[Relationship between executive functions, body mass index and the DRD4 VNTR 7-repeat allele]. / A végrehajtó funkciók összefüggése a testtömegindexszel és a DRD4-VNTR 7-es alléllal.

Introduction and aim: Earlier results in the literature suggest that overweight subjects show weaker performance in executive function tasks as compared to normal weight people. Dopaminergic system is strongly linked to executive functions, body mass regulation and ingestion. The aim of the present study was to examine the possible relationship between DRD4 VNTR 7-repeat allele, body mass index and Stroop performance in a healthy adult population, and to draw psychogenetic conclusions. Method: 152 subjects without diabetic or psychiatric history participated in the study. Along with non-invasive DNA sampling, demographic, weight and height data were collected. The participants also solved the computerized Stroop task. 11 subjects belonged to the underweight (mean body mass index = 17.9 kg/m2), 98 subjects to the normal (mean body mass index = 21.8 kg/m2), and 43 subjects to the overweight (mean body mass index = 28.9 kg/m2) category. After grouping participants according to their body mass index and DRD4 VNTR genotype, we compared their mean performance to investigate the possible psychogenetic associations. Results: Body mass index and stimuli type showed significant interaction on error number (p = 0.045): subjects with normal body mass index made significantly less error as compared to under- and overweight subjects in incongruent trials. The 7-repeat allele carriers made tendentiously more errors than non-carriers. Normal weight people made less error - independently from their genotype -, while subjects with either low or high BMI carrying the 7-repeat allele made more errors compared to non-carriers. Conclusion: Under- and overweight subjects perform weaker where inhibition is necessary in the task. This may reflect their reactions to food-related situations. Orv Hetil. 2019; 160(39): 1554-1562.

Dopamine D4 Receptor-Selective Compounds Reveal Structure-Activity Relationships that Engender Agonist Efficacy.

The dopamine D4 receptor (D4R) plays important roles in cognition, attention, and decision making. Novel D4R-selective ligands have promise in medication development for neuropsychiatric conditions, including Alzheimer's disease and substance use disorders. To identify new D4R-selective ligands, and to understand the molecular determinants of agonist efficacy at D4R, we report a series of eighteen novel ligands based on the classical D4R agonist A-412997 (1, 2-(4-(pyridin-2-yl)piperidin-1-yl)- N-( m-tolyl)acetamide). Compounds were profiled using radioligand binding displacement assays, ß-arrestin recruitment assays, cyclic AMP inhibition assays, and molecular dynamics computational modeling. We identified several novel D4R-selective ( Ki ≤ 4.3 nM and >100-fold vs other D2-like receptors) compounds with diverse partial agonist and antagonist profiles, falling into three structural groups. These compounds highlight receptor-ligand interactions that control efficacy at D2-like receptors and may provide insights into targeted drug discovery, leading to a better understanding of the role of D4Rs in neuropsychiatric disorders.

Fear Memory Recall Potentiates Opiate Reward Sensitivity through Dissociable Dopamine D1 versus D4 Receptor-Dependent Memory Mechanisms in the Prefrontal Cortex.

Disturbances in prefrontal cortical (PFC) dopamine (DA) transmission are well established features of psychiatric disorders involving pathological memory processing, such as post-traumatic stress disorder and opioid addiction. Transmission through PFC DA D4 receptors (D4Rs) has been shown to potentiate the emotional salience of normally nonsalient emotional memories, whereas transmission through PFC DA D1 receptors (D1Rs) has been demonstrated to selectively block recall of reward- or aversion-related associative memories. In the present study, using a combination of fear conditioning and opiate reward conditioning in male rats, we examined the role of PFC D4/D1R signaling during the processing of fear-related memory acquisition and recall and subsequent sensitivity to opiate reward memory formation. We report that PFC D4R activation potentiates the salience of normally subthreshold fear conditioning memory cues and simultaneously potentiates the rewarding effects of systemic or intra-ventral tegmental area (VTA) morphine conditioning cues. In contrast, blocking the recall of salient fear memories with intra-PFC D1R activation, blocks the ability of fear memory recall to potentiate systemic or intra-VTA morphine place preference. These effects were dependent upon dissociable PFC phosphorylation states involving calcium-calmodulin-kinase II or extracellular signal-related kinase 1-2, following intra-PFC D4 or D1R activation, respectively. Together, these findings reveal new insights into how aberrant PFC DAergic transmission and associated downstream molecular signaling pathways may modulate fear-related emotional memory processing and concomitantly increase opioid addiction vulnerability.SIGNIFICANCE STATEMENT Post-traumatic stress disorder is highly comorbid with addiction. In this study, we use a translational model of fear memory conditioning to examine how transmission through dopamine D1 or D4 receptors, in the prefrontal cortex (PFC), may differentially control acquisition or recall of fear memories and how these mechanisms might regulate sensitivity to the rewarding effects of opioids. We demonstrate that PFC D4 activation not only controls the salience of fear memory acquisition, but potentiates the rewarding effects of opioids. In contrast, PFC D1 receptor activation blocks recall of fear memories and prevents potentiation of opioid reward effects. Together, these findings demonstrate novel PFC mechanisms that may account for how emotional memory disturbances might increase the addictive liability of opioid-class drugs.

The effects of buspirone on occupancy of dopamine receptors and the rat gambling task.

BACKGROUND: The dopamine D3 receptor (DRD3) has been proposed as a target for drug development for the treatment of addictive disorders. Recently, the anxiolytic buspirone has been shown to have affinity for DRD3 and DRD4, and interest in repurposing it for addictive disorders has grown. METHODS: Binding of [3H]-(+)-PHNO in the rat cerebellum and striatum was used to measure occupancy by buspirone of DRD3 or DRD2, respectively. Effects of buspirone in the rat gambling task (rGT) and the five-choice serial reaction time task (5-CSRTT) were examined. RESULTS: Buspirone occupied both the DRD2 and DRD3 at high doses and the DRD3, but not the DRD2, in the narrow dose range of 3 mg/kg. At 10 mg/kg, a disruption of performance on rGT was observed. All measures of performance on the rGT, except for perseverations, were affected at 3 mg/kg. On the 5-CSRTT, omissions were increased. Impairments in the rGT were not mimicked by the effects induced by satiation. Further, buspirone did not impair food-maintained responding under a progressive ratio schedule of reinforcement at any dose, suggesting that the effects of buspirone on the rGT cannot be explained by non-selective actions. CONCLUSIONS: Although buspirone had effects on the rGT at the dose that selectively occupied the DRD3, the effects found do not parallel those found in previous studies of the effects of selective DRD3 antagonists on the rGT. Thus, buspirone may impair performance on the rGT through actions at multiple receptor sites.

Inhibition of D4 Dopamine Receptors on Insulin Receptor Expression and Effect in Renal Proximal Tubule Cells.

BACKGROUND: Ion transport in the renal proximal tubule (RPT), which is increased in essential hypertension, is regulated by numerous hormones and humoral factors, including insulin and dopamine. Activation of dopamine receptor inhibits sodium reabsorption, whereas activation of insulin receptor increases sodium reabsorption in RPTs, and hyperinsulinemic animals and patients have defective renal dopaminergic system. We presume that there is an inhibition of D4 receptor on insulin receptor expression and effect, and the regulation is lost in spontaneously hypertensive rats (SHRs). METHODS AND RESULTS: Insulin receptor expression was determined by immunoblotting, and Na(+)-K(+)-ATPase activity was detected in both Wistar-Kyoto (WKY) and SHR RPT cells. Stimulation of D4 receptor with PD168077 decreased expression of insulin receptors, which was blocked in the presence of the calcium-channel blocker, nicardipine (10(-6) mol/L per 24 hours), in cell culture medium without calcium or in the presence of inositol 1,4,5-trisphosphate (IP3) receptor blocker (2-aminoethyl diphenylborinate [2-ADB]; 10(-6) mol/L per 24 hours), indicating that extracellular calcium entry and calcium release from the endoplasmic reticulum were involved in the signal pathway. Stimulation of the insulin receptor stimulated Na(+)-K(+)-ATPase activity, whereas pretreatment with PD168077 for 24 hours decreased the inhibitory effects of insulin receptor on Na(+)-K(+)-ATPase activity in WKY cells. However, in SHR cells, inhibition of D4 receptor on insulin receptor expression and effect were lost. CONCLUSIONS: Activation of D4 receptor inhibits insulin receptor expression in RPT cells from WKY rats. The aberrant inhibition of D4 receptor on insulin receptor expression and effect might be involved in the pathogenesis of essential hypertension.

Distinct Physiological Effects of Dopamine D4 Receptors on Prefrontal Cortical Pyramidal Neurons and Fast-Spiking Interneurons.

Dopamine D4 receptor (D4R), which is strongly linked to neuropsychiatric disorders, such as attention-deficit hyperactivity disorder and schizophrenia, is highly expressed in pyramidal neurons and GABAergic interneurons in prefrontal cortex (PFC). In this study, we examined the impact of D4R on the excitability of these 2 neuronal populations. We found that D4R activation decreased the frequency of spontaneous action potentials (sAPs) in PFC pyramidal neurons, whereas it induced a transient increase followed by a decrease of sAP frequency in PFC parvalbumin-positive (PV+) interneurons. D4R activation also induced distinct effects in both types of PFC neurons on spontaneous excitatory and inhibitory postsynaptic currents, which drive the generation of sAP. Moreover, dopamine substantially decreased sAP frequency in PFC pyramidal neurons, but markedly increased sAP frequency in PV+ interneurons, and both effects were partially mediated by D4R activation. In the phencyclidine model of schizophrenia, the decreasing effect of D4R on sAP frequency in both types of PFC neurons was attenuated, whereas the increasing effect of D4R on sAP in PV+ interneurons was intact. These results suggest that D4R activation elicits distinct effects on synaptically driven excitability in PFC projection neurons versus fast-spiking interneurons, which are differentially altered in neuropsychiatric disorder-related conditions.

Synthesis and receptor binding assay of indolin-2-one derivatives as dopamine D4 receptor ligands.

Five indolin-2-one derivatives bearing piperazinylbutyl side chains attached to the amide nitrogen were synthesized from 2-indolinone. 1-(4-Bromobutyl)-indolin-2-one was reacted with 1-piperazinecarboxaldehyde to form 1-(4-(4-formyl-1-piperazinyl)butyl)indolin-2-one (2). In the presence of H2SO4, the aldehyde moiety was removed from 1-(4-(4-formyl-1-piperazinyl)butyl)indolin-2-one and then 1-(4-(1-piperazinyl)butyl)indolin-2-one (3) was obtained, this compound was reacted with benzaldehyde derivatives to give the target compounds 4 a-e by N-alkylation reaction. The structures of the intermediates and the target compounds were characterized by 1H NMR, ESI-MS spectra and elemental analyses. In vitro receptor binding assays at D2, D3, D4 receptor subtypes of the target compounds were performed and the five compounds showed selectivity towards D2-like receptors. Among them, 1-(4-(4-(4-hydroxybenzy)-1-piperazinyl)butyl) indolin-2-one (4c) exhibited a remarkable affinity and selectivity to D4 receptor with K(i) value of 0.5 nM. The results indicated that 1-(4-(4-(4-hydroxybenzy)-1-piperazinyl)butyl)indolin-2-one might be a potential dopamine D4 receptor ligand.

Dopaminergic Polymorphisms, Academic Achievement, and Violent Delinquency.

Recent research in the field of educational psychology points to the salience of self-control in accounting for the variance in students' report card grades. At the same time, a novel empirical study from molecular genetics drawing on the National Longitudinal Study of Adolescent Health (Add Health) data has revealed that polymorphisms in three dopaminergic genes (dopamine transporter [DAT1], dopamine D2 receptor [DRD2], and dopamine D4 receptor [DRD4]) are also linked to adolescents' grade point averages (GPAs). Juxtaposing these two lines of research, the current study reanalyzed the Add Health genetic subsample to assess the relative effects of these dopaminergic genes and self-control on GPAs. The results showed that the effects of the latter were far stronger than those of the former. The interaction effects between the dopaminergic genes and a set of environmental factors on academic performance were also examined, producing findings that are aligned with the "social push hypothesis" in behavioral genetics. Finally, based on the criminological literature on the link between academic performance and delinquency, we tested whether dopaminergic effects on violent delinquency were mediated by GPAs. The results demonstrated that academic performance fully mediated the linkage between these genes and violent delinquency.

Epigenetic histone modification regulates developmental lead exposure induced hyperactivity in rats.

Lead (Pb) exposure was commonly considered as a high environmental risk factor for the development of attention-deficit/hyperactivity disorder (ADHD). However, the molecular basis of this pathological process still remains elusive. In light of the role of epigenetics in modulating the neurological disease and the causative environment, the alterations of histone modifications in the hippocampus of rats exposed by various doses of lead, along with concomitant behavioral deficits, were investigated in this study. According to the free and forced open field test, there showed that in a dosage-dependent manner, lead exposure could result in the increased locomotor activity of rats, that is, hyperactivity: a subtype of ADHD. Western blotting assays revealed that the levels of histone acetylation increased significantly in the hippocampus by chronic lead exposure, while no dramatic changes were detected in terms of expression yields of ADHD-related dopaminergic proteins, indicating that histone acetylation plays essential roles in this toxicant-involved pathogenesis. In addition, the increased level of histone acetylation might be attributed to the enzymatic activity of p300, a typical histone acetyltransferase, as the transcriptional level of p300 was significantly increased upon higher-dose Pb exposure. In summary, this study first discovered the epigenetic mechanism bridging the environmental influence (Pb) and the disease itself (ADHD) in the histone modification level, paving the way for the comprehensive understanding of ADHD's etiology and in further steps, establishing the therapy strategy of this widespread neurological disorder.

The role of dopamine D2, but not D3 or D4, receptor subtypes, in quinpirole-induced inhibition of the cardioaccelerator sympathetic outflow in pithed rats.

BACKGROUND AND PURPOSE: Quinpirole (a dopamine D2-like receptor agonist) inhibits the cardioaccelerator sympathetic outflow in pithed rats by sympathoinhibitory D2-like receptors. The present study was designed to identify pharmacologically the specific D2-like receptor subtypes (i.e. D2 , D3 and D4) involved in this sympathoinhibition by quinpirole. EXPERIMENTAL APPROACH: One hundred fourteen male Wistar rats were pithed, artificially ventilated with room air and prepared for either preganglionic spinal (C7-T1) stimulation of the cardioaccelerator sympathetic outflow (n = 102) or i.v. bolus injections of exogenous noradrenaline (n = 12). This approach resulted in frequency-dependent and dose-dependent tachycardic responses, respectively, as previously reported by our group. KEY RESULTS: I.v. continuous infusions of quinpirole (0.1-10 µg kg(-1) min(-1)), but not of saline (0.02 mL min(-1)), dose-dependently inhibited the sympathetically induced tachycardic responses. Moreover, the cardiac sympathoinhibition induced by 3 µg kg(-1) min(-1) quinpirole (which failed to affect the tachycardic responses to i.v. noradrenaline) was: (i) unchanged after i.v. injections of the antagonists SB-277011-A (D3 ; 100-300 µg kg(-1)) or L-745,870 (D4 ; 30-100 µg kg(-1)); and (ii) markedly blocked and abolished by, respectively, 100 and 300 µg kg(-1) of the D2 preferring receptor subtype antagonist L-741,626. These doses of antagonists, which did not affect per se the sympathetically induced tachycardic responses, were high enough to completely block their respective receptors. CONCLUSIONS AND IMPLICATIONS: The cardiac sympathoinhibition induced by 3 µg kg(-1) min(-1) quinpirole involves the dopamine D2 receptor subtype, with no evidence for the involvement of the D3 or D4 subtypes. This provides new evidence for understanding the modulation of the cardioaccelerator sympathetic outflow.

Irrational choice under uncertainty correlates with lower striatal D(2/3) receptor binding in rats.

Individual differences in dopamine (DA) signaling, including low striatal D(2/3) receptors, may increase vulnerability to substance abuse, although whether this phenotype confers susceptibility to nonchemical addictions is unclear. The degree to which people use "irrational" cognitive heuristics when choosing under uncertainty can determine whether they find gambling addictive. Given that dopaminergic projections to the striatum signal reward expectancy and modulate decision-making, individual differences in DA signaling could influence the extent of such biases. To test this hypothesis, we used a novel task to model biased, risk-averse decision-making in rats. Animals chose between a "safe" lever, which guaranteed delivery of the wager, or an "uncertain" lever, which delivered either double the wager or nothing with 50:50 odds. The bet size varied from one to three sugar pellets. Although the amount at stake did not alter the options' utility, a subgroup of "wager-sensitive" rats increased their preference for the safe lever as the bet size increased, akin to risk aversion. In contrast, wager-insensitive rats slightly preferred the uncertain option consistently. Amphetamine increased choice of the uncertain option in wager-sensitive, but not in wager-insensitive rats, whereas a D(2/3) receptor antagonist decreased uncertain lever choice in wager-insensitive rats alone. Micro-PET and autoradiography using [(11)C]raclopride confirmed a strong correlation between high wager sensitivity and low striatal D(2/3) receptor density. These data suggest that the propensity for biased decision-making under uncertainty is influenced by striatal D(2/3) receptor expression, and provide novel support for the hypothesis that susceptibility to chemical and behavioral addictions may share a common neurobiological basis.

Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine D3/D2 receptors.

Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D(3)/D(2) compound (1) led to a series of new piperazine derivatives having affinity to both dopamine D(3) and D(2) receptors. Several members of this group showed excellent pharmacokinetic and pharmacodynamic properties as demonstrated by outstanding activities in different antipsychotic tests. The most promising representative, 2m (cariprazine) had good absorption, excellent brain penetration and advantageous safety profile. Based on its successful clinical development we are looking forward to the NDA filing of cariprazine in 2012.

Potential serotonin 5-HT(1A) and dopamine D(4) receptor modulation of the discriminative stimulus effects of amphetamine in rats.

Activation of the dopaminergic system underlies the behavioral effects of (+)-amphetamine, and plays a major role in its discriminative stimulus properties. Although serotonin receptors modulate dopamine levels in the brain, and 5-HT(1A) and 5-HT(2) receptor agonists do not mimic (+)-amphetamine, pretreatment with 5-HT(2A/2C) agonists significantly potentiates the (+)-amphetamine cue. Further, 5-HT(2) antagonists do not modify the discriminative stimulus effect of (+)-amphetamine, but 5-HT(1A) antagonists have never been tested in (+)-amphetamine-trained rats. This study sought to characterize the effects of the 5-HT(1A) antagonist WAY 100635 on (+)-amphetamine-induced discriminative stimulus effects. Male Sprague-Dawley rats were trained in a two-lever, fixed ratio 50, food-reinforced task with (+)-amphetamine sulfate (1.0 mg/kg, i.p., 30 min pretreatment time) as the discriminative stimulus. Substitution and combination tests with WAY 100635 were then performed. WAY 100635 did not produce substitution in amphetamine-trained rats, but significantly increased behavioral disruption. In combination tests 0.4 and 5.4 mg/kg doses of WAY 100635 potentiated the amphetamine cue. We suggest that low doses of WAY 100635 potentiated the (+)-amphetamine cue by blockade of 5-HT(1A) receptors, but stimulation of the dopamine D(4) receptor by higher doses of WAY 100635 may be responsible for potentiation of amphetamine-induced behavioral sensitization. The high percentage of behavioral disruption in substitution tests might suggest that rats trained to discriminate (+)-amphetamine from saline show behavioral sensitization that is not detectable by the drug discrimination assay but may be expressed as hyperactivity and stereotypic behavior that disrupts operant behavior.

Effect of acute and continuous morphine treatment on transcription factor expression in subregions of the rat caudate putamen. Marked modulation by D4 receptor activation.

Acute administration of the dopamine D(4) receptor (D(4)R) agonist PD168,077 induces a down-regulation of the µ opioid receptor (MOR) in the striosomal compartment of the rat caudate putamen (CPu), suggesting a striosomal D(4)R/MOR receptor interaction in line with their high co-distribution in this brain subregion. The present work was designed to explore if a D(4)R/MOR receptor interaction also occurs in the modulation of the expression pattern of several transcription factors in striatal subregions that play a central role in drug addiction. Thus, c-Fos, FosB/ΔFosB and P-CREB immunoreactive profiles were quantified in the rat CPu after either acute or continuous (6-day) administration of morphine and/or PD168,077. Acute and continuous administration of morphine induced different patterns of expression of these transcription factors, effects that were time-course and region dependent and fully blocked by PD168,077 co-administration. Moreover, this effect of the D(4)R agonist was counteracted by the D(4)R antagonist L745,870. Interestingly, at some time-points, combined treatment with morphine and PD168,077 substantially increased c-Fos, FosB/ΔFosB and P-CREB expression. The results of this study give indications for a general antagonistic D(4)R/MOR receptor interaction at the level of transcription factors. The change in the transcription factor expression by D(4)R/MOR interactions in turn suggests a modulation of neuronal activity in the CPu that could be of relevance for drug addiction.

Synthesis of benzopyrano[3,4-c]pyridin-5-ones as dopamine D4 receptor ligands.

The dopamine D4 receptor is highly expressed in prefrontal cortex, hippocampus, amygdala, hypothalamus and is hypothesized to relate with the pathophysiology and pharmacotherapy of schizophrenia while its level in brain regions is much lower. To date, no specific ligand is available for the study of D4 receptor in vivo. In this study, we report the synthesis and in vitro receptor binding assay of three benzopyrano[3,4-c]pyridin-5-ones as potential dopamine D4 receptor ligands. These new compounds have higher affinity and selectivity toward dopamine D4 receptor and their K(i) values for D4 receptor are in the nanomolar (nM) range.

The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children's ADHD symptoms.

OBJECTIVE: Food additives can exacerbate ADHD symptoms and cause non-immunoglobulin E-dependent histamine release from circulating basophils. However, children vary in the extent to which their ADHD symptoms are exacerbated by the ingestion of food additives. The authors hypothesized that genetic polymorphisms affecting histamine degradation would explain the diversity of responses to additives. METHOD: In a double-blind, placebo-controlled crossover trial, challenges involving two food color additive and sodium benzoate (preservative) mixtures in a fruit drink were administered to a general community sample of 3-year-old children (N = 153) and 8/9-year-old children (N = 144). An aggregate ADHD symptom measure (based on teacher and parent blind ratings of behavior, blind direct observation of behavior in the classroom, and--for 8/9-year-old children only--a computerized measure of attention) was the main outcome variable. RESULTS: The adverse effect of food additives on ADHD symptoms was moderated by histamine degradation gene polymorphisms HNMT T939C and HNMT Thr105Ile in 3- and 8/9-year-old children and by a DAT1 polymorphism (short versus long) in 8/9-year-old children only. There was no evidence that polymorphisms in catecholamine genes COMT Val108Met, ADRA2A C1291G, and DRD4-rs7403703 moderated the effect on ADHD symptoms. CONCLUSIONS: Histamine may mediate the effects of food additives on ADHD symptoms, and variations in genes influencing the action of histamine may explain the inconsistency between previous studies. Genes influencing a range of neurotransmitter systems and their interplay with environmental factors, such as diet, need to be examined to understand genetic influences on ADHD symptoms.

Transmembrane segment five serines of the D4 dopamine receptor uniquely influence the interactions of dopamine, norepinephrine, and Ro10-4548.

Conserved serines of transmembrane segment (TM) five (TM5) are critical for the interactions of endogenous catecholamines with alpha(1)- and alpha(2)-adrenergic, beta(2)-adrenergic, and D1, D2, and D3 dopamine receptors. The unique high-affinity interaction of the D4 dopamine receptor subtype with both norepinephrine and dopamine, and the fact that TM5 serine interactions have never been studied for this receptor subtype, led us to investigate the interactions of ligands with D4 receptor TM5 serines. Serine-to-alanine mutations at positions 5.42 and 5.46 drastically decreased affinities of dopamine and norepinephrine for the D4 receptor. The D4-S5.43A receptor mutant had substantially reduced affinity for norepinephrine, but a modest loss of affinity for dopamine. In functional assays of cAMP accumulation, norephinephrine was unable to activate any of the mutant receptors, even though the agonist quinpirole displayed wild-type functional properties for all of them. Dopamine was unable to activate the S5.46A mutant and had reduced potency for the S5.43A mutant and reduced potency and efficacy for the S5.42A mutant. In contrast, Ro10-4548 [RAC-2'-2-hydroxy-3-4-(4-hydroxy-2-methoxyphenyl)-1-piperazinyl-propoxy-acetanilide], a catechol-like antagonist of the wild-type receptor unexpectedly functions as an agonist of the S5.43A mutant. Other noncatechol ligands had similar properties for mutant and wild-type receptors. This is the first example of a dopamine receptor point mutation selectively changing the receptor's interaction with a specific antagonist to that of an agonist, and together with other data, provides evidence, supported by molecular modeling, that catecholamine-type agonism is induced by different ligand-specific configurations of intermolecular H-bonds with the TM5 conserved serines.

Dopamine receptor D4 polymorphism predicts the effect of L-DOPA on gambling behavior.

BACKGROUND: There is ample evidence that a subgroup of Parkinson's disease patients who are treated with dopaminergic drugs develop certain behavioral addictions such as pathological gambling. The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between dopaminergic drug treatment and individual susceptibility factors. These are potentially of genetic origin, since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the dopamine receptor D4 (DRD4) gene. Using a pharmacogenetic approach, we investigated how variation in this gene modulates the impact of dopaminergic stimulation on gambling behavior in healthy subjects. METHODS: We administered 300 mg of L-dihydroxyphenylalanine (L-DOPA) or placebo to 200 healthy male subjects who were all genotyped for their DRD4 polymorphism. Subjects played a gambling task 60 minutes after L-DOPA administration. RESULTS: Without considering genetic information, L-DOPA administration did not lead to an increase in gambling propensity compared with placebo. As expected, however, an individual's DRD4 polymorphism accounted for variation in gambling behavior after the administration of L-DOPA. Subjects who carry at least one copy of the 7-repeat allele showed an increased gambling propensity after dopaminergic stimulation. CONCLUSIONS: These findings demonstrate that genetic variation in the DRD4 gene determines an individual's gambling behavior in response to a dopaminergic drug challenge. They may have implications for the treatment of Parkinson's disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior.

[(3)H]-YM-09151-2 binding sites in human brain postmortem.

The controversial and limited data on the distribution of dopamine (DA) receptors of type 4 (D(4)) in the human brain prompted us to explore their density and pharmacological characteristics in the prefrontal cortex, striatum and hippocampus, through a series of binding assays. Brain samples were taken during autopsy from seven subjects. Tissue homogenates were incubated with increasing concentration of [(3)H]-YM-09151-2, a D(2)-like receptor antagonist, and L-745,870 and/or sulpiride to define the non-specific binding, while PPAP was used to block sigma receptors. The results showed a low density of D(4) receptors in the hippocampus only, with a preponderance of D(2)/D(3) and sigma receptors in the prefrontal cortex and striatum. In conclusion, these findings underline that it is possible to label D(4) receptors by means of [(3)H]-YM-09151-2, provided that D(2), D(3) and sigma receptors are blocked.

Role of the neurokinin-1 receptors in ejaculation in anesthetized rats.

INTRODUCTION: Several lines of evidence indicate a role for substance P in the control of ejaculation, although its mode of action needs to be clarified. AIM: The effects and sites of action of a selective antagonist for the substance P-preferred receptor (neurokinin-1 receptor subtype; NK1) were investigated in a pharmacological model of ejaculation. METHODS: Ejaculation was induced in anesthetized rats by intracerebroventricular (i.c.v.) delivery of the dopamine D3 receptor preferring agonist 7-hydroxy-2-(di-N-propylamino)tetralin (7-OH-DPAT). The effects of the selective NK1 antagonist RP67580 on 7-OH-DPAT-induced ejaculation were measured following intraperitoneal (i.p.), i.c.v., or intrathecal (i.t.) (third lumbar spinal segment; L3) administration. MAIN OUTCOME MEASURES: Intraseminal vesicle pressure (SVP) and electromyogram of the bulbospongiosus muscle (BS) were recorded as physiological markers of emission and expulsion phases of ejaculation, respectively. RESULTS: Upon i.p., i.c.v., or i.t. administration, RP67580 significantly reduced the occurrence of ejaculation elicited by 7-OH-DPAT. A mild decrease in the occurrence of SVP and BS responses was observed in rats treated ip with RP67580, whereas only SVP responses were moderately affected following i.c.v. or i.t. administration. CONCLUSION: These results show the multilevel regulation of 7-OH-DPAT-induced ejaculation by NK1 receptors.