Selective Dopamine D2 Receptor Antagonist Research Articles

Search for novel antipsychotic drugs: dopamine forever?

During the history of antipsychotic medications, the dopamine D2 receptor has been the crucial main target of drug action. Typical antipsychotics, which dominated the first 25 years of antipsychotic treatment as well as atypical antipsychotics, medications of the last three decades, all retained dopamine D2 receptor antagonism as the basic mode of action. Whether the superior side-effect profile (fewer extrapyramidal symptoms) of atypical antipsychotic agents is due to their serotonin 5-HT2A receptor antagonist activity or to their looser binding to the dopamine D2 receptor is still a matter of debate. Brain imaging studies demonstrating a strong relationship between dopamine D2 receptor occupancy and clinical effects and side effects of antipsychotics gave fundamental support for a central role of dopamine D2 receptors in the pathology and therapy of schizophrenia. The clinical failure of alternative approaches lacking the D2 component, such as selective serotonin 5-HT2A and dopamine D4 receptor antagonists further pointed at the indispensable role of D2 antagonism. The recently developed atypical antipsychotic agent, aripiprazole, while preserving the predominant D2 action, introduced a new pharmacological approach: dopamine D2 receptor partial agonism. An appropriate degree of partial agonism presumably results in effective blockade of overstimulated dopamine D2 receptors and improvement in psychotic symptoms, while it prevents the induction of extrapyramidal side effects or secondary negative symptoms by avoiding complete silencing of dopaminergic transmission. In recent years, the glutamatergic hypothesis for the pathology of the disease has gradually gained acceptance. Beside theoretical considerations, this concept was initially fuelled by some successful trials with the glutamate NMDA receptor co-agonists glycine, D-cycloserine and D-serine on the negative symptoms of the disease. However, their efficacy was modest and these compounds were still applied as adjunct therapy to the standard D2 dopaminergic antipsychotics. The most recent and, perhaps, most promising ''challenge'' to the D2 centred therapy of schizophrenia has been the successful proof of concept trial with the selective metabotropic glutamatergic receptor mGlu2/mGlu3 agonist prodrug compound, LY2140023. However, confirmation of the clinical efficacy of the compound is still awaited, and it has been raised that the compound may eventually affect - though indirectly - dopaminergic mechanisms. It seems, despite several burial attempts and attractive alternative hypotheses and tremendous drug development efforts, the therapy of schizophrenia cannot - so far - detach itself from the dopaminergic system.

The dopamine D2 receptor antagonist sulpiride modulates striatal BOLD signal during the manipulation of information in working memory

RationaleDopamine (DA) plays an important role in working memory. However, the precise functions supported by different DA receptor subtypes in different neural regions remain unclear.ObjectiveThe present study used pharmacological, event-related fMRI to test the hypothesis that striatal dopamine is important for the manipulation of information in working memory.MethodsTwenty healthy human subjects were scanned twice, once after placebo and once after sulpiride 400 mg, a selective DA D2 receptor antagonist, while performing a verbal working memory task requiring different levels of manipulation.ResultsWhilst there was no overall effect of sulpiride on task-dependent activation, individual variation in sulpiride plasma levels predicted the effect of working memory manipulation on activation in the putamen, suggesting a dose-dependent effect of DA antagonism on a striatally based manipulation process. These effects occurred in the context of a drug-induced improvement in performance on trials requiring the manipulation of information in working memory but not on simple retrieval trials. No significant drug effects were observed in the prefrontal cortex.ConclusionsThese results support models of dopamine function that posit a ‘gating’ function for dopamine D2 receptors in the striatum, which enables the flexible updating and manipulation of information in working memory.

Dopamine D3 receptor antagonists: The quest for a potentially selective PET ligand. Part two: Lead optimization

The lead optimization process to identify new selective dopamine D3 receptor antagonists is reported. DMPK parameters and binding data suggest that selective D3 receptor antagonists as potential PET ligands might have been identified.

Delay of Ejaculation Induced by SB-277011, a Selective Dopamine D3 Receptor Antagonist, in the Rat

Dopamine (DA) plays a key role in different aspects of the male sexual response, including sexual motivation and arousal, penile erection, and ejaculation. The modalities of action of DA are however unclear, although the various DA receptors may differentially mediate the activity of DA in different aspects of the male sexual response. To clarify the role of DA D(3) receptors in the control of the male sexual response. The effects of a highly selective DA D(3) receptors antagonist (SB-277011; intraperitoneal) were tested in experimental paradigms exploring several aspects of the male sexual response in (i) anesthetized rats using 7-hydroxy-N,N-di-n-propylaminotetralin to induce ejaculation and (ii) conscious rats using sexual incentive motivation and mating tests. Physiological markers of erection and emission and expulsion phases of ejaculation were measured in anesthetized rats. Behavioral parameters of sexual incentive motivation and mating tests were quantified. In anesthetized rats, we found that SB-277011 specifically and dose-dependently inhibited the expulsion phase of ejaculation without impairing either emission phase or erection, and this resulted in delayed ejaculation. Administration of SB-277011 had no effect on the spontaneous preference that males displayed for sexually receptive females as shown in sexual incentive motivation test. Delayed ejaculation was confirmed when male rats were administered with the highest dose of SB-277011 (10 mg/kg) in mating test, where males were free to copulate with estrous females. In addition, the refractory period following ejaculation was lengthened in rats treated with SB-277011. As a whole, the present data demonstrate the specific and primary role of D(3) receptors in the expulsion phase of ejaculation and provide preclinical evidence for the investigation of the therapeutic potential of D(3) antagonism for treating premature ejaculation.

The preferential dopamine D3 receptor antagonist S33138 inhibits cocaine reward and cocaine-triggered relapse to drug-seeking behavior in rats

We have previously reported that selective dopamine (DA) D3 receptor antagonists are effective in a number of animal models of drug addiction, but not in intravenous drug self-administration, suggesting a limited ability to modify drug reward. In the present study, we evaluated the actions of S33138, a novel partially selective D3 receptor antagonist, in animal models relevant to drug addiction. S33138, at doses of 0.156 or 0.625mg/kg (i.p.), attenuated cocaine-enhanced brain-stimulation reward (BSR), and the highest dose tested (2.5mg/kg) produced a significant aversive-like rightward shift in BSR rate-frequency reward functions. Further, S33138 produced biphasic effects on cocaine self-administration, i.e., a moderate dose (2.5mg/kg, p.o.) increased, while a higher dose (5mg/kg, p.o.) inhibited, cocaine self-administration. The increase in cocaine self-administration likely reflects a compensatory response to a partial reduction in drug reward after S33138. In addition, S33138 (0.156–2.5mg/kg, p.o.) also dose-dependently inhibited cocaine-induced reinstatement of drug-seeking behavior. The reduction in cocaine-enhanced BSR and cocaine-triggered reinstatement produced by lower effective doses (e.g., 0.156 or 0.625mg/kg) of S33138 is unlikely due to impaired locomotion, as lower effective doses of S33138 decreased neither Ymax levels in the BSR paradigm, rotarod performance, nor locomotion. However, the higher doses (2.5 or 5mg/kg) of S33138 also significantly inhibited sucrose self-administration and rotarod performance, suggesting non-D3 receptor-mediated effects on non-drug reward and locomotion. These data suggest that lower doses of S33138 interacting essentially with D3 receptors have pharmacotherapeutic potential in treatment of cocaine addiction, while higher doses occupying D2 receptors may influence locomotion and non-drug reward.

Separately Administered Selective Dopamine D1 and D2 Antagonists do not Affect Performance Accuracy in a Conditional Response Task in Rats

Abstract The acute effects of separately administered selective dopamine D1 and D2 receptor antagonists–SCH 23390 and raclopride, respectively–on the performance of a conditional response task were tested in a preliminary (small group, n = 6) study in rats. The effects of four doses of each drug (SCH 23390: 0–0.1 mg/kg; raclopride: 0–0.4 mg/kg) were tested consecutively in the same rats, using blinded Latin square designs. The conditional response task was performed in T-maze using tactile discrimination stimuli and spatial responses. The number of errors was not affected by the dopamine antagonists. However, the average response latency was significantly increased after administration of the highest doses of SCH 23390 and raclopride compared to saline. it seems that antagonism at either D1 or D2 receptors alone is not sufficient to produce impairments in performance accuracy using the present conditional response task.

Selective Antagonism at Dopamine D3 Receptors as a Target for Drug Addiction Pharmacotherapy: A Review of Preclinical Evidence

The focal distribution of the dopamine (DA) D(3) receptor in brain regions implicated in emotional and cognitive functions has made this target a main focus of drug discovery efforts. This paper will review the most recent lines of research in support of the use of selective DA D(3) receptor antagonists for the pharmacotherapeutic management of drug addiction: (1) expression of the DA D(3) receptor in the rodent and human brain; (2) changes in expression of the DA D(3) receptor following exposure to drugs of abuse, and (3) efficacy of selective DA D(3) receptor antagonists in preclinical paradigms assessing the behavioral effects of drugs such as cocaine, nicotine, alcohol, methamphetamine, and heroin. This manuscript, however, will not review the effects of nonselective DA D(2)/D(3) receptor antagonists or partial D(3) receptor agonists. Growing evidence suggests that selective DA D(3) receptor antagonists do not affect the primary reinforcing effects of drugs of abuse, but rather seem to regulate the motivation to self-administer drugs under schedules of reinforcement that require an increase in work demand. In addition, selective antagonism at DA D(3) receptors appears to disrupt significantly the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior. These preclinical findings will be discussed in the context of translational research relevant to the design of early clinical trials and hypothesis testing in humans.

Responses of limbic and extrapyramidal substance P systems to nicotine treatment.

Neuropeptides are linked to the psychopathology of stimulants of abuse, principally through dopamine mechanisms. Substance P (SP) is one of these neuropeptides and is associated with both limbic and extrapyramidal dopaminergic pathways and likely contributes to the pharmacology of these stimulants. The effects of nicotine on these dopamine systems have also been extensively studied; however, its effects on the associated SP pathways have received little attention. In the present study, we elucidated the effects of nicotine treatment on limbic and extrapyramidal SP systems by measuring changes in associated SP tissue concentrations. Male Sprague-Dawley rats received (+/-)nicotine 4.0 mg/kg/day (0.8 mg/kg, intraperitoneally; five injections at 2-h intervals) in the presence or absence of selective dopamine D1 and D2 receptor antagonists or a nonselective nicotinic acetylcholine receptor antagonist. The nicotine treatment significantly but temporarily decreased substance P-like immunoreactivity (SPLI) content in the ventral tegmental area (VTA) and substantia nigra 12-18 h after drug exposure. The nicotine-mediated changes in SPLI were selectively blocked by pretreatment with mecamylamine as well as a dopamine D1, D2, or both receptor antagonists. Other brain areas that also selectively demonstrated nicotine-related declines in SPLI content included prefrontal cortex, the nucleus accumbens shell, and the very posterior caudate. These findings indicate that some limbic and basal ganglia SP systems are significantly affected by exposure to nicotine through processes mediated by nicotinic and dopaminergic receptors, suggesting a role for SP pathways in nicotine's limbic and extrapyramidal effects.

Selective dopamine D3 receptor antagonists. A decade of progress: 1997 – 2007

Background: A growing number of patent applications on dopamine (DA) D3 receptors have been filed over the last 10 years. The increased interest in this target correlates with evidence that implicates the DA D3 receptor in the control of drug-seeking behavior and in the pathophysiology of some impulse control disorders and schizophrenia. Objectives: This manuscript provides an overview of the most recent literature in support of the biologic rationale for the use of selective DA D3 receptor antagonists for neuropsychiatric indications, and reviews > 80 patents that reflect 10-year advances in the discovery of these compounds by pharmaceutical companies, national research institutes and academic groups. Methods: Analysis of > 100 primary literature and 80 patent references of the last 10 years. Conclusions: The recent synthesis and profiling of new highly potent and selective DA D3 receptor antagonists over the last 10 years has permitted the testing of these compounds in a wide range of preclinical animal models of neuropsychiatric diseases. Clinical trials have now been initiated and clinical proof-of-concept is expected in the forthcoming years.

S.01.03 Dopamine partial agonists – do they live up to their expectations?

Pramipexole (SND 919) is a dopamine D2 autoreceptor agonist which is structurally related to talipexole (B-HT 920), a potential antipsychotic agent. The aim of this study was to investigate the effects of pramipexole on the extracellular concentration of dopamine in vivo. Dopamine and its metabolites, 3,4-dihydrophenylacetic acid and homovanillic acid, were measured in the anterior striatum of freely moving rats by microdialysis and high-performance liquid chromatography with electrochemical detection. Pramipexole (30 and 100 μg/kg) caused long-lasting decreases in the extracellular concentrations of dopamine and its metabolites. Talipexole (30 μg/kg) produced similar effects. Sulpiride (5 mg/kg), a selective dopamine D2 antagonist, caused a transient increase in the concentration of dopamine and long-lasting increases in the concentrations of its metabolites; it also reversed the effects of pramipexole. SCH-23390 (100 μg/kg), a selective dopamine D1 receptor antagonist, caused a transient increase in the concentration of dopamine but did not affect the concentrations of the metabolites. SCH-23390 failed to reverse the effects of pramipexole. These results indicate that pramipexole reduces the extracellular concentrations of dopamine and its metabolites in vivo through a reversible interaction with the dopamine D2 receptor.

Development of conditioned place preference induced by intra-accumbens infusion of amphetamine is attenuated by co-infusion of dopamine D1 and D2 receptor antagonists

The present study investigated the role of dopamine receptors within the nucleus accumbens in place conditioning induced by d-amphetamine. Previous work has shown that conditioned place preference can be established by intra-accumbens infusion of amphetamine. The present study further examined whether bilateral co-infusion of the selective dopamine receptor antagonists with d-amphetamine into this region would disrupt the development of conditioned place preference induced by intra-accumbens amphetamine treatment. Bilateral infusions of d-amphetamine into the nucleus accumbens at the dose of 10 μg per side significantly induced conditioned place preference. At the tested doses of 1 μg and 10 μg, either the selective D1 dopamine receptor antagonist (SCH23390) or the selective D2 dopamine receptor antagonist (raclopride) infused with the high dose into the nucleus accumbens significantly blocked the development of conditioned place preference induced by intra-accumbens amphetamine treatment. Furthermore, the sole infusion of SCH23390 or raclopride into the nucleus accumbens produced little or no place conditioning effect. It is concluded that the dopamine D1 and D2 receptors in the nucleus accumbens are critically involved in the development of amphetamine induced conditioned place preference.

New fused benzazepine as selective D3 receptor antagonists. Synthesis and biological evaluation. Part 2: [g]-Fused and hetero-fused systems

The synthesis and the SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The new scaffolds of the [g]-fused and the hetero-fused tricyclic benzazepine are here reported together with their pharmacokinetic profile.

Selegilin Exerts Antidepressant-Like Effects During the Forced Swim Test in Adrenocorticotropic Hormone–Treated Rats

In the present study, we investigated the effect of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test after the administration of selegiline, a selective and irreversible monoamine oxidase (MAO)-B inhibitor. Single and repeated administration of selegiline significantly decreased the duration of immobility in normal rats. When selegiline was administered for 15 days, we observed a significant decrease in immobility in rats treated with ACTH for 14 days. The immobility-decreasing effect of selegiline was blocked by nafadotride, a selective dopamine D3–receptor antagonist in normal and ACTH-treated rats. Selegiline may be useful in an animal model of depressive conditions resistant to tricyclic antidepressant treatment via the dopamine D3receptor.

Effects of dopamine D4 receptor antagonist on spontaneous alternation in rats

BackgroundThe present study was a component of a series of studies scrutinising the neuroreceptor substrate of behavioural flexibility in a rat model. Spontaneous alternation paradigms model the natural tendency of rodents to spontaneously and flexibly shift between alternative spatial responses. In the study it was tested for the first time if the neurochemical substrate mediating spontaneous alternation behaviour includes the dopamine D4 receptor.MethodsThe acute effects of the highly selective dopamine D4 receptor antagonist L-745,870 on rats' performance in a spontaneous alternation paradigm in a T-maze were examined. The paradigm was a food-rewarded continuous trial procedure performed for 20 trials.ResultsThe spontaneous alternation rate was not affected by the doses of the drug administered (0.02 mg/kg; 0.2 mg/kg; 2 mg/kg), but the position bias of the group receiving the highest L-745,870 dose (2 mg/kg) was significantly increased compared to the group that received the lowest dose (0.02 mg/kg). No significant effects on position bias were found compared to saline. The drug did not increase response perseveration.ConclusionThe results show that the neural substrate mediating the spatial distribution of responses in the spontaneous alternation paradigm includes the D4 receptor. However, the statistically significant effect of L-745,870 on position bias was found comparing a high drug dose with a low drug dose, and not comparing the drug doses with saline. For the tested doses of L-745,870 the effect on position bias was not large enough to affect the alternation rate.

The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats.

We have previously reported that selective antagonism of brain D3 receptors by SB-277011A or NGB 2904 significantly attenuates cocaine- or nicotine-enhanced brain stimulation reward (BSR). In the present study, we investigated whether the selective D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 agonist BP-897 similarly reduce methamphetamine (METH)-enhanced BSR. Rats were trained to respond for rewarding electrical self-stimulation of the medial forebrain bundle. To assess the degree of drug-induced changes in BSR, a rate-frequency curve shift paradigm was used to measure brain-reward threshold (theta 0). METH (0.1-0.65 mg/kg, i.p.) dose-dependently lowered ( approximately 10-50%) BSR thresholds, producing an enhancement of BSR. Pretreatment with SB-277011A (12 mg/kg, but not 24 mg/kg, i.p.) significantly attenuated METH-enhanced BSR. NGB 2904 (0.1-1.0 mg/kg, but not 10 mg/kg) also attenuated METH-enhanced BSR. SB-277011A or NGB 2904 alone, at the doses tested, had no effect on BSR. Pretreatment with BP-897 (0.1-5 mg/kg) dose-dependently attenuated METH-enhanced BSR. However, when the dose was increased to 10 mg/kg, BP-897 shifted the stimulation-response curve to the right (inhibited BSR itself) in the presence or absence of METH. Selective antagonism of D3 receptors by SB-277011A or NGB 2904 attenuates METH-enhanced BSR in rats, while the METH-enhanced BSR attenuation produced by BP-897 may involve both D3 and non-D3 receptors. These findings support a potential use of selective D3 receptor antagonists for the treatment of METH addiction.

1,2,4-Triazol-3-yl-thiopropyl-tetrahydrobenzazepines: A Series of Potent and Selective Dopamine D3 Receptor Antagonists

The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.

Pharmacological actions of NGB 2904, a selective dopamine D3 receptor antagonist, in animal models of drug addiction.

As a continuation of our work with SB-277011A, we have examined the effects of another highly elective dopamine (DA) D3 receptor antagonist, N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904), in animal models of addiction. Our results indicate that by systemic administration, NGB 2904 inhibits intravenous cocaine self-administration maintained under a progressive-ratio (PR) reinforcement schedule, cocaine- or cocaine cue-induced reinstatement of cocaine-seeking behavior, and cocaine- or other addictive drug-enhanced brain stimulation reward (BSR). The action of NGB 2904 on PR cocaine self-administration was long-lasting (1-2 days) after a single injection, supporting its potential use in treatment of cocaine addiction. The effects of NGB 2904 in the BSR paradigm were dose-dependent for both NGB 2904 and cocaine; that is, only lower doses of NGB 2904 were effective, and their putative antiaddiction effect could be overcome by increasing the doses of cocaine or other addictive drugs. A dopamine-dependent mechanism is proposed to explain the effects of NGB 2904 on cocaine's actions in these animal models of drug addiction. The data reviewed in this paper suggest that NGB 2904 or other D3-selective antagonists may have potential in controlling motivation for drug-taking behavior or relapse to drug-seeking behavior, but may have a limited role in antagonizing the acute rewarding effects produced by cocaine or other addictive drugs. In addition, NGB 2904 may also act as a useful tool to study the role of D3 receptors in drug addiction.

L-Stepholidine increases the frequency of sEPSC via the activation of D1dopamine signaling pathway in rat prelimbic cortical neurons

To investigate the effect of l-stepholidine (SPD) on the frequency of spontaneous excitatory postsynaptic currents (sEPSC) in the pyramidal cells between layers V and VI in the prelimbic cortex (PL). A whole-cell patch clamp in rat brain slices was used. SPD significantly increased the frequency of sEPSC in a concentration-dependent manner. A selective D1 dopamine receptor antagonist SCH23390 blocked SPD-mediated effects, whereas the D1 agonist SKF38393, but not the D2/3 antagonist sulpiride, mimicked SPD-mediated increase in the frequency of sEPSC. Moreover, both protein kinase A (PKA) inhibitor N-(2- [p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide hydrochloride and protein kinase C (PKC) inhibitor chelerythrine attenuated the effect of SPD on sEPSC. SPD elicits its effect on the frequency of sEPSC on the PL pyramidal cells via presynaptic D1 receptors, and is dependent on PKA and PKC signaling pathways.

Pharmacological modulation of functional connectivity: the correlation structure underlying the phMRI response to d-amphetamine modified by selective dopamine D3 receptor antagonist SB277011A

Pharmacological MRI (phMRI) experiments utilise fMRI time series methods to map the central effect of pharmaceutical compounds. The typical univariate maps may, however, integrate the effects of several different neurotransmitter systems or underlying mechanisms. The results may thus be spatially and/or mechanistically nonspecific. Intersubject correlation analysis based on the phMRI response amplitude can more directly identify patterns of functional connectivity underlying the central effects of an acutely administered compound. In this article, we extend this approach to experiments where the effects of one compound in modulating the response to another are of interest. Specifically, we show a modulation of the correlation structure of a probe compound (d-amphetamine) by pretreatment with the selective dopamine D3 receptor antagonist SB277011A in the rat. The strongest modifications in the correlation patterns occurred in connection with the ventral tegmental area, the source of mesolimbic dopamine projections and a key substrate in the reward system.

Stimulation of dopamine receptors in the paraventricular nucleus of the hypothalamus of male rats induces penile erection and increases extra-cellular dopamine in the nucleus accumbens: Involvement of central oxytocin

The effect of a pro-erectile dose of apomorphine, a mixed dopamine receptor agonist, and of PD-168077 ( N-[4-(2-cyanophenyl)piperazin-1-ylmethyl]-3-methylbenzamide maleate), a selective dopamine D4 receptor agonist, injected into the paraventricular nucleus of the hypothalamus on the concentration of extra-cellular dopamine and its main metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the dialysate from the nucleus accumbens was studied in male rats. As expected, apomorphine (0.1 μg) and PD-168077 (0.1 μg) induced penile erection episodes, which occurred concomitantly to an increase in extra-cellular dopamine and DOPAC concentration in the dialysate from the shell of the nucleus accumbens, as measured by intracerebral microdialysis. When induced by apomorphine, these effects were reduced by 80% by raclopride, a selective D2/D3 receptor antagonist (1 μg) and only by 40–45% by L-745,870 (1 μg), a selective dopamine D4 receptor antagonist. When induced by PD-168077, these effects were reduced by more than 80% by L-745,870 (1 μg), but only by 35–40% by raclopride. Irrespective of the dopamine agonist used to induce penile erection, the pro-erectile effect and the concomitant increase in dopamine and DOPAC concentration in the nucleus accumbens dialysate were almost completely abolished by d(CH 2) 5Tyr(Me) 2-Orn 8-vasotocin(1 μg), a potent oxytocin receptor antagonist, given into the lateral ventricles. The present results suggest that stimulation of dopamine receptors (mainly of the D2 to D4 subtype) in the paraventricular nucleus induces the release of oxytocin in brain areas that influence the activity of mesolimbic dopaminergic neurons mediating the appetitive and reinforcing effects of sexual activity. This provides evidence for a role of oxytocin in neural circuits that integrate the activity of neural pathways controlling the consummatory aspects of sexual behaviour (e.g., penile erection) with those controlling sexual motivation and sexual arousal.