Modulate Dopamine Transmission Research Articles

Self-reported intake of high-fat and high-sugar diet is not associated with cognitive stability and flexibility in healthy men

Animal studies indicate that a high-fat/high-sugar diet (HFS) can change dopamine signal transmission in the brain, which could promote maladaptive behavior and decision-making. Such diet-induced changes may also explain observed alterations in the dopamine system in human obesity. Genetic variants that modulate dopamine transmission have been proposed to render some individuals more prone to potential effects of HFS. The objective of this study was to investigate the association of HFS with dopamine-dependent cognition in humans and how genetic variations might modulate this potential association. Using a questionnaire assessing the self-reported consumption of high-fat/high-sugar foods, we investigated the association with diet by recruiting healthy young men that fall into the lower or upper end of that questionnaire (low fat/sugar group: LFS, n = 45; high fat/sugar group: HFS, n = 41) and explored the interaction of fat and sugar consumption with COMT Val158Met and Taq1A genotype. During functional magnetic resonance imaging (fMRI) scanning, male participants performed a working memory (WM) task that probes distractor-resistance and updating of WM representations. Logistic and linear regression models revealed no significant difference in WM performance between the two diet groups, nor an interaction with COMT Val158Met or Taq1A genotype. Neural activation in task-related brain areas also did not differ between diet groups. Independent of diet group, higher BMI was associated with lower overall accuracy on the WM task. This cross-sectional study does not provide evidence for diet-related differences in WM stability and flexibility in men, nor for a predisposition of COMT Val158Met or Taq1A genotype to the hypothesized detrimental effects of an HFS diet. Previously reported associations of BMI with WM seem to be independent of HFS intake in our male study sample.

DA-9805, a Herbal Mixture, Restores Motor Manifestations in 6-Hydroxydopamine-induced Parkinson's Disease Mouse Model by Regulating Striatal Dopamine and Acetylcholine Levels.

Loss of dopamine (DA) is one of the primary features of Parkinson’s disease (PD); however, imbalances of non-dopaminergic neurotransmitters significantly contribute to the disabilities noted in advanced PD patients. DA-9805 is the ethanolic extraction of the root bark of Paeonia × suffruticosa Andrews (Paeoniaceae), the root of Angelica dahurica (Hoffm.) Benth. and Hook.f. ex Franch. and Sav. (Apiaceae) and the root of Bupleurum falcatum L. (Apiaceae), which have been widely utilized as an enhancer of motor function in East Asia. This study aimed to investigate whether DA-9805 modified motor dysfunctions and imbalances associated with DA and other neurotransmitters in a 6-hydroxydopamine-induced PD mouse. We confirmed the expressions of proteins related with neurotransmissions in the striatum. In addition, we measured the striatal neurotransmitters using HPLC and analyzed their correlation. DA-9805 significantly improved motor impairments and restored the altered levels of neurotransmitters in the striatum. Moreover, DA-9805 improved the altered expressions of tyrosine hydroxylase (TH), DA transporter, and choline acetyltransferase (ChAT) in the ipsilateral part of mouse striatum or SNpc, which implies the neuroprotection. We also found that the level of striatal acetylcholine (Ach) has the moderate negative correlation with motor functions and TH expression in the SNpc. This study indicates that DA-9805 restores motor dysfunctions by normalizing the increased levels of striatal Ach via modulating DA transmission and ChAT expressions as well as its neuroprotective effects.

Cigarette Smoking, nicotine and Parkinson’s disease: Controversies in clinical trials data and medical practice.

It’s well known that smoking cigarettes is causally linked to a number of serious mortal diseases. These include laryngeal, lung, bladder, and digestive tract cancers, chronic obstructive pulmonary disease and a number of cardiovascular diseases, such as aortic aneurysm, stroke, and ischemic heart disease. In 2014, U.S. Surgeon General Report states that smoking is causally associated with inflammation and impaired immune function, and that regular smokers are at higher risk of developing pneumonia, tuberculosis, and other airway infections. So the best way to avoid harm from smoking is to never start, and for smokers to quit. However, evidence from epidemiological studies suggests a relationship between cigarette smoking and low risk of Parkinson’s disease. As a major component of tobacco smoke, nicotine has been proposed to be a substance for preventing against Parkinson’s disease risk, with a key role in regulating striatal activity and behaviors mediated through the dopaminergic system. Another data suggests quick deterioration and disease exacerbation after smoking cessation. Animal studies also showed that nicotine could modulate dopamine transmission and reduce levodopa-induced dyskinesias. Smoking cessation, proposed because of the health issues as certainly reducing the risk of cardiovascular events and cancer, must be definitely accepted as major health paramount procedure, but in the case of Parkinson’s disease nicotine-substitute supplements must be provided. As a small amount of nicotine can saturate a substantial portion of nicotine receptors in the brain, nicotine from other sources, such as less harmful smoking advanced devices as well as diet, could be a promising therapeutic substance for motility support and protection against Parkinson’s disease.

Acupuncture reduces cocaine psychomotor responses by activating the rostromedial tegmental nucleus.

The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine (DA) neurons, has emerged as an integral player in both rewarding and nociceptive responses. While previous studies have demonstrated that acupuncture modulates DA transmission in the mesolimbic reward system originating in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc) and can reduce drug self-administration, the central links between peripheral acupuncture signals and brain reward systems are not well-characterized. Thus, we hypothesised that acupuncture would elicit inhibitory signals from RMTg neurons to brain reward systems. Acupuncture reduced acute cocaine-induced locomotor activity and DA release in a point-specific manner, which was blocked by optogenetic silencing or chemical lesion of the RMTg. The acupuncture effect was mimicked by chemical activation of the RMTg. Acupuncture activated RMTg GABA neurons. In addition, the inhibitory effects of acupuncture on acute cocaine-induced locomotor activity were prevented by electrolytic lesions of the lateral habenula (LHb) or fasciculus retroflexus (FR), areas known to project to the RMTg. These findings suggest that acupuncture recruits the RMTg to reduce the psychomotor responses enhanced by acute cocaine.

TAAR1 agonists attenuate extended-access cocaine self-administration and yohimbine-induced reinstatement of cocaine-seeking.

The trace amine-associated receptor 1 (TAAR1) negatively modulates dopamine transmission. Our previous studies demonstrated that TAAR1 agonists attenuated cue- and drug-induced cocaine-seeking and increased the elasticity of the cocaine demand curve, in the short-access cocaine self-administration model. Compulsive use of cocaine, which is an essential criterion of cocaine use disorder, can be induced by extended access to cocaine self-administration. To characterize the role of TAAR1 in compulsive cocaine use, we evaluated the effects of activation of TAAR1 on cocaine intake, cocaine binge and cue-induced cocaine-seeking using the extended-access cocaine self-administration model in adult male Sprague-Dawley rats. We also investigated the role of TAAR1 in stress-triggered cocaine relapse by using the α2 -adrenoceptor antagonist yohimbine-induced reinstatement of cocaine-seeking. The selective TAAR1 partial agonist RO5263397 attenuated cocaine intake and did not develop tolerance during the 10-day extended-access cocaine self-administration. RO5263397 reduced a 12-h binge intake of cocaine after forced abstinence. RO5263397 also decreased cue-induced cocaine-seeking after prolonged abstinence from extended-access cocaine self-administration. Furthermore, RO5263397 and the selective TAAR1 full agonist RO5166017 reduced yohimbine-induced reinstatement of cocaine-seeking behaviour. Activation of TAAR1 attenuated extended-access cocaine self-administration and stress-induced cocaine reinstatement. These results suggest that TAAR1 agonists are promising pharmacological interventions to treat cocaine use disorder and relapse.

Dopaminergic system and its relationship with the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-thyroid systems (review)

This article reviews literature data on the activity of the central and peripheral dopaminergic systems, as well as its relationship with the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-thyroid systems. Studies have shown that dopamine levels vary depending on the territory of residence, while the data on the age dynamics of the plasma dopamine level contradict each other, which does not allow an unambiguous conclusion about a decrease or increase in its level with age. Most studies focus on the functions of dopamine in the central nervous system. Symptoms of several brain diseases, including schizophrenia, Parkinson’s disease, attention deficit and hyperactivity disorders and depression, are alleviated by the pharmacological modulation of dopamine transmission. However, there is evidence of a functional role of peripheral dopamine. While dopamine of the central dopaminergic system inhibits the secretion of thyrotropin, dopamine synthesized by sympathoadrenal nerve cells, heparinocytes, and thyroid parafollicular cells on the periphery stimulates the formation and release of iodothyronines. The neuroprotective effects of sex steroids determine the prevalence of studies of their role in preservation and maintaining the activity of the dopaminergic system. The dopaminergic system also affects the levels of sex hormones, enhancing aromatase activity, inhibiting the synthesis or secretion of prolactin, regulating the levels of gonadotropins and steroidogenesis in Leydig cells. The peripheral and central dopamine systems are sensitive to environmental influences, which indicate the relationship between the peripheral and central links.

Alterations in effort-related decision-making induced by stimulation of dopamine D1, D2, D3, and corticotropin-releasing factor receptors in nucleus accumbens subregions.

Nucleus accumbens (NAc) dopamine (DA) plays an integral role in overcoming effort costs, as blockade of D1 and D2 receptors reduces the choice of larger, more-costly rewards. Similarly, the stress neuropeptide corticotropin-releasing factor (CRF) modulates DA transmission and mediates stress-induced alterations in effort-related choice. The current study explored how excessive stimulation of different DA receptors within the NAc core and shell alters effort-related decision-making and compared these effects to those induced by CRF stimulation. Male Long Evans rats were well-trained on an effort-discounting task wherein they choose between a low-effort/low-reward and a high-effort/high-reward lever where the effort requirement increased over blocks (2-20 presses). Dopamine D1 (SKF 81297, 0.2-2μg), D2/3 (quinpirole, 1-10μg), or D3 (PD 128,907, 1.5-3μg) receptor agonists, or CRF (0.5μg), were infused into the NAc core or shell prior to testing. Stimulation of D2/3 receptors with quinpirole in the NAc core or shell markedly reduced the choice of high-effort option and increase choice latencies, without altering preference for larger vs smaller rewards. Stimulation of D1 or D3 receptors did not alter choice, although SKF 81297 infusions into the shell reduced response vigor. In comparison, core infusions of CRF flattened the discounting curve, reducing effortful choice when costs were low and increasing it when costs were high. Excessive stimulation of NAc D2 receptors has detrimental effects on effort-related decision-making. Furthermore, CRF stimulation induces dissociable effects on decision-making compared with those induced the effects of stimulation of different DA receptors.

SU6 - SYNERGISTIC EFFECT OF COMT AND KIAA0319 GENES IN MODULATING ADHD BEHAVIORS

Background ADHD and Learning Disorder (LD) are complex disorders with genetic and environmental determinants. Twenty to 30% of the children with ADHD have an associated LD. These problems usually persist into adolescence and are associated with chronic academic underachievement and failure to complete school. Hypothesis: Given the evidence for overlapping heritability between ADHD and LD, we hypothesize KIAA0319, a gene associated with LD, may interact with genes that have shown to be implicated in ADHD. As proof of concept, we have selected the COMT gene because of the well-documented role of its Val/Met polymorphism in modulating dopamine transmission in the frontal cortex. We also anticipated that the interaction between these two genes would be more evident in the school environment. Methods 400 children with ADHD (9–12 years old) were included in a double-blind placebo controlled study with methylphenidate. Teachers and parents were asked to evaluate the child's behavior at baseline, placebo, and MPH weeks using the appropriate version of Conners’ scale. The association between genotypes and ADHD behaviors were tested using repeated measure ANOVA, the two genes were the between-subject factors and the behaviors under the three experimental conditions (EC), were the within-subject factor. Results A highly significant 3-way interaction (KIAA0319⁎COMT⁎EC) was revealed in two SNPs of the KIAA0319 gene (rs4504469 p= 0.006 and rs7766230 p= 0.004) only according to teachers. By stratifying the children according to their COMT genotypes, we found that within the Met/Met genotype group, there were no significant differences in Conner's-T scores at baseline and on Placebo. However, significantly different patterns of response to MPH between KIAA0319 genotype groups were observed. Discussion This is the first study identifying an interaction between a gene involved in LD and a gene implicated in ADHD. This might help to individualize treatments for children with comorbid ADHD and learning disorders.

Expression of dopamine signaling genes in the post-mortem brain of individuals with mental illnesses is moderated by body mass index and mediated by insulin signaling genes

Preclinical studies implicate insulin signaling as a modulator of dopamine transmission, but human data is currently limited. We hypothesize that changes in the expression of insulin receptor-related genes in the post-mortem brain tissue of patients with mood and psychotic disorders mediate the expression of dopamine regulation-related genes. From a database containing microarray data from the post-mortem dorsolateral prefrontal cortex (dlPFC) (healthy controls [HC]: n = 209; patients: n = 321) and hippocampus (HC: n = 180; patients: n = 196), we conducted a hypothesis-driven analysis through the a priori selection of 12 dopamine- and 3 insulin-related genes. Mediation and moderated mediation models, accounting for the role of body mass index (BMI), were used. In the dlPFC, expressions of insulin receptor- and dopamine regulation-related genes were moderated by BMI, with significantly lower expression in high BMI patients. In the hippocampus, there were significantly lower expressions of these genes, which were not moderated by BMI. Illnesses by BMI effects on expression of dopamine genes were fully mediated by expression of insulin receptor gene (INSR). Analysis of conditional indirect effects showed interactions between INSR and BMI, indicating significantly stronger indirect effects at higher BMI values. In the hippocampus we observed that expression of insulin receptor substrate 1 and 2 fully mediated the effects of illnesses on expression of dopamine genes. In conclusion, differential expression of dopamine-related genes was related to altered expression of insulin signaling genes. BMI had region-specific effects, supporting the hypothesis that metabolic systems are critical mediators of dopaminergic function.

Long lasting effects of chronic WIN55,212-2 treatment on mesostriatal dopaminergic and cannabinoid systems in the rat brain

Cannabinoid administration modulates dopamine transmission via an indirect, multisynaptic mechanism that includes the activation of cannabinoid type-1 receptor (CB1R). The present study evaluated in rodents, the effects of acute and chronic (20 days) WIN55,212-2 administration, a non-selective CB1R agonist, on dopamine uptake and synthesis in the mesolimbic and nigrostriatal dopaminergic pathways and associate them to its effects on the endocannabinoid system. The effect of spontaneous withdrawal, after different abstinence periods (7 days, 20 days), was also assessed. Acute and chronic administration of WIN55,212-2 decreased dopamine transporter (DAT) binding and mRNA levels, as well as tyrosine hydroxylase (TH) mRNA expression in the substantia nigra (SN) and ventral tegmental area (VTA). In the striatum, chronic WIN55,212-2 administration led to decreased protein expression of DAT and TH, whereas no alterations were observed after acute administration, suggesting a diminished dopamine uptake and synthesis after chronic agonist treatment. Furthermore, after chronic agonist treatment, we observed reduced CB1R binding and mRNA levels in SN and striatum, providing evidence for a possible regulatory role of the endocannabinoid system on dopaminergic function. Seven days after WIN55,212-2 cessation, we observed a rebound increase in mRNA, binding and total protein levels of DAT and TH in VTA, SN and striatum proposing the existence of a biphasic expression pattern, which was also observed in CB1R binding levels. Within the 20-day period of abstinence, TH mRNA and protein levels and CB1R binding levels remain increased. The above results indicate that chronic CB1R agonist treatment induces long-lasting control of the mesostriatal dopaminergic activity.

Distinctive Modulation of Dopamine Release in the Nucleus Accumbens Shell Mediated by Dopamine and Acetylcholine Receptors

Nucleus accumbens (NAc) shell shows unique dopamine (DA) signals in vivo and plays a unique role in DA-dependent behaviors such as reward-motivated learning and the response to drugs of abuse. A disynaptic mechanism for DA release was reported and shown to require synchronized firing of cholinergic interneurons (CINs) and activation of nicotinic acetylcholine (ACh) receptors (nAChRs) in DA neuron (DAN) axons. The properties of this disynaptic mechanism of DA transmission are not well understood in the NAc shell. In this study, in vitro fast-scan cyclic voltammetry was used to examine the modulation of DA transmission evoked by CINs firing in the shell of mice and compared with other striatal regions. We found that DA signals in the shell displayed significant degree of summation in response to train stimulation of CINs, contrary to core and dorsal striatum. The summation was amplified by a D2-like receptor antagonist and experiments with mice with targeted deletion of D2 receptors to DANs or CINs revealed that D2 receptors in CINs mediate a fast inhibition observed within 100 ms of the first pulse, whereas D2 autoreceptors in DAN terminals are engaged in a slower inhibition that peaks at ∼500 ms. ACh also contributes to the use-dependent inhibition of DA release through muscarinic receptors only in the shell, where higher activity of acetylcholinesterase minimizes nAChR desensitization and promotes summation. These findings show that DA signals are modulated differentially by endogenous DA and ACh in the shell, which may underlie the unique features of shell DA signals in vivoSIGNIFICANCE STATEMENT The present study reports that dopamine (DA) release evoked by activation of cholinergic interneurons displays a high degree of summation in the shell and shows unique modulation by endogenous DA and acetylcholine. Desensitization of nicotinic receptors, which is a prevailing mechanism for use-dependent inhibition in the nucleus accumbens core and dorsal striatum, is also minimal in the shell in part due to elevated acetylcholinesterase activity. This distinctive modulation of DA transmission in the shell may have functional implications in the acquisition of reward-motivated behaviors and reward seeking.

In vivo systems pharmacology of IRL752, a novel compound for treatment of BPSD and cognitive impairment in dementia, enhancing prefrontal synaptic activity by modulation of dopamine transmission

In vivo systems pharmacology of IRL752, a novel compound for treatment of BPSD and cognitive impairment in dementia, enhancing prefrontal synaptic activity by modulation of dopamine transmission

Cortical Control of Striatal Dopamine Transmission via Striatal Cholinergic Interneurons

Corticostriatal regulation of striatal dopamine (DA) transmission has long been postulated, but ionotropic glutamate receptors have not been localized directly to DA axons. Striatal cholinergic interneurons (ChIs) are emerging as major players in striatal function, and can govern DA transmission by activating nicotinic receptors (nAChRs) on DA axons. Cortical inputs to ChIs have historically been perceived as sparse, but recent evidence indicates that they strongly activate ChIs. We explored whether activation of M1/M2 corticostriatal inputs can consequently gate DA transmission, via ChIs. We reveal that optogenetic activation of channelrhodopsin-expressing corticostriatal axons can drive striatal DA release detected with fast-scan cyclic voltammetry and requires activation of nAChRs on DA axons and AMPA receptors on ChIs that promote short-latency action potentials. By contrast, DA release driven by optogenetic activation of intralaminar thalamostriatal inputs involves additional activation of NMDA receptors on ChIs and action potential generation over longer timescales. Therefore, cortical and thalamic glutamate inputs can modulate DA transmission by regulating ChIs as gatekeepers, through ionotropic glutamate receptors. The different use of AMPA and NMDA receptors by cortical versus thalamic inputs might lead to distinct input integration strategies by ChIs and distinct modulation of the function of DA and striatum.

Chemokines and cocaine: CXCR4 receptor antagonist AMD3100 attenuates cocaine place preference and locomotor stimulation in rats

Plasma levels of the chemokine CXCL12 are elevated in mice following acute cocaine exposure and decreased in human cocaine abusers during withdrawal. CXCL12 is also one of the few chemokines located in the brain and can modulate dopamine transmission through activation of its receptor CXCR4. To assess a role for the CXCL12/CXCR4 system in behavioral effects of cocaine, we tested the hypothesis that AMD 3100 (Plerixafor), a CXCR4 antagonist, would inhibit conditioned place preference (CPP) and locomotor activation produced by cocaine. Rats injected with cocaine (10mg/kg) displayed CPP relative to saline-injected controls following 4 conditioning sessions. AMD 3100 (1, 2.5, 5mg/kg) administered prior to cocaine conditioning reduced development of cocaine CPP. AMD 3100 (5mg/kg) also inhibited expression of cocaine-induced CPP in a paradigm in which it was injected once (following cocaine conditioning and just prior to CPP testing). In addition, AMD 3100 (5, 10mg/kg) pretreatment reduced locomotor activation produced by an acute cocaine injection (15mg/kg) but did not affect basal locomotor activity relative to saline-injected controls. Repeated cocaine exposure produced a significant increase (1.49-fold) in CXCL12 mRNA expression in the ventral tegmental area (VTA). Our results suggest that the CXCL12/CXCR4 system in the brain reward circuit is impacted by cocaine exposure and influences behavioral effects related to the abuse liability of cocaine.

Distinct Effects of Nalmefene on Dopamine Uptake Rates and Kappa Opioid Receptor Activity in the Nucleus Accumbens Following Chronic Intermittent Ethanol Exposure.

The development of pharmacotherapeutics that reduce relapse to alcohol drinking in patients with alcohol dependence is of considerable research interest. Preclinical data support a role for nucleus accumbens (NAc) κ opioid receptors (KOR) in chronic intermittent ethanol (CIE) exposure-induced increases in ethanol intake. Nalmefene, a high-affinity KOR partial agonist, reduces drinking in at-risk patients and relapse drinking in rodents, potentially due to its effects on NAc KORs. However, the effects of nalmefene on accumbal dopamine transmission and KOR function are poorly understood. We investigated the effects of nalmefene on dopamine transmission and KORs using fast scan cyclic voltammetry in NAc brain slices from male C57BL/6J mice following five weeks of CIE or air exposure. Nalmefene concentration-dependently reduced dopamine release similarly in air and CIE groups, suggesting that dynorphin tone may not be present in brain slices. Further, nalmefene attenuated dopamine uptake rates to a greater extent in brain slices from CIE-exposed mice, suggesting that dopamine transporter-KOR interactions may be fundamentally altered following CIE. Additionally, nalmefene reversed the dopamine-decreasing effects of a maximal concentration of a KOR agonist selectively in brain slices of CIE-exposed mice. It is possible that nalmefene may attenuate withdrawal-induced increases in ethanol consumption by modulation of dopamine transmission through KORs.

Behavioural and Neurochemical Assessment of Heantos 4 on Preclinical Models of Morphine-Dependence

Objective: Opiate addiction is characterized by compulsive drug use and severe withdrawal symptoms during abstinence. Heantos 4, an herbal pharmacotherapy recently approved for opiate withdrawal treatment in Vietnam, has shown anti-craving properties. The present study is the first preclinical assessment of the effects of Heantos 4 on opiate withdrawal and the rewarding properties of morphine, along with its action on a critical neural substrate of addiction, the mesolimbic dopamine (DA) system. Methods: Rats received morphine treatments (10 mg/kg, i.p.) for seven days. On Day 8, Heantos 4 (100, 250 or 500 mg/kg, p.o.) was administered prior to naloxone (1 or 10 mg/kg, i.p.). Affective withdrawal symptoms were measured using conditioned place aversion (CPA) and somatic withdrawal symptoms were scored separately. The effect of Heantos 4 on morphine-induced (5 mg/kg, i.p.) conditioned place preference (CPP) was assessed by administering it prior to conditioning, expression or morphine-induced reinstatement. Additionally, the effect of Heantos 4 on the long-term maintenance of morphine-induced CPP was assessed bi-weekly for 6 weeks. Microdialysis studies assessed DA efflux in the nucleus accumbens of rats receiving one or seven repeated treatments of Heantos 4 (500 mg/kg, p.o.) and morphine, or receiving Heantos 4 and naloxone (10 mg/kg, i.p.). Results: Heantos 4 reduced somatic but not affective components of naloxone-precipitated opiate withdrawal. It attenuated acquisition but not expression or reinstatement of morphine-induced CPP. Long-term maintenance of morphine-induced CPP was also reduced. Heantos 4 by itself enhanced DA efflux but blunted morphine-evoked DA release on Day 1 and 7. Heantos 4 attenuated naloxone-induced decrease in DA in morphine-dependent rats. Conclusion: These findings demonstrate that Heantos 4 alleviates symptoms of somatic opiate withdrawal and indicate potential effects on incentive motivation. Moreover, Heantos 4 may modulate DA transmission that limits or antagonizes non-physiological fluctuations in mesolimbic DA activity induced by morphine and naloxone.

In-vivo pharmacology of Trace-Amine Associated Receptor 1

Trace-amines (TAs) are endogenous amines that are implicated in several physiological processes including modulation of aminergic neurotransmission. These compounds exert their effect by activating a class of G protein-coupled receptors termed Trace-Amine Associated Receptors (TAARs), where TAAR1 is the only human receptor that has been shown to bind endogenous TAs. Most of the studies have focused on studying the role of TAAR1 on modulation of the dopamine transmission. These studies indicate that TAAR1 is a negative regulator of dopamine transmission making TAAR1 a novel target for neuropsychiatric disorders that arises from dopamine dysfunction such as schizophrenia. This review discusses the unique pharmacology of TAAR1 with the major focus on the physiological role of TAAR1 and its modulation of dopamine transmission.

Mechanism of Action of Antipsychotic Medications

Article AbstractA variety of antipsychotic medications exist for treating patients with schizophrenia. Knowledge of pharmacokinetics (the body's effect on the drug) and pharmacodynamics (the drug's effect on the body) can help clinicians select antipsychotics and make timely dose adjustments to improve patient outcomes. Currently, the only known effective mechanism to reduce positive psychotic symptoms is dopamine D2 blockade. However, several relevant dopamine pathways exist, and increasingly sophisticated insight into the role of subsections of the striatum has helped link dopamine D2 blockade in specific pathways to the beneficial and adverse effects of antipsychotics, including extrapyramidal side effects (EPS) and secondary negative or cognitive effects. Antipsychotics with low D2 affinity (partial D2 agonism) that modulate dopamine transmission via blockade of histamine or cholinergic receptors or that bind more tightly to serotonin 5-HT2A receptors than D2 receptors generally have less risk for EPS. However, some of the mechanisms that balance dopamine tone can be associated with sedation, central and peripheral anticholinergic effects, weight gain and metabolic abnormalities. Thus, treatment selection needs to be individualized based on the pharmacokinetic and pharmacodynamic profiles of available antipsychotics as well as their effects in a given patient with past treatment response patterns, comorbidities, and preferences. Importantly, new medications with either additional or exclusive nondopaminergic pharmacologic mechanisms need to be developed that can address not only positive symptoms of schizophrenia but also negative and cognitive symptoms, which do not appear to be primarily related to dopamine dysfunction.See the entire activity.

Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism

Salvinorin A (SalA), a selective κ-opioid receptor (KOR) agonist, produces dysphoria and pro-depressant like effects. These actions have been attributed to inhibition of striatal dopamine release. The dopamine transporter (DAT) regulates dopamine transmission via uptake of released neurotransmitter. KORs are apposed to DAT in dopamine nerve terminals suggesting an additional target by which SalA modulates dopamine transmission. SalA produced a concentration-dependent, nor-binaltorphimine (BNI)- and pertussis toxin-sensitive increase of ASP+ accumulation in EM4 cells coexpressing myc-KOR and YFP-DAT, using live cell imaging and the fluorescent monoamine transporter substrate, trans 4-(4-(dimethylamino)-styryl)-N-methylpyridinium) (ASP+). Other KOR agonists also increased DAT activity that was abolished by BNI pretreatment. While SalA increased DAT activity, SalA treatment decreased serotonin transporter (SERT) activity and had no effect on norepinephrine transporter (NET) activity. In striatum, SalA increased the Vmax for DAT mediated DA transport and DAT surface expression. SalA up-regulation of DAT function is mediated by KOR activation and the KOR-linked extracellular signal regulated kinase-½ (ERK1/2) pathway. Co-immunoprecipitation and BRET studies revealed that DAT and KOR exist in a complex. In live cells, DAT and KOR exhibited robust FRET signals under basal conditions. SalA exposure caused a rapid and significant increase of the FRET signal. This suggests that the formation of KOR and DAT complexes is promoted in response to KOR activation. Together, these data suggest that enhanced DA transport and decreased DA release resulting in decreased dopamine signalling may contribute to the dysphoric and pro-depressant like effects of SalA and other KOR agonists.

The galanin receptor agonist, galnon, attenuates cocaine-induced reinstatement and dopamine overflow in the frontal cortex.

Relapse represents one of the most significant problems in the long-term treatment of drug addiction. Cocaine blocks plasma membrane monoamine transporters and increases dopamine (DA) overflow in the brain, and DA is critical for the motivational and primary reinforcing effects of the drug as well as cocaine-primed reinstatement of cocaine seeking in rats, a model of relapse. Thus, modulators of the DA system may be effective for the treatment of cocaine dependence. The endogenous neuropeptide galanin inhibits DA transmission, and both galanin and the synthetic galanin receptor agonist, galnon, interfere with some rewarding properties of cocaine. The purpose of this study was to further assess the effects of galnon on cocaine-induced behaviors and neurochemistry in rats. We found that galnon attenuated cocaine-induced motor activity, reinstatement and DA overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self-administration of cocaine, baseline extracellular DA levels or cocaine-induced DA overflow in the nucleus accumbens (NAc). Similar to cocaine, galnon had no effect on stable food self-administration but reduced food-primed reinstatement. These results indicate that galnon can diminish cocaine-induced hyperactivity and relapse-like behavior, possibly in part by modulating DA transmission in the frontal cortex.