Central Dopamine Receptors Research Articles

Central dopamine receptors: Radiotracers unveiling the Role of dopaminergic tone in obesity.

Brain dopamine type 2 and 3 receptors (D2/3R) have been postulated to play a role in obesity. However, results from molecular neuroimaging studies exploring these receptors in obesity are not consensual. These inconsistencies may be due to the distinct characteristics of radiotracers that confound the interpretation of D2/3R assessment. Only three meta-analyses reported their results across radiotracers. Although all agree that obesity severity influences D2/3R availability, results vary for [11C]raclopride. Further, D2/3R assessment has been commonly interpreted as reflecting receptor density or availability. An alternative interpretation could be related to changes in endogenous central dopaminergic tone. The main question is whether the hypothesis of a quadratic relationship between dopaminergic tone and degree of obesity is suitable for the distinct characteristics of radiotracers. To answer this question and clarify the role of dopaminergic tone in obesity, we systematically reviewed this issue across radiotracers. Out of 514 articles, 15 articles were selected for review. Besides obesity severity, this study highlights the influence of radiotracer characteristics when assessing D2/3R. The tested hypothesis proved to be more suitable for radiotracers more susceptible to endogenous dopamine or with a lower affinity to D2/3R, supporting the quadratic relationship between dopaminergic tone and degree of obesity. While the role of D2/3R density in obesity may be relevant, dopaminergic tone seems to have a greater impact on the obesity-related differences found in these receptors. Finally, neuropsychological factors should be tested in addition to body mass index, as they may better reflect altered brain dopaminergic function.

Features of Stress-Induced Changes in Heart Rate Variability During Blockade of Central and Stimulation of Peripheral Serotonin and Dopamine Receptors in Rats.

The dynamics of heart rate variability (HRV) during acute stress was studied in male nonlinear rats that received single injection of serotonin (200 μg/kg) or dopamine (60 μg/kg), regular (4-fold) injections of central serotonin receptor blockers (ketanserin and granisetron, 0.1 mg/kg each) or central dopamine receptor blockers (0.1 mg/kg SCH-23390 and 10 mg/kg sulpiride), as well as a combination of central receptor blockers with the administration of serotonin or dopamine, respectively. During stress against the background of serotonin receptors blockade, a weak tachycardia, low stress index, high rhythm variability, especially in the low-frequency range were recorded; against the background of dopamine receptors blockade, increased reactivity to stress at high HR, an initial increase in the stress index, and a decrease in rhythm variability, followed by an increase in the proportion of very low frequency waves in the spectrum were revealed. Serotonin and dopamine, by stimulating peripheral receptors, predominantly weakened stress-induced changes in HRV (especially serotonin), but in combination with blockade of the corresponding central receptors contributed to maintaining tachycardia, reduced rhythm variability, and potentiated the effects of blockers in relation to stress induced changes in the wave structure of the HRV spectrum. We believe that central and peripheral serotoninergic and dopaminergic structures are involved in the formation of HRV by modulating the activity of components of the autonomous and central circuits of HR regulation, respectively.

Portuguese observational cross-sectional clinical imaging study protocol to investigate central dopaminergic mechanisms of successful weight loss through bariatric surgery

IntroductionBariatric surgery (BS) is the treatment of choice for refractory obesity. Although weight loss (WL) reduces the prevalence of obesity-related comorbidities, not all patients maintain it. It has been suggested...

Nicotine Abuse and Neurodegeneration: Novel Pharmacogenetic Targets to Aid Quitting and Reduce the Risk of Dementia.

Nicotine dependence has deleterious neurological impacts. Previous studies found an association between cigarette smoking and accelerating age-related thinning of the brain's cortex and subsequent cognitive decline. Smoking is considered the third most common risk factor for dementia, which prompted the inclusion of smoking cessation in dementia prevention strategies. Traditional pharmacologic options for smoking cessation include nicotine transdermal patches, bupropion and varenicline. However, based on smokers' genetic makeup, pharmacogenetics can be used to develop novel therapies to replace these traditional approaches. Genetic variability of cytochrome P450 2A6 has a major impact on smokers' behavior and their response to quitting therapies. Gene polymorphism in nicotinic acetylcholine receptor subunits also has a great influence on the ability to quit smoking. In addition, polymorphism of certain nicotinic acetylcholine receptors was found to affect the risk of dementia and the impact of tobacco smoking on the development of Alzheimer's disease. Nicotine dependence involves the activation of pleasure response through the stimulation of dopamine release. Central dopamine receptors, catechol-o-methyltransferase and the dopamine transporter protein, regulate synaptic dopamine levels. The genes of these molecules are potential targets for novel smoking cessation drugs. Pharmacogenetic studies of smoking cessation also investigated other molecules, such as ANKK1 and dopamine-beta-hydroxylase (DBH). In this perspective article, we aim to highlight the promising role of pharmacogenetics in the development of effective drugs for smoking cessation, which can increase the success rate of smoking quitting plans and ultimately reduce the incidence of neurodegeneration and dementia.

Antipyretic Efficacy of Bromocriptine in Central Fever: an Exploratory Analysis.

'Central' fevers are thought to result from disruption of hypothalamic thermoregulatory pathways following severe brain injuries. Bromocriptine, due to its central dopamine receptor agonism, has been hypothesized to have antipyretic effect in this setting. However, clinical evidence for this off-label use is limited to a few case reports. In this retrospective cohort study, we analyzed the effect of bromocriptine administration on body temperature in acute brain injury patients with suspected central fever. We screened a cohort of adult patients that received bromocriptine in the neurologic-intensive care unit of a tertiary care hospital between January 2018 and December 2021. Indication of central fever was ascertained by review of clinical documentation. A generalized additive mixed model (GAMM) was used to model temperature as a function of time relative to bromocriptine initiation. We adjusted for potential confounding due to the following covariates: temperature recording method (invasive vs surface), concurrent antipyretic administration within 8h, and surface cooling device use within 4h of temperature measurement. Temperature-time function was modeled using a cubic spline with k = 10 knots. A total of 33 patients were included in the analysis (14 women; mean age: 50 y, standard deviation 14 y). Median dose of bromocriptine was 7.5mg (range 2.5-40) for a median of 13 d (range 5-160). Age and sex did not impact the function of temperature over time. Predicted temperatures were significantly (p < 0.05) higher by 0.4°C with invasive compared to surface recording methods, lower by 0.2°C in the presence of cooling device use and lower by 0.1°C with concurrent antipyretic use. On adjusted analysis with the GAMM, there was decline (p < 0.05) in temperature following bromocriptine initiation by - 0.3°C at 24h, - 0.5°C at 48h, and - 0.7°C at 72h. Bromocriptine use was associated with modest but statistically significant decline in temperature, with nadir at 72h post initiation. The findings provide a data driven basis for prospective evaluation.

Psychotropic Drug Effects on Steroid Stress Hormone Release and Possible Mechanisms Involved.

There is no doubt that chronic stress accompanied by adrenocortical stress hormone release affects the development and treatment outcome of several mental disorders. Less attention has been paid to the effects of psychotropic drugs on adrenocortical steroids, particularly in clinical studies. This review focuses on the knowledge related to the possible modulation of cortisol and aldosterone secretion under non-stress and stress conditions by antipsychotic drugs, which are being used in the treatment of several psychotic and affective disorders. The molecular mechanisms by which antipsychotic drugs may influence steroid stress hormones include the modulation of central and/or adrenocortical dopamine and serotonin receptors, modulation of inflammatory cytokines, influence on regulatory mechanisms in the central part of the hypothalamic-pituitary axis, inhibition of corticotropin-releasing hormone gene promoters, influencing glucocorticoid receptor-mediated gene transcription, indirect effects via prolactin release, alteration of signaling pathways of glucocorticoid and mineralocorticoid actions. Clinical studies performed in healthy subjects, patients with psychosis, and patients with bipolar disorder suggest that single and repeated antipsychotic treatments either reduce cortisol concentrations or do not affect its secretion. A single and potentially long-term treatment with dopamine receptor antagonists, including antipsychotics, has a stimulatory action on aldosterone release.

Role of central dopamine receptors in regulation of plasma glucose levels

Role of central dopamine receptors in regulation of plasma glucose levels

Synthesis, Characterisation and In Vitro Permeation, Dissolution and Cytotoxic Evaluation of Ruthenium(II)-Liganded Sulpiride and Amino Alcohol

Sulpiride (SPR) is a selective antagonist of central dopamine receptors but has limited clinical use due to its poor pharmacokinetics. The aim of this study was to investigate how metal ligation to SPR may improve its solubility, intestinal permeability and prolong its half-life. The synthesis and characterisation of ternary metal complexes [Ru(p -cymene)(L)(SPR)]PF6 (L1 = (R)-(+)-2-amino-3-phenyl-1-propanol, L2 = ethanolamine, L3 = (S)-(+)-2-amino-1-propanol, L4 = 3-amino-1-propanol, L5 = (S)-(+)-2-pyrrolidinemethanol) are described in this work. The stability constant of the [Ru(p -cymene)(SPR)] complex was determined using Job’s method. The obtained value revealed higher stability of the metal complex in the physiological pH than in an acidic environment such as the stomach. The ternary metal complexes were characterised by elemental analysis, Fourier transform infrared spectroscopy (FT-IR), 1H and 13C nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), thermal analyses, Ultraviolet-Visible (UV-Vis). Solubility studies showed higher aqueous solubility for complexed SPR than the free drug. Dissolution profiles of SPR from the metal complexes exhibited slower dissolution rate of the drug. Permeation studies through the pig’s intestine revealed enhanced membrane permeation of the complexed drug. In vitro methyl thiazolyl tetrazolium (MTT) assay showed no noticeable toxic effects of the ternary metal complexes on Caco-2 cell line.

High Throughput Screening and Molecular Docking of Calmodulin with Antagonists of Trifluoperazine and Phenothiazine Chemical Class

Background: Calmodulin (CaM) is a ubiquitous, calcium-binding protein that can bind to and regulate a multitude of different protein targets, thereby affecting many different cellular functions. Binding ofsmall, hydrophobic molecules alter its function, as in the case of Phenothiazine (PTZ). PTZ isan organic compound with a history of use as an antihelminth and frequently quoted as a classic example of a pharmaceutical lead structure.Its derivatives are currently used as antipsychotic drugs. Triflouperazine (TFP) is a phenothiazine derivative and a dopamine antagonist, with antiemetic and antipsychotic activities. TFP exerts its antipsychotic effect by blocking central dopamine receptors, thereby preventing effects like delusions and hallucinations caused by an excess of dopamine. This agent also functions as a calmodulin inhibitor, thereby leading to an elevation of cytosolic calcium. We have attempted to screen the extent of CaM specificity towards different classes of TFP and PTZ. Methods: Molecular docking approach using the Lamarckian Genetic Algorithm was used to elucidate the basis of structural similarity of TFP and PTZ with CaM. In total, 3000 compounds were studied. All of the antagonists were taken from PubChem database on the basis of the structural similarity of TFP and PTZ. Results: The docking result of these molecules with CaM demonstrated favored binding energies in the range of -11.50 kcal/mol to -4.51 kcal/mol, with 8 molecules showing hydrogen bonds with the active site residue Met124. Compound 1 was found to be the best CaM inhibitor. The Drug like and chemical toxicity was also predicted for this compound. Conclusion: Computational docking is a feasible method to screen inhibitor compounds against a biomolecule of interest.

BENEFICIAL EFFECT OF BROMOCRIPTINE ON HIGH FAT DIET-INDUCED BODY WEIGHT GAIN, ADIPOSITY AND BIOCHEMICAL ANOMALIES IN WISTAR RATS

Objectives: Dopamine plays a critical role in various vital functions, including hormonal regulation, reward, emotions, and food intake. It affects on the multiple aspects of food intake that include food selection, satiety, and energy expenditure. Dopamine D2 receptors (D2R) were found to be lower in several brain regions in both obese experimental animals and humans, and it has been observed that dopamine D2 agonist bromocriptine (BC) can exert favorable metabolic changes in seasonal obesity. The aim of this study was to investigate the beneficial effect of chronic administration of BC a central dopamine receptor agonist on body weight gain, adiposity, and biochemical anomalies in rats.Methods: In this study, chronic administration of BC (2.5 and 5 mg/kg/day, i.p) a dopamine agonist for 8 weeks along with high-fat diet (HFD) to the obese rats which were pretreated with HFD feeding for 8 weeks on the various parameters of obesity were analyzed. The effects of these treatments on body weight, feed intake (kcal), weight and size of fat pads, levels of serum glucose, triglycerides (TG), total cholesterol (TC), high-density lipoproteins (HDL), and low-density lipoprotein were analyzed.Results: Treatment with BC (2.5 and 5 mg/kg/day, i.p) produced significant dose-dependent decrease (p&lt;0.05) in body weight gain, feed intake (kcal), weight and size of fat pads, levels of serum glucose, TG, TC, and low-density lipoproteins as compared to HFD group. Moreover, the level of serum HDL was increased as compared to HFD group. BC a dopamine receptor agonist positively modulate the parameters of obesity, and the effect was comparable to orlistat, a well-reported drug for obesity.Conclusion: In conclusion, the study demonstrates that BC ameliorated established obesity and associated biochemical consequences.

Do doctors agree on doses of antipsychotic medications?

The objective of this study was to investigate the concordance in attitudes of psychiatrists towards the doses of antipsychotics given to stable outpatients with schizophrenia and to examine the psychiatrists' estimates of equally potent doses of haloperidol and olanzapine. We asked all 22 doctors serving at the psychiatry department of Jönköping County Hospital if they considered the combined dose of antipsychotics for 20 individual patients to be 'low', 'medium' or 'high'. We also asked each doctor to state the dose of haloperidol that they considered to be clinically equivalent to 20 mg/day of olanzapine. The inter-rater reliability (Krippendorff's alpha (α)) was 0.50, and the mean estimated dose haloperidol considered clinically equivalent to 20 mg/day of olanzapine was 4.45 mg/day. The inter-rater reliability (Krippendorff's α) was low, suggesting lack of agreement. The dose of antipsychotics given to a patient might thus be more influenced by which doctor they meet than the severity of the disease. The respondents in this study considered a mean dose of 4.45 mg/day of haloperidol to be clinically equivalent to 20 mg/day of olanzapine. This is a considerably lower dose than was determined by an international consensus study of antipsychotic dosing, and more in line with the available PET studies measuring central dopamine receptor blockage of optimal clinical doses.

Neurocognitive dysfunction and pharmacological intervention using guanfacine in a rhesus macaque model of self-injurious behavior

Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs=0.662, P=0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs=0.563, P=0.045 and rs=0.692, P=0.009, respectively). We also tested the efficacy of guanfacine, an α2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P=0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs=−0.761, P=0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.

Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat

Tesofensine is a triple monoamine reuptake inhibitor which inhibits noradrenaline, 5-HT and dopamine reuptake. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong and sustained effects in obesity management is not clarified. Tesofensine effectively induces appetite suppression in the diet-induced obese (DIO) rat partially being ascribed to an indirect stimulation of central dopamine receptor function subsequent to blocked dopamine transporter activity. This is interesting, as obese patients have reduced central dopaminergic activity thought to provide a drive for compensatory overeating, but whether treatment with an uptake inhibitor counteracts these changes or not has not been investigated. Tesofensine treatment (2.0mg/kg/day for 14days) caused a pronounced anorexigenic and weight-reducing response in DIO rats as compared to age-matched chow-fed rats. DIO rats also exhibited a marked reduction in baseline extracellular dopamine levels in the nucleus accumbens (NAcc) and prefrontal cortex (PFC), as compared to chow-fed rats using microdialysis. While acute administration of tesofensine (2.0mg/kg) normalized accumbal dopamine levels in DIO rats, the drug had no effect on dopamine levels in chow-fed rats. Tesofensine evoked a stronger stimulatory response on NAcc and PFC dopamine levels in DIO rats, and also induced discrete changes in striatal dopamine D2 receptor expression and transporter binding. In conclusion, tesofensine produces weight loss together with reversal of lowered forebrain dopamine levels in DIO rats, suggesting that tesofensine's anti-obesity effects, at least in part, are associated with positive modulation of central dopaminergic activity.

Dopaminergic symptoms in migraine

Migraine pain is often preceded, accompanied and followed by dopaminergic symptoms (premonitory yawning and somnolence, accompanying nausea and vomiting, postdromal somnolence, euphoria and polyuria). After reviewing evidence from pharmacological, biochemical, genetic and animal experimental studies on the relationship between dopamine and migraine, and matching these data with patients' clinical features, we postulate that migraine attacks could be characterized by an ictal dopamine release in a subject with dopamine receptor hypersensitivity due to a chronic dopaminergic deficit synergistic to serotoninergic impairment. Our review suggests that when the attack begins, a low dopamine plasma concentration stimulates hypersensitive central presynaptic dopamine receptors thus causing prodromal symptoms such as yawning and somnolence. Increasing dopamine levels, though still insufficient to stop trigeminovascular activation, stimulate postsynaptic dopamine receptors thus inducing nausea, vomiting and hypotension. Finally, dopamine levels slowly return to baseline, giving rise to somnolence and fatigue, but, in some cases, continue to rise triggering postdromal symptoms such as euphoria and polyuria.

Central manipulation of dopamine receptors attenuates the orexigenic action of ghrelin

Recent evidence suggests that ghrelin, a peptidic hormone stimulating food intake, interacts with the dopamine signaling. This interaction has been demonstrated to modulate several effects of ghrelin, such as locomotor activity, memory, and food intake. Ghrelin increases dopamine levels in the shell of the nucleus accumbens stimulating food intake, while ablation of the ghrelin receptor attenuates the hypophagia caused by the activation of dopamine receptor 2. However, it is not known whether the orexigenic action of ghrelin is due to changes in central dopamine receptors. We used Sprague-Dawley rats injected with different dopamine receptor agonists, antagonists, and ghrelin. We demonstrate that the specific central blockade of dopamine receptor 1, 2, and 3 (D1, D2, and D3, respectively) reduces the orexigenic action of ghrelin. Similarly, specific central stimulation, either singly of dopamine receptor 1 or dopamine receptors 2 and 3 simultaneously, causes a significant decrease in ghrelin-induced food intake. Co-stimulation of all three receptors (D1, D2, and D3) also led to a marked attenuation in ghrelin-induced food intake. Importantly, the reduction in ghrelin-induced feeding was not caused by malaise or any type of behavioral alteration. Taken together, these data indicate that dopamine receptors play an important role in acute stimulation of feeding behavior induced by central injection of ghrelin.

The selective D3receptor antagonist SB-277011A attenuates morphine-triggered reactivation of expression of cocaine-induced conditioned place preference

We examined the effect of acute administration of the selective D3 receptor antagonist SB-277011A on morphine-triggered reactivation of cocaine-induced conditioned place preference (CPP) in adult male Sprague-Dawley rats. Repeated pairing of animals with 15 mg/kg i.p. of cocaine HCl or vehicle to cue-specific CPP chambers produced a significant CPP response compared to animals paired only with vehicle in both chambers. Expression of the CPP response to cocaine was then extinguished by repeatedly giving the animals vehicle injections in the cocaine-paired chambers. The magnitude of the CPP response after extinction was not significantly different from that of animals paired only with vehicle. Expression of the extinguished CPP response was reactivated by acute administration of 5 mg/kg i.p. of morphine but not by vehicle. Acute administration of 6 or 12 mg/kg i.p. (but not 3 mg/kg) of SB-277011A significantly attenuated morphine-triggered reactivation of the cocaine-induced CPP. SB-277011A itself (12 mg/kg i.p.) did not reactivate the extinguished CPP response. Overall, SB-277011A decreases the incentive motivational actions of morphine. The present findings suggest that central D₃ dopamine receptors are involved in relapse to cocaine-seeking behavior, that a final common neural mechanism exists to mediate the incentive motivational effects of psychostimulants and opiates, and that selective dopamine D₃ receptor antagonists constitute promising compounds for treating addiction.

Clavulanic acid induces penile erection and yawning in male rats: Comparison with apomorphine

The beta-lactamase inhibitor clavulanic acid induced penile erection and yawning in a dose dependent manner when given intraperitoneally (IP, 0.05–5mg/kg), perorally (OS, 0.1–5mg/kg) and intracereboventricularly (ICV, 0.01–5μg/rat) to male rats. The effect resembles that of the dopamine receptor agonist apomorphine given subcutaneously (SC) (0.02–0.25mg/kg), although the responses of the latter followed a U inverted dose–response curve, disappearing at doses higher than 0.1mg/kg. Clavulanic acid responses were reduced by about 55% by haloperidol, a dopamine D2 receptor antagonist (0.1mg/kg IP), and by d(CH2)5Tyr(Me)2-Orn8-vasotocin, an oxytocin receptor antagonist (2μg/rat ICV), both given 15min before clavulanic acid. A higher reduction of clavulanic acid responses (more than 80%) was also found with morphine, an opioid receptor agonist (5mg/kg IP), and with mianserin, a serotonin 5HT2c receptor antagonist (0.2mg/kg SC). In contrast, no reduction was found with naloxone, an opioid receptor antagonist (1mg/kg IP). The ability of haloperidol, d(CH2)5Tyr(Me)2-Orn8-vasotocin and morphine to reduce clavulanic acid induced penile erection and yawning suggests that clavulanic acid induces these responses, at least in part, by increasing central dopaminergic neurotransmission. Dopamine in turn activates oxytocinergic neurotransmission and centrally released oxytocin induces penile erection and yawning. However, since both penile erection and yawning episodes were reduced not only by the blockade of central dopamine and oxytocin receptors and by the stimulation of opioid receptors, which inhibits oxytocinergic neurotransmission, but also by mianserin, an increase of central serotonin neurotransmission is also likely to participate in these clavulanic acid responses.

Reduced Dopamine Receptor Sensitivity as an Intermediate Phenotype in Alcohol Dependence and the Role of the COMT Val158Met and DRD2 Taq1A Genotypes

Alcohol dependence is a common neuropsychiatric disorder with high heritability. However, genetic association studies on alcohol dependence are often troubled by nonreplication. The use of intermediate phenotypes may help make clear the mode of action of various candidate genes and improve the reproducibility of genetic association studies. To test central dopamine receptor sensitivity as an intermediate phenotype for alcohol dependence, specifically evaluating the hypothesis that the dopaminergic genes COMT Val158Met and DRD2 Taq1A affect dopamine receptor sensitivity. Case-control pharmacogenetic challenge study. Patients with alcohol dependence admitted for detoxification were compared with healthy control subjects matched for age and level of education. Patients (n = 110) were a consecutive sample, whereas controls (n = 99) were recruited through advertisements in regional newspapers. A dopamine challenge test was subcutaneously administered using the dopamine agonist apomorphine hydrochloride (0.005 mg/kg). Outcome measures were plasma growth hormone levels and results of a continuous performance task. Central dopamine receptor sensitivity is reduced in alcohol dependence, and this is modulated by dopaminergic genes. Specifically, DRD2 Taq1A genotype affected dopamine receptor sensitivity as measured by plasma growth hormone levels, and COMT Val158Met genotype affected dopamine receptor sensitivity as measured by performance on a continuous performance task. In a logistic regression analysis, reduced dopamine receptor sensitivity on both measures predicted alcohol dependence, without an additive effect of the COMT Val158Met and DRD2 Taq1A genotypes. COMT Val158Met and DRD2 Taq1A may affect the intermediate phenotype of central dopamine receptor sensitivity. COMT Val158Met and DRD2 Taq1A may confer their risk of alcohol dependence through reduced dopamine receptor sensitivity in the prefrontal cortex and hindbrain, respectively.

Ventricular Tachycardia during Treatment with Modafinil for Narcolepsy: A Case Report

Pharmacological treatment of narcolepsy is complex. We reported a case of recurrent episodes of polymorphic ventricular tachycardia attributed to the use of modafinil, a recently approved wake-promoting agent for narcolepsy and shift work sleep disorder. Modafinil is also approved as adjunctive treatment of obstructive sleep apnea/hypopnea syndrome. While the exact mechanism of action for modafinil is not known, central dopamine receptors seem to play an essential role. Adverse influences on the electrocardiogram (ECG) or drug-related cardiac arrhythmias are rarely reported, but are considered as clinically important.

Central dopamine receptors and their role in digoxin-induced cardiotoxicity in the dog

The role of the dopaminergic system in digoxin-induced cardiotoxicity has been examined. Specific dopaminergic agonists and antagonists were administered into the ventriculocisternal system of pentobarbitone-anaesthetized dogs before systemic administration of digoxin. Pretreatment with apomorphine, a specific dopamine agonist, did not significantly alter the arrhythmogenic or lethal doses of digoxin. However, the digoxin-induce increase in CSF noradrenaline was decreased significantly in apomorphine-pretreated animals. Pretreatment with pimozide, a specific dopamine antagonist, significantly decreased the arrhythmogenic dose of digoxin but did not alter the lethal dose. As with apomorphine, pimozide-pretreated animals accumulated significantly less noradrenaline in CSF compared with control dogs. These results suggest that dopamine receptors are not directly related to the cardiotoxic actions of digoxin. However, dopaminergic receptors may influence the balance of central catecholaminergic systems that influence the peripheral cardiovascular system.