeochromocytoma (PC12) cells and synaptic vesicles prepared from human striatum. 4,4′-DMAR inhibited uptake mediated by human DAT, NET or SERT, respectively in the low micromolar range (IC50 values < 2 μM). Release assays identified 4,4′-DMAR as a substrate type releaser, capable of inducing transporter-mediated reverse transport via DAT, NET and SERT. Furthermore, 4,4′-DMAR inhibited both the rat and human isoforms of VMAT2 at a potency similar to 3,4-methylenedioxymethylamphetamine (MDMA). This study identified 4,4′-DMAR as a potent non-selective monoamine releasing agent. In contrast to the known effects of aminorex and 4-methylaminorex, 4,4′-DMAR exerts profound effects on human SERT. The latter finding is consistent with the idea that fatalities associated with its abuse may be linked to monoaminergic toxicity including serotonin syndrome. The activity at VMAT2 suggests that chronic abuse of 4,4′-DMAR may result in long-term neurotoxicity.

Monoamine Transporter and Receptor Interaction Profiles in Vitro Predict Reported Human Doses of Novel Psychoactive Stimulants and Psychedelics.

BackgroundPharmacological profiles of new psychoactive substances can be established rapidly in vitro and provide information on potential psychoactive effects in humans. The present study investigated whether specific in vitro monoamine transporter and receptor interactions can predict effective psychoactive doses in humans.MethodsWe correlated previously assessed in vitro data of stimulants and psychedelics with human doses that are reported on the Internet and in books.ResultsFor stimulants, dopamine and norepinephrine transporter inhibition potency was positively correlated with human doses, whereas serotonin transporter inhibition potency was inversely correlated with human doses. Serotonin 5-hydroxytryptamine-2A (5-HT2A) and 5-HT2C receptor affinity was significantly correlated with psychedelic doses, but 5-HT1A receptor affinity and 5-HT2A and 5-HT2B receptor activation potency were not.ConclusionsThe rapid assessment of in vitro pharmacological profiles of new psychoactive substances can help to predict psychoactive doses and effects in humans and facilitate the appropriate scheduling of new psychoactive substances.

Cognitive Function and Monoamine Neurotransmission in Schizophrenia: Evidence From Positron Emission Tomography Studies.

Positron emission tomography (PET) is a non-invasive imaging technique used to assess various brain functions, including cerebral blood flow, glucose metabolism, and neurotransmission, in the living human brain. In particular, neurotransmission mediated by the monoamine neurotransmitters dopamine, serotonin, and norepinephrine, has been extensively examined using PET probes, which specifically bind to the monoamine receptors and transporters. This useful tool has revealed the pathophysiology of various psychiatric disorders, including schizophrenia, and the mechanisms of action of psychotropic drugs. Because monoamines are implicated in various cognitive processes such as memory and executive functions, some PET studies have directly investigated the associations between monoamine neurotransmission and cognitive functions in healthy individuals and patients with psychiatric disorders. In this mini review, I discuss the findings of PET studies that investigated monoamine neurotransmission under resting conditions, specifically focusing on cognitive functions in patients with schizophrenia. With regard to the dopaminergic system, some studies have examined the association of dopamine D1 and D2/D3 receptors, dopamine transporters, and dopamine synthesis capacity with various cognitive functions in schizophrenia. With regard to the serotonergic system, 5-HT1A and 5-HT2A receptors have been studied in the context of cognitive functions in schizophrenia. Although relatively few PET studies have examined cognitive functions in patients with psychiatric disorders, these approaches can provide useful information on enhancing cognitive functions by administering drugs that modulate monoamine transmission. Moreover, another paradigm of techniques such as those exploring the release of neurotransmitters and further development of radiotracers for novel targets are warranted.

Effects of monoamines on the intrinsic excitability of lateral orbitofrontal cortex neurons in alcohol-dependent and non-dependent female mice

Changes in brain reward and control systems of frontal cortical areas including the orbitofrontal cortex (OFC) are associated with alcohol use disorders (AUD). The OFC is extensively innervated by monoamines, and drugs that target monoamine receptors have been used to treat a number of neuropsychiatric diseases, including AUDs. Recent findings from this laboratory demonstrate that D2, α2-adrenergic and 5HT1A receptors all decrease the intrinsic excitability of lateral OFC (lOFC) neurons in naïve male mice and that this effect is lost in mice exposed to repeated cycles of chronic intermittent ethanol (CIE) vapor. As biological sex differences may influence an individual's response to alcohol and contribute to the propensity to engage in addictive behaviors, we examined whether monoamines have similar effects on lOFC neurons in control and CIE exposed female mice. Dopamine, norepinephrine and serotonin all decreased spiking of lOFC neurons in naïve females via activation of Giα-coupled D2, α2-adrenergic and 5HT1A receptors, respectively. Firing was also inhibited by the direct GIRK channel activator ML297, while blocking these channels with barium eliminated the inhibitory actions of monoamines. Following CIE treatment, evoked spiking of lOFC neurons from female mice was significantly enhanced and monoamines and ML297 no longer inhibited firing. Unlike in male mice, the enhanced firing of neurons from CIE exposed female mice was not associated with changes in the after-hyperpolarization and the small-conductance potassium channel blocker apamin had no effect on current-evoked tail currents from either control or CIE exposed female mice. These results suggest that while CIE exposure alters monoamine regulation of OFC neuron firing similarly in males and female mice, there are sex-dependent differences in processes that regulate the intrinsic excitability of these neurons.

Mechanisms of imidazoline I2 receptor agonist-induced antinociception in rats: involvement of monoaminergic neurotransmission.

Although the antinociceptive efficacies of imidazoline I2 receptor agonists have been established, the exact post-receptor mechanisms remain unknown. This study tested the hypothesis that monoaminergic transmission is critical for I2 receptor agonist-induced antinociception. von Frey filaments were used to assess antinociceptive effects of two I2 receptor agonists, 2-BFI and CR4056 on chronic constriction injury (CCI)-induced neuropathic pain or complete Freund's adjuvant (CFA)-induced inflammatory pain in rats. Rectal temperature was measured to assess hypothermic effects of 2-BFI. A two-lever drug discrimination paradigm in which rats were trained to discriminate 5.6mg·kg-1 2-BFI (i.p.) from its vehicle was used to examine the discriminative stimulus effects of 2-BFI. In each experiment, pharmacological mechanisms were investigated by combining 2-BFI or CR4056 with various pharmacological manipulations of the monoaminergic system including selective reuptake inhibition, monoamine depletion and monoamine receptor antagonism. In the CCI model, selective reuptake inhibitors of 5-HT (fluoxetine) or noradrenaline (desipramine), but not dopamine (GBR12909), enhanced 2-BFI-induced antinociception. Selective depletion of 5-HT or noradrenaline almost abolished 2-BFI-induced antinociception. 5-HT1A , 5-HT2A and α1 -adrenoceptor antagonists, but not other monoaminergic antagonists, attenuated 2-BFI and CR4056-induced antinociception in CCI and/or CFA models. However, none of these monoamine receptor antagonists significantly altered 2-BFI-induced hypothermia or discriminative stimulus effects. Antinociception induced by I2 receptor agonists was mediated by serotonergic and noradrenergic mechanisms with 5-HT1A , 5-HT2A and α1 -adrenoceptor being particularly important. In contrast, the hypothermic and discriminative stimulus effects of I2 receptor agonists were mediated by distinct, independent mechanisms.

Functionality versus dimensionality in psychological taxonomies, and a puzzle of emotional valence.

This paper applies evolutionary and functional constructivism approaches to the discussion of psychological taxonomies, as implemented in the neurochemical model Functional Ensemble of Temperament (FET). FET asserts that neurochemical systems developed in evolution to regulate functional-dynamical aspects of construction of actions: orientation, selection (integration), energetic maintenance, and management of automatic behavioural elements. As an example, the paper reviews the neurochemical mechanisms of interlocking between emotional dispositions and performance capacities. Research shows that there are no specific neurophysiological systems of positive or negative affect, and that emotional valence is rather an integrative product of many brain systems during estimations of needs and the capacities required to satisfy these needs. The interlocking between emotional valence and functional aspects of performance appears to be only partial since all monoamine and opioid receptor systems play important roles in non-emotional aspects of behaviour, in addition to emotionality. This suggests that the Positive/Negative Affect framework for DSM/ICD classifications of mental disorders oversimplifies the structure of non-emotionality symptoms of these disorders. Contingent dynamical relationships between neurochemical systems cannot be represented by linear statistical models searching for independent dimensions (such as factor analysis); nevertheless, these relationships should be reflected in psychological and psychiatric taxonomies.This article is part of the theme issue ‘Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences’.

S(+)-ketamine : Current trends in emergency and intensive care medicine.

SummaryS(+)-ketamine, the pure dextrorotatory enantiomer of ketamine has been available for clinical use in analgesia and anesthesia for more than 25 years. The main effects are mediated by non-competitive inhibition of the N-methyl-D-aspartate (NMDA) receptor but S(+)-ketamine also interacts with opioid receptors, monoamine receptors, adenosine receptors and other purinergic receptors. Effects on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, metabotropic glutamate receptors (mGluR) and L‑type calcium chanels have also been described. S(+)-ketamine stimulates the sympathetic nerve system, making it an ideal drug for analgosedation or induction of anesthesia in instable patients. In addition, the neuroprotective properties, bronchodilatory, antihyperalgesic or antiepileptic effects provide interesting therapeutic options. In this article we discuss the numerous effects of S(+)-ketamine under pharmacological and clinical aspects especially for typical indications in emergency medicine as well as intensive care.

The effect of antipsychotic drug on monoamine receptors in peripheral blood mononuclear cells: affinity linked mechanism

Schizophrenia is one of the most serious and common mental disorders, which is characterized by high levels of pathogenic heterogeneity as well as neuroimmune abnormalities, which require treatment with antipsychotic drugs. Monoamines are one of the key neurotransmitters which play an important role in neuroimmune interactions of the human organism. We suggest that the quantity of the monoamine receptors on mononuclear cells of the peripheral blood (PBMCs) can be associated with the cytokine profile of patients. With this quantity being a key component of the mental status correction mechanism in antipsychotic therapy. In this study we measured cytokine levels (IL-6, IL-1b and TGF-b) in blood serum, the protein expression status of the serotonin receptor 5HTR2A and the dopamine receptors D1 (DRD1), DRD2, DRD3 in PBMCs of drug-naive, first episode schizophrenia patients before and after the treatment with olanzapine and haloperidol. This study has shown for the first time that the antipsychotic therapy leads to a decrease in protein levels of monoamine receptors in PBMCs associated with the affinity of the drug used. Blood cytokine levels were significantly higher in serum from studied patients as compared with the reference values. The antipsychotic-linked change of the TGF-b production caused by the therapy is probably associated with the reduction of various monoamine receptors. The relationship between the psychopathological status and the protein level of 5THR2A suggests that the amount of 5HTR2A may serve as a potential biomarker for the personalized appointment of the antipsychotic therapy.

Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances.

New psychoactive substances (NPS) with amphetamine-, aminoindan-, and benzofuran basic chemical structures have recently emerged for recreational drug use. Detailed information about their psychotropic effects and health risks is often limited. At the same time, it emerged that the pharmacological profiles of these NPS resemble those of amphetamine or 3,4-methylenedioxymethamphetamine (MDMA). Amphetamine-like NPS induce psychostimulation and euphoria mediated predominantly by norepinephrine (NE) and dopamine (DA) transporter (NET and DAT) inhibition and transporter-mediated release of NE and DA, thus showing a more catecholamine-selective profile. MDMA-like NPS frequently induce well-being, empathy, and prosocial effects and have only moderate psychostimulant properties. These MDMA-like substances primarily act by inhibiting the serotonin (5-HT) transporter (SERT) and NET, also inducing 5-HT and NE release. Monoamine receptor interactions vary considerably among amphetamine- and MDMA-like NPS. Clinically, amphetamine- and MDMA-like NPS can induce sympathomimetic toxicity. The aim of this chapter is to review the state of knowledge regarding these substances with a focus on the description of the in vitro pharmacology of selected amphetamine- and MDMA-like NPS. In addition, it is aimed to provide links between pharmacological profiles and in vivo effects and toxicity, which leads to the conclusion that abuse liability for amphetamine-like NPS may be higher than for MDMA-like NPS, but that the risk for developing the life-threatening serotonin syndrome may be increased for MDMA-like NPS.

Explaining Depression

Explaining Depression James Phillips (bio) The author has reviewed the history of biological theories of depression with a fascinating account of how researchers have argued backward, starting with the neurochemical effects of antidepressants on the monoamine system in the brain, and ending with etiological theories that place the biological cause of depression in disturbances of the monoamine system. He explains how further work in biological etiology (monoamine receptor theories and neuroplasticity theories) has followed the same backward path. In carrying out this task, he has done such an excellent job that I have little to offer as a critique of his work. The author uses a research model developed by Lakatos, and he points out that Lakatos's approach to philosophy of science has already been criticized by others. My own interest is in pursuing the question of depression begins at the point where the author stops. He has clarified progress in the biology of depression, but his interest in depression does not extend beyond the biological dimension. Is there more to depression than its biology? I would say yes, that understanding depression does not begin and end with biology. Moving beyond biology, we encounter all the nonbiological factors that play a role in the etiology of depression. These include developmental factors such inadequate parenting, and environmental factors such as early sexual abuse. These factors might be called psychological, because they all work through the mind of the sufferer. In studying them, we leave psychopharmacology and the pharmacological bridge. If, for instance, we are studying the effects of childhood sexual abuse on depression, biology and the pharmacological bridge play no role in our research. This does not mean that the nonbiological factors totally exclude biology and neuropathophysiology. In his review of biological theories of depression, the author writes that the original monoamine theories ended up in the 1990s in neuroplasticity theories of depression. Aside from direct biological effects on brain structure, neuroplasticity could be involved in the effects of mental phenomena on brain structure. One such path would involve epigenetics, in which an environmental factor creates a change in the individual's mental state, which in turn activates a genetic locus that plays a role in depression. Let me now take a step further away from biology. I have pointed out that developmental and environmental etiological factors may elude the pharmacological bridge but still be connected to neuropathophysiology. This next step would involve phenomena such as mental conflict, severe enough to play a role in depression, but with no obvious link to pathophysiology. Hard-core reductionists would insist, of course, that everything is in one way or another biological, even if we do not understand the exact mechanism. Whatever is going on in my 'mind' is going on in my brain and can, even if not yet, be explained by specific brain changes. [End Page 303] We are now entering on a long discussion of mind/brain reductionism, but I will try to abbreviate the discussion with reference to a recent article by philosopher Simon Critchley. Writing about his early mentor, philosopher Frank Cioffi, and the latter's attitude toward such reductionism, Critchley says: This is the risk of what some call "scientism"–the belief that natural science can explain everything, right down to the detail of our subjective and social lives. All we need is a better form of science, a more complete theory, a theory of everything. Lord knows, there are even Oscar-winning Hollywood movies made about this topic. Frank's point, which is still hugely important, is that there is no theory of everything, nor should there be. There is a gap between nature and society. The mistake, for which scientism is the name, is the belief that this gap can or should be filled. (Critchley, 2015, p. 10) This is a rather dramatic statement that flies in the face of the reductionist tendencies of the biomedical model. In the context of the etiology of depression, Critchley and Cioffi are saying that the mental conflict involved in the etiology of depression may not map onto brain structure, and that more broadly, mind and brain may involve different, incommensurable discourses that cannot be subsumed under one...

Effects of the new psychoactive substances diclofensine, diphenidine, and methoxphenidine on monoaminergic systems

Diclofensine, diphenidine, and methoxphenidine are new psychoactive substances (NPSs) that recently appeared on the illicit drug market. Pharmacological profiling of such newly emerged drugs is crucial for a better understanding of their psychotropic effects and toxicity. We therefore investigated the potential of these NPSs to inhibit the norepinephrine, dopamine, and serotonin transporters in human embryonic kidney cells stably transfected with the respective transporters. In addition, we determined monoamine transporter and receptor affinities for the substances. Diclofensine potently bound to the monoamine transporters in the submicromolar range and had similar inhibition potential for all three transporters in the range of 2.5–4.8μM. Moreover, diclofensine bound to adrenergic, dopamine, serotonin, and trace amine-associated receptors. Diphenidine was an equipotent inhibitor of the norepinephrine and dopamine transporters in the low micromolar range and a very weak inhibitor of the serotonin transporter. Besides binding to transporters, diphenidine bound to adrenergic α1A and α2A receptors and serotonin 5-hydroxytryptamine 1A (5-HT1A) and 5-HT2A receptors in the range of 4–11μM. Methoxphenidine bound to all transporters, but considerable inhibition (IC50 < 10μM) was observed only for the norepinephrine transporter. Moreover, methoxphenidine bound to adrenergic α2A and serotonin 5-HT2A and 5-HT2C receptors in the range of 2.5–8.2μM. None of the test drugs mediated substrate-type efflux of monoamines. These data demonstrate that the monoamine transporter inhibition and receptor interactions most likely mediate the psychoactive effects of diclofensine and possibly play a contributory role for diphenidine and methoxphenidine.

Valbenazine for the treatment of tardive dyskinesia

ABSTRACTIntroduction: Chronic intake of typical neuroleptics or centrally acting dopamine receptor blocking antiemetics may cause onset of tardive syndromes. Various types exist. One of them is tardive dyskinesia, characterised by often stigmatising, purposeless, rapid, repetitive, stereotypic, involuntary movements of face, limbs or trunk. Effective symptomatic drug treatment options beyond application of tetrabenazine are rare. Tetrabenazine is usually administered three times daily due to the short half life of this agent.Areas covered: This narrative review discusses the value of valbenazine for the treatment of tardive dyskinesia as a therapeutic alternative to tetrabenazine.Expert commentary: Valbenazine is a selective inhibitor of vesicular monoamine transporter 2, which is metabolized to (+)-alpha-dihydrotetrabenazine. Valbenazine and particularly its metabolite inhibit vesicular monoamine transporter 2 function. Once daily intake of valbenazine ameliorated the severity of tardive dyskinesia. The chiral purity of valbenazine circumvents generation of the (-)alpha and (+) and (-)beta dihydrotetrabenazine metabolites of tetrabenazine or deutetrabenazine. Valbenazine and its metabolite do not antagonize postsynaptic monoamine receptors in contrast to the tetrabenazine formulations. Therefore one may hypothesize that fewer and less severe motor and psychopathological side effects will occur during valbenazine long term application compared with tetrabenazine or deutretrabenazine.

The significance of complete distributional analysis of the serotonin receptor

Monoamines, including serotonin, dopamine, noradrenaline, and adrenaline are essential neurotransmitters of the central nervous system (CNS). Although monoamine-containing neuronal somata are located in the brainstem, their axons project throught the brain. Thus, the monoamine system features a widespread network and is involved in diverse brain functions. Because individual neural functions are dependent on different types of monoamine receptors, it is important to understand the expression of each receptor within the CNS. In order to further elucidate the monoamine system, we performed distributional analysis in the entire CNS, targeted for 5-hydroxytryptamine 3A receptor (5-HT3AR), the only ionotropic receptor amongst the monoamine receptors. Because our method has high sensitivity and contrast, our findings reveal 5-HT3AR expression in novel regions as well as detailed localization throughout the entire CNS. These findings will facilitate further studies on the serotonin system. In this article, we illustrate the detailed distributional analysis of 5-HT3AR expression and suggest a renewed focus on the importance of whole distributional analysis of monoamine neurotransmitters. We hope for future studies to further investigate distribution of monoamine receptors throughout the entire CNS.

Laminar and Cellular Distribution of Monoamine Receptors in Rat Medial Prefrontal Cortex.

The prefrontal cortex (PFC) is deeply involved in higher brain functions, many of which are altered in psychiatric conditions. The PFC exerts a top-down control of most cortical and subcortical areas through descending pathways and is densely innervated by axons emerging from the brainstem monoamine cell groups, namely, the dorsal and median raphe nuclei (DR and MnR, respectively), the ventral tegmental area and the locus coeruleus (LC). In turn, the activity of these cell groups is tightly controlled by afferent pathways arising from layer V PFC pyramidal neurons. The reciprocal connectivity between PFC and monoamine cell groups is of interest to study the pathophysiology and treatment of severe psychiatric disorders, such as major depression and schizophrenia, inasmuch as antidepressant and antipsychotic drugs target monoamine receptors/transporters expressed in these areas. Here we review previous reports examining the presence of monoamine receptors in pyramidal and GABAergic neurons of the PFC using double in situ hybridization. Additionally, we present new data on the quantitative layer distribution (layers I, II–III, V, and VI) of monoamine receptor-expressing cells in the cingulate (Cg), prelimbic (PrL) and infralimbic (IL) subfields of the medial PFC (mPFC). The receptors examined include serotonin 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT3, dopamine D1 and D2 receptors, and α1A-, α1B-, and α1D-adrenoceptors. With the exception of 5-HT3 receptors, selectively expressed by layers I–III GABA interneurons, the rest of monoamine receptors are widely expressed by pyramidal and GABAergic neurons in intermediate and deep layers of mPFC (5-HT2C receptors are also expressed in layer I). This complex distribution suggests that monoamines may modulate the communications between PFC and cortical/subcortical areas through the activation of receptors expressed by neurons in intermediate (e.g., 5-HT1A, 5-HT2A, α1D-adrenoceptors, dopamine D1 receptors) and deep layers (e.g., 5-HT1A, 5-HT2A, α1A-adrenoceptors, dopamine D2 receptors), respectively. Overall, these data provide a detailed framework to better understand the role of monoamines in the processing of cognitive and emotional signals by the PFC. Likewise, they may be helpful to characterize brain circuits relevant for the therapeutic action of antidepressant and antipsychotic drugs and to improve their therapeutic action, overcoming the limitations of current drugs.

Pharmacological profile of methylphenidate-based designer drugs

BackgroundMethylphenidate-based designer drugs are new psychoactive substances (NPS) that are used outside medical settings and their pharmacology is largely unexplored. The aim of the present study was to characterize the pharmacology of methylphenidate-based substances in vitro. MethodsWe determined the potencies of the methylphenidate-based NPS N-benzylethylphenidate, 3,4-dichloroethylphenidate, 3,4-dichloromethylphenidate, ethylnaphthidate, ethylphenidate, 4-fluoromethylphenidate, isopropylphenidate, 4-methylmethylphenidate, methylmorphenate, and propylphenidate and the potencies of the related compounds cocaine and modafinil with respect to norepinephrine, dopamine, and serotonin transporter inhibition in transporter-transfected human embryonic kidney 293 cells. We also investigated monoamine efflux and monoamine receptor and transporter binding affinities. Furthermore, we assessed the cell integrity under assay conditions. ResultsAll methylphenidate-based substances inhibited the norepinephrine and dopamine transporters 4 to >1000-fold more potently than the serotonin transporter. Similar to methylphenidate and cocaine, methylphenidate-based NPS did not elicit transporter-mediated efflux of monoamines. Besides binding to monoamine transporters, several test drugs had affinity for adrenergic, serotonergic, and rat trace amine-associated receptors but not for dopaminergic or mouse trace amine-associated receptors. No cytotoxicity was observed after drug treatment at assay concentrations. ConclusionMethylphenidate-based substances had pharmacological profiles similar to methylphenidate and cocaine. The predominant actions on dopamine transporters vs. serotonin transporters may be relevant when considering abuse liability.This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’