Dopamine D2 Receptor Antagonist Raclopride Research Articles

Methamphetamine-induced lethal toxicity in zebrafish larvae.

The use of novel psychoactive substances has been steadily increasing in recent years. Given the rapid emergence of new substances and their constantly changing chemical structure, it is necessary to develop an efficient and expeditious approach to examine the mechanisms underlying their pharmacological and toxicological effects. Zebrafish (Danio rerio) have become a popular experimental subject for drug screening due to their amenability to high-throughput approaches. In this study, we used methamphetamine (METH) as an exemplary psychoactive substance to investigate its acute toxicity and possible underlying mechanisms in 5-day post-fertilization (5 dpf) zebrafish larvae. Lethality and toxicity of different concentrations of METH were examined in 5-dpf zebrafish larvae using a 96-well plate format. METH induced lethality in zebrafish larvae in a dose-dependent manner, which was associated with initial sympathomimetic activation, followed by cardiotoxicity. This was evidenced by significant heart rate increases at low doses, followed by decreased cardiac function at high doses and later time points. Levels of ammonia in the excreted water were increased but decreased internally. There was also evidence of seizures. Co-administration of the glutamate AMPA receptor antagonist GYKI-52466 and the dopamine D2 receptor antagonist raclopride significantly attenuated METH-induced lethality, suggesting that this lethality may be mediated synergistically or independently by glutamatergic and dopaminergic systems. These experiments provide a baseline for the study of the toxicity of related amphetamine compounds in 5-dpf zebrafish as well as a new high-throughput approach for investigating the toxicities of rapidly emerging new psychoactive substances.

Microinjection of the dopamine D2-receptor antagonist Raclopride into the medial preoptic area reduces REM sleep in lactating rats.

The medial preoptic area (mPOA) is a brain structure classically related to both non-REM (NREM) sleep and maternal behavior. Although the dopaminergic system is known to play a role in the control of the states of sleep and wakefulness, its effects within the mPOA on sleep are still not clear. Microinjection of the dopamine D2 receptor antagonist Raclopride into the mPOA has been shown to promote nursing postures in lactating dams with no effects on active maternal behavior. We hypothesized that the facilitation of nursing postures may be also associated with the promotion of NREM sleep. In order to test the hypothesis, Raclopride was microinjected into the mPOA and maternal behavior and sleep were assessed in lactating rats. The changes observed included a reduction of the latency to start nursing and an increase of the time to reunite the entire litter. Contrary to our hypothesis, NREM sleep was not affected by Raclopride. On the other hand, REM sleep and its transitional stage from NREM sleep, were significantly reduced by this pharmacological agent. These data suggest that dopamine D2 receptors within the mPOA are involved in the transition from NREM to REM sleep.

Improvement by methylphenidate and atomoxetine of social interaction deficits and recognition memory impairment in a mouse model of valproic acid-induced autism.

Rodents exposed prenatally to valproic acid (VPA) show autism-related behavioral abnormalities. We recently found that prenatal VPA exposure causes a reduction of dopaminergic activity in the prefrontal cortex of male, but not female, mice. This suggests that reduced prefrontal dopaminergic activity is associated with behavioral abnormalities in VPA-treated mice. In the present study, we examined whether the attention deficit/hyperactivity disorder drugs methylphenidate and atomoxetine (which increase dopamine release in the prefrontal cortex, but not striatum, in mice) could alleviate the behavioral abnormalities and changes in dendritic spine morphology induced by prenatal VPA exposure. We found that methylphenidate and atomoxetine increased prefrontal dopamine and noradrenaline release in VPA-treated mice. Acute treatment with methylphenidate or atomoxetine did not alleviate the social interaction deficits or recognition memory impairment in VPA-treated mice, while chronic treatment for 2 weeks did. Methylphenidate or atomoxetine for 2 weeks also improved the prenatal VPA-induced decrease in dendritic spine density in the prefrontal cortex. The effects of these drugs on behaviors and dendritic spine morphology were antagonized by concomitant treatment with the dopamine-D1 receptor antagonist SCH39166 or the dopamine-D2 receptor antagonist raclopride, but not by the α2 -adrenoceptor antagonist idazoxan. These findings suggest that chronic treatment with methylphenidate or atomoxetine improves abnormal behaviors and diminishes the reduction in spine density in VPA-treated mice via a prefrontal dopaminergic system-dependent mechanism. Autism Res 2016, 9: 926-939. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Synthesis of ([11C]carbonyl)raclopride and a comparison with ([11C]methyl)raclopride in a monkey PET study

IntroductionThe selective dopamine D2 receptor antagonist raclopride is usually labeled with carbon-11 using [11C]methyl iodide or [11C]methyl triflate for use in the quantification of dopamine D2 receptors in human brain. The aim of this work was to label raclopride at the carbonyl position using [11C]carbon monoxide chemistry and to compare ([11C]carbonyl)raclopride with ([11C]methyl)raclopride in non-human primate (NHP) using PET with regard to quantitative outcome measurement, metabolism of the labeled tracers and protein binding. MethodsPalladium-mediated carbonylation using [11C]carbon monoxide, 4,6-dichloro-2-iodo-3-methoxyphenol and (S)-(-)-2-aminomethyl-1-ethylpyrrolidine was applied in the synthesis of ([11C]carbonyl)raclopride. The reaction was performed at atmospheric pressure using xantphos as supporting phosphine ligand and palladium (π-cinnamyl) chloride dimer as the palladium source. ([11C]Methyl)raclopride was prepared by a previously published method. In the PET study, two female cynomolgus monkeys were used under gas anesthesia of sevoflurane. A dynamic PET measurement was performed for 63min with an HRRT PET camera after intravenous injection of ([11C]carbonyl)raclopride and ([11C]methyl)raclopride, respectively, during the same day. The order of injection of the two PET radioligands was changed between the two monkeys. The venous blood sample for measurement of protein binding was taken 3min prior to the PET scan. Binding potential (BPND) of the putamen and caudate was calculated with SRTM using the cerebellum as a reference region. ResultsThe target compound ([11C]carbonyl)raclopride was obtained with 50±5% decay corrected radiochemical yield and 95% radiochemical purity. The trapping efficiency (TE) of [11C]carbon monoxide was 65±5% and the specific radioactivity of the final product was 34±1GBq/μmol after a 50min of synthesis time. The radiochemical yield of ([11C]methyl)raclopride was in the same range as published previously i. e. 50–60% and specific radioactivity of those two batches which were used in the present PET study were 192GBq/μmol and 638GBq/μmol respectively after a synthesis time of 32min. In monkey PET studies, the percentage difference of BPND in putamen was <3% and that in caudate was <9% for the two radioligands. The plasma protein binding was 86.2±0.3% and 85.7±0.6% for ([11C]carbonyl)raclopride and ([11C]methyl)raclopride, respectively. The radiometabolite pattern was similar for both radioligands. ConclusionRaclopride was 11C-labeled at the carbonyl position using a palladium-mediated [11C]carbonylation reaction. A comparison between ([11C]carbonyl)raclopride and ([11C]methyl)raclopride with regard to quantitative PET outcome measurements, metabolism of radioligands and protein binding in monkey was performed. The monkey PET study with ([11C]carbonyl)raclopride showed similar results as for ([11C]methyl)raclopride. The PET studies were performed on 2 subjects.

Examination of the role of dopamine D2 and adrenergic α2 receptors in resurgence of food seeking

Resurgence refers to the reappearance of an extinguished operant behavior when reinforcement for an alternative behavior is also subsequently discontinued. Resurgence has been noted as a source of relapse to problem behavior following interventions involving alternative reinforcement, and has also been recently used as an animal model of relapse to drug seeking induced by reinforcement loss. Existing information about the neuropharmacology of resurgence is scarce, but suggests overlap between relapse observed in the resurgence model and relapse observed in reinstatement and renewal models. In the present experiment rats earned food pellets for pressing a target lever in Phase I. In Phase II lever pressing no longer produced food, but food was delivered for an alterative nose poke response. Finally in Phase III, neither response produced food deliveries. Prior to these Phase III sessions, separate groups of rats were injected with 0, 50, or 100μg/kg of the dopamine D2 receptor antagonist raclopride or 0, 20, or 40μg/kg of α2 agonist clonidine. Both doses of raclopride were effective in blocking resurgence, but there was evidence that the higher dose did so via motor rather than motivational impairment. Only the higher dose of clonidine blocked resurgence, but did so with no evidence of motor impairment. Raclopride significantly impacted extinction of the alternative poke at both doses tested, whereas clonidine had no effect at either dose. The results of the present study provide additional information about the neuropharmacology of resurgence, as well as additional evidence of overlap between resurgence, reinstatement, and renewal.

Effects of Blockade of Dopamine D2 Receptors on the Activity of the Nitrergic System of the Nucleus Accumbens in the Rat Brain

In vivo intracerebral microdialysis studies with high-performance liquid chromatography and electrochemical detection in Sprague–Dawley rats showed that administration of the dopamine D2 receptor antagonist raclopride (20 and 100 μM) into the nucleus accumbens did not alter the baseline extracellular citrulline level (a co-product of NO synthesis) in the nucleus accumbens. Administration of NMDA (100 μM), an NMDA glutamate receptor agonist, into the nucleus accumbens induced an increase in the extracellular citrulline level in this structure. Administration of 7-nitroindazole (0.5 mM), an inhibitor of the neuronal isoform of NO synthase, into the nucleus accumbens blocked this increase, while administration of raclopride (20 and 100 μM) into this structure decreased the increase. These data suggest that dopamine D2 receptors in the nucleus accumbens are involved in regulation of the extent of activation of neuronal NO synthase induced by local stimulation of NMDA glutamate receptors.

Opposing regulation of dopaminergic activity and exploratory motor behavior by forebrain and brainstem cholinergic circuits

Dopamine transmission is critical for exploratory motor behaviour. A key regulator is acetylcholine; forebrain acetylcholine regulates striatal dopamine release, whereas brainstem cholinergic inputs regulate the transition of dopamine neurons from tonic to burst firing modes. How these sources of cholinergic activity combine to control dopamine efflux and exploratory motor behaviour is unclear. Here we show that mice lacking total forebrain acetylcholine exhibit enhanced frequency-dependent striatal dopamine release and are hyperactive in a novel environment, whereas mice lacking rostral brainstem acetylcholine are hypoactive. Exploratory motor behaviour is normalized by the removal of both cholinergic sources. Involvement of dopamine in the exploratory motor phenotypes observed in these mutants is indicated by their altered sensitivity to the dopamine D2 receptor antagonist raclopride. These results support a model in which forebrain and brainstem cholinergic systems act in tandem to regulate striatal dopamine signalling for proper control of motor activity.

Raclopride lessens the ability of clozapine to suppress alcohol drinking in Syrian golden hamsters

Emerging evidence suggests that the atypical antipsychotic clozapine decreases alcohol consumption in patients with schizophrenia, while typical antipsychotics, all of which are potent dopamine (DA) D2 receptor antagonists, do not. We have proposed that clozapine, through its weak DA D2 receptor blocking action, coupled with its ability to potentiate noradrenergic and serotonergic activity, may ameliorate a dysfunction in the mesocorticolimbic DA reward circuitry that underlies alcohol use disorder in patients with schizophrenia. In prior studies, we have demonstrated that clozapine also decreases alcohol drinking in the Syrian golden hamster, but haloperidol does not. The purposes of the current study were: (1) to further assess the effect of clozapine (2 or 4 mg/kg/day, s.c.) on alcohol consumption in hamsters, using a continuous access, 2-bottle choice paradigm; and (2) to examine whether clozapine’s effect on alcohol drinking is affected by increasing its DA D2 blockade through adjunctive use of the potent DA D2 receptor antagonist raclopride (2, 4, or 6 mg/kg/day, s.c.). The major findings were: (1) clozapine suppressed both initiation and maintenance of alcohol drinking in hamsters; and (2) these effects of clozapine were lessened when raclopride was given adjunctively with clozapine. These data suggest that clozapine may limit alcohol drinking in the golden hamster (and possibly in patients with schizophrenia) in part because of its weak blockade of the DA D2 receptor.

Role of neurokinin-1 and dopamine receptors on the striatal methamphetamine-induced proliferation of new cells in mice

A neurotoxic dose of methamphetamine (METH) induces the loss of some striatal neurons. Interestingly, the METH-induced apoptosis in the striatum is immediately followed by the generation of new cells (cytogenesis). In the present study, we investigated the role of the neurokinin-1, dopamine D1 and D2 receptors on the METH-induced cytogenesis. To that end, male mice were given a single injection (30 mg/kg, ip) or a binge of METH (10 mg/kg, 4× at two-hour intervals, ip). BrdU (100 mg/kg, ip) was given 36 h after the last injection of METH. Newly generated cells were detected by immunohistochemistry and cell counts were performed using unbiased computerized stereology. Either single or binge exposure to METH resulted in the generation of new cells. The single optimized dose was used for subsequent mechanistic studies. Pretreatment with the dopamine D1 receptor antagonist SCH23390 (0.1 mg/kg, ip) 30 min prior to METH abrogated the METH-induced striatal cytogenesis. Pretreatment with the dopamine D2 receptor antagonist raclopride (1 mg/kg, ip) failed to affect this phenomenon. Finally, pretreatment with the neurokinin-1 receptor antagonist WIN 51,708 (5 mg/kg, ip) 30 min prior to METH abrogated the METH-induced cytogenesis. In conclusion, neurokinin-1 and dopamine D1 receptors are required for the METH-induced striatal cytogenesis while the D2 receptor is without effect.

Taste reward in rat models of obesity and gastric bypass surgery

Event Abstract Back to Event Taste reward in rat models of obesity and gastric bypass surgery András Hajnal1* 1 Penn State University, College of Medicine, Department Neural and Behavioral Sciences, and Surgery, The Milton S. Hershey Medical Center, United States Currently, the Roux-en-Y gastric bypass surgery (GBS) is the most effective treatment for morbid obesity and associated type 2 diabetes. We used behavioral, electrophysiological and pharmacological methods in genetic (OLETF and Zucker) and diet-induced obese (DIO) rats to test the hypothesis that overeating in obesity and the success of GBS in reducing appetite are related to altered taste reward. Compared to pair-fed sham-operated (SH) controls, obese GBS rats expressed reduced 24-h 2-bottle preference and decreased 10-s lick responses for sucrose (0.3-1.5M) compared to SH controls. A similar effect was noted for other sweet compounds but not for salty, sour or bitter tastants. In lean rats, GBS did not alter responses to any stimulus tested. Extracellular recordings from taste-responsive neurons of the pontine parabrachial nucleus revealed an overall reduced responsiveness and a right-ward shift in concentration-responses to oral sucrose in obese compared to lean rats. These effects were reversed by GBS. In addition, obese rats demonstrated increased sensitivity to dopamine D2 receptor antagonist raclopride in reducing sucrose intake, an effect that was also alleviated by GBS. As a potential underlying mechanism we investigated secretion of intestinal hormones glucagon-like peptide-1 (GLP-1) and peptide YY in patients and obese rats and found that GBS increased postprandial plasma levels of both peptides. One-week treatment with GLP-1 analogue Exendin-4 reduced sweet taste preferences in DIO rats similar to the effect of GBS. These findings confirm obesity-related alterations in taste and reward functions for sweet and demonstrate the ability of GBS to alleviate these impairments. The effects of GBS on taste likely contribute to changes in food preferences observed in GBS patients. An improved understanding of the underlying mechanisms could help in developing effective non-invasive treatments for obesity. This research is supported by NIH grant DK080899. Conference: IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010. Presentation Type: Oral Presentation Topic: Abstracts Citation: Hajnal A (2010). Taste reward in rat models of obesity and gastric bypass surgery. Front. Neurosci. Conference Abstract: IBRO International Workshop 2010. doi: 10.3389/conf.fnins.2010.10.00220 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 May 2010; Published Online: 04 May 2010. * Correspondence: András Hajnal, Penn State University, College of Medicine, Department Neural and Behavioral Sciences, and Surgery, The Milton S. Hershey Medical Center, Hershey, United States, ahajnal@psu.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers András Hajnal Google András Hajnal Google Scholar András Hajnal PubMed András Hajnal Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Dopamine D1 and D2 receptors in the nucleus accumbens core and shell mediate Pavlovian-instrumental transfer

Pavlovian stimuli previously paired with food can markedly elevate the rate of food-reinforced instrumental responding. This effect, termed Pavlovian-instrumental transfer (PIT), depends both on general activating and specific cueing properties of Pavlovian stimuli. Recent evidence suggests that the general activating properties of Pavlovian stimuli are mediated by mesoaccumbens dopamine systems; however, the role of NAC dopamine D1 and D2 receptors is still unknown. Here we examined the effects of a selective dopamine D1 and D2 receptor blockade in the shell and core subregion of the NAC on general PIT. Rats were trained to press a single lever for food, and the effect of a single Pavlovian stimulus previously associated with the same food on performance of that lever was measured in extinction. Results reveal that PIT, that is, the increase in instrumental responding during presentation of the Pavlovian stimulus, was reduced by microinjections of the dopamine D1 receptor antagonist SCH-23390 and, less pronounced, by microinjections of the dopamine D2 receptor antagonist raclopride into the NAC core or shell, respectively. Our data suggest that dopamine D1 and D2 receptors in the NAC core and shell mediate the general activating effects of Pavlovian stimuli on instrumental behavior.

Biomechanical and electromyogram characterization of neuroleptic-induced rigidity in the rat

Rodent models of Parkinson’s disease (PD) are usually assessed using measures of akinesia, but other important parkinsonian symptoms such as rigidity are only rarely quantified. This is in part due to technical difficulties in obtaining such measures in small animals. In the present study we developed quantitative methods to provide time-course assessment of the alternations of muscle tone of parkinsonian rats. A portable and miniature biomechanical stretching device was established to manually stretch the hindlimb of awake rats with muscle rigidity induced by dopamine D2-receptor antagonist raclopride (5 mg/kg, i.p.). From the measured angular displacement angle and reactive torque of sinusoidal stretches at five varied frequencies, viscoelastic components of the muscle tone can be derived. In addition, non-invasive multielectrode was applied to record the tonic and phasic components of the gastrocnemius muscle electromyogram (EMG). Our biomechanical measurements showed not only increase in stiffness (P<0.05) but also increase in viscous components (P<0.05) that matched the time course of increased amplitude of EMG activity (P<0.05). There was a significant positive correlation between all of these measures and akinesia, as measured by the conventional bar-test for catalepsy (with a correlation coefficient of 0.87 at stiffness, 0.92 at viscosity and 0.96 at amplitude of EMG). Phasic contraction counts (PCC) of voluntary EMG exhibited a significantly negative correlation with the bar test scores (correlation coefficient=−0.78). These results confirm that akinesia induced by D2-receptor blockade also induces a rigidity that shares many features with human PD. These novel techniques for quantifying biomechanical and electromyographic parameters provide objective assessment methods for investigating the time-course changes of abnormal muscle tone in rat models of PD that will be useful for evaluating novel treatments.

Topiramate augments the antipsychotic-like effect and cortical dopamine output of raclopride

Recent clinical studies have shown that the anticonvulsant drug topiramate may improve negative symptoms in schizophrenia when added to a stable regimen of neuroleptic medication. It has also been shown that addition of topiramate to neuroleptics might be beneficial in treatment-resistant schizophrenia. Clinically effective doses of antipsychotic drugs (APDs) have been found to suppress conditioned avoidance response behavior (CAR), a preclinical test of antipsychotic activity with high predictive validity, in rats. Therefore, we investigated the putative antipsychotic-like activity of topiramate when added to the selective dopamine (DA) D2 receptor antagonist raclopride, using the CAR model in the rat. Extrapyramidal side effect liability of the drug combination was evaluated in parallel by means of the catalepsy test. We also examined the effect of this drug treatment on DA release in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), using in vivo microdialysis in freely moving animals. Topiramate (40 mg/kg), while ineffective when given alone, significantly augmented the antipsychotic-like effect of raclopride (0.075 mg/kg) on CAR without any concomitant catalepsy. Addition of topiramate to rats treated with raclopride generated a large increase in DA output in the mPFC, whereas no additional effect on the raclopride-induced DA release in the NAC was obtained. These data support the adjunctive use of topiramate in schizophrenia to ameliorate negative symptoms and suggest that this treatment may increase the efficacy, but not the extrapyramidal side effect liability, of the APDs used.

Noradrenaline Reuptake Inhibition Enhances the Antipsychotic-like Effect of Raclopride and Potentiates D2-blockage–induced Dopamine Release in the Medial Prefrontal Cortex of the Rat

We have previously observed that addition of an α2-adrenoceptor antagonist to a selective dopamine (DA) D2 receptor antagonist enhances the antipsychotic-like effect of the D2 blocker and also selectively increases DA output in the medial prefrontal cortex (mPFC) in rats. These data also correlate well with previous clinical trials showing augmentation by an equivalent drug combination in schizophrenia. Since the selective noradrenaline reuptake inhibitor reboxetine was found to cause similar effects on the mesolimbocortical DA system as α2-adrenoceptor antagonists, the present study was undertaken to explore whether also reboxetine might augment the effect of the DA D2 receptor antagonist raclopride in the same preclinical model of antipsychotic activity, the conditioned avoidance response (CAR) test. We also investigated the effect of this combination in the catalepsy test for extrapyramidal side effect liability, as well as on DA output in the mPFC and the nucleus accumbens, respectively. Reboxetine (6 mg/kg, i.p.) significantly enhanced the suppressant effect of raclopride (0.1 mg/kg, s.c.) on CAR without affecting catalepsy. Administration of raclopride (0.1 mg/kg, s.c.) to rats pretreated with reboxetine (6 mg/kg, i.p.) resulted in a greatly enhanced effect on DA output in the mPFC but not in the nucleus accumbens when compared with raclopride alone. Consequently, these results suggest that noradrenaline reuptake inhibition may provide means of augmenting the efficacy of classical D2-antagonists in the treatment of schizophrenia, and, in principle, to generate an atypical antipsychotic drug profile.

DR4004, a putative 5-HT7 receptor antagonist, also has functional activity at the dopamine D2 receptor

The tetrahydrobenzindole, 2a-(4-(4-phenyl-1,2,3,6-tetrahydropyridyl)butyl)-2a,3,4,5-tetrahydrobenzo[cd]indol-2(1H)-one (DR4004) has been described as a highly selective antagonist for the 5-hydroxytryptamine7 (5-HT7) receptor [J. Med. Chem. 42 (1999) 533]. Consistent with original data, DR4004 bound to rat hypothalamic membranes with an affinity of 7.3±0.2 (pKi±S.E.M.) for the 5-HT7 receptor. However, competition binding studies showed that DR4004 had poor receptor selectivity with the following affinity profile; dopamine D2 receptor, α1-adrenoceptor ≥5-HT7 receptor>histamine H1 receptor, α2-adrenoceptor>dopamine D1 receptor>β-adrenoceptor, muscarinic and 5-HT2A/C receptors. In conscious rats DR4004 (1, 5 or 10 mg/kg i.p.) produced a dose-dependent hyperglycaemia and hypothermia, but the former was reduced by the dopamine D2 receptor antagonist raclopride. Another 5-HT7 receptor antagonist, (R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970) produced hypothermia but no hyperglycaemia. This study confirms that DR4004 has high affinity for the 5-HT7 receptor but suggests that dopamine D2 receptor activity contributes to some of the in vivo effects.

Local Dopaminergic Modulation of the Motor Activity Induced by N-methyl-D-aspartate Receptor Stimulation in the Ventral Hippocampus

Dopaminergic neurotransmission has been implicated in the motor activating effects induced by the local infusion of NMDA in the ventral hippocampus (VH). The nucleus accumbens and the ventral tegmental area (VTA) have been proposed to be the main loci where dopamine is acting as a positive modulator of the VH NMDA receptor-mediated motor activating effects. However, the existence of a relatively high dopamine innervation and dopamine receptor density in the VH suggests the possibility of local dopamine/NMDA receptor interactions. This hypothesis was tested by studying the effects of the bilateral local VH infusion of NMDA (0.05, 0.1, 0.5 and 1.0 microg/side), the dopamine D1/D5 receptor antagonist SCH 23390 (1 microg/side) and the dopamine D2 receptor antagonist raclopride (1 and 5 microg/side). Neither SCH 23390 nor raclopride induced any significant change in motor activity compared with the vehicle control group, but both compounds significantly antagonized the motor activation induced by NMDA. SCH 23390 (1 microg/side) was more potent that raclopride (minimal effective dose: 5 microg/side). These results demonstrate the existence of a strong tonic facilitating effect of dopamine, acting preferentially at dopamine D1/D5 receptors, on NMDA receptor-mediated effects in the VH.

Prepulse Inhibition Deficits and Perseverative Motor Patterns in Dopamine Transporter Knock-Out Mice: Differential Effects of D1 and D2 Receptor Antagonists

Dopamine is known to regulate several behavioral phenomena, including sensorimotor gating and aspects of motor activity. The roles of dopamine D1 and D2 receptors in these behaviors have been documented in the rat literature, but few reports exist on their role in mice. We used dopamine transporter (DAT) (-/-) mice to examine the behavioral consequences of a chronically hyperdopaminergic state, challenging them with the preferential dopamine D2 receptor antagonist raclopride and D1 receptor antagonist SCH23390. At baseline, DAT (-/-) mice exhibited deficient sensorimotor gating as measured by prepulse inhibition (PPI) of the startle response, exhibited nonfocal preservative patterns of locomotion, and were hyperactive in a novel environment. Pretreatment with raclopride significantly increased PPI in the DAT (-/-) mice, whereas SCH23390 had no significant effect. Blockade of D2 receptors did not affect the predominantly straight patterns of motor behavior produced by the DAT (-/-) mice, but antagonism of D1 receptors significantly attenuated the preservative patterns, producing more of a meandering behavior seen in the DAT (+/+) control mice. Both D1 and D2 receptor antagonists decreased the hyperactivity seen in the DAT (-/-) mice. These findings support the role of the D2, but not the D1, receptor in the modulation of PPI in mice. Furthermore, D1 receptor activation appears to be the critical substrate for the expression of preservative patterns of motor behavior, whereas both D1 and D2 receptors appear to regulate the amount of motor activity.

The effect of the dopamine D2 receptor antagonist raclopride on the pattern of licking microstructure induced by midazolam in the rat

The role of dopamine in the effects of midazolam on ingestive behaviour was investigated using microstructural analysis of licking behaviour in the rat. Midazolam (1.8 mg/kg i.p.) was administered alone or in combination with the dopamine D2 receptor antagonist raclopride (0.1 and 0.3 mg/kg i.p.). The effect on licking patterns during 60 s exposure to a range of concentrations of sucrose solution was recorded using an automated lickometer. Midazolam increased the total number of licks via an increase in mean bout duration, an effect consistent with the proposal that these drugs enhance palatability. Midazolam also decreased the intrabout lick rate, probably because of muscle relaxant effects. Pre-treatment with raclopride blocked midazolam-induced increases in mean bout duration, at doses that by themselves were ineffective, but did not reverse the decrease in intrabout lick rate. These data point to the interdependence of benzodiazepine and dopamine substrates in the mediation of palatability.

Enhancement of antipsychotic-like effects by combined treatment with the alpha1-adrenoceptor antagonist prazosin and the dopamine D2 receptor antagonist raclopride in rats.

Blockade of central alpha1-adrenoceptors has been implicated as a possible factor contributing to the atypical antipsychotic profile of clozapine. Thus, in the present study we examined the effects of concomitant alpha1-adrenoceptor and dopamine D2 receptor blockade on conditioned avoidance response performance, as an index of antipsychotic-like activity, and on the induction of catalepsy, as a test for extrapyramidal side effect liability, in rats. It was found that pretreatment with the alpha1-adrenoceptor antagonist prazosin (0.2mg kg(-1) s.c.) caused an enhancement of a suppression of conditioned avoidance response in the presence of the dopamine D2 receptor antagonist raclopride (0.05-0.20 mg kg(-1) s.c.). The effect was most prominent at a subthreshold dose of raclopride (0.05 mg kg(-1)). At these doses, prazosin or raclopride by themselves, or in combination, did not produce catalepsy. In addition, pretreatment with prazosin (0.2mgkg(-1) s.c.) did not alter the catalepsy produced by a higher dose of raclopride (1.0 mg kg(-1) s.c.). It is suggested that, in the presence of low dopamine D2 receptor occupancy, additional alpha1-adrenoceptor blockade might improve antipsychotic efficacy, and thereby improve the therapeutic window with regard to parkinsonism.

The role of catecholamines in desmopressin induced locomotor stimulation.

Central and peripheral administration of DDAVP increase locomotor activity in rats in doses that alter brain dopamine neurochemistry. In order to delineate the role of catecholamines in this behavioural effect of DDAVP, the effects of different catecholamine manipulating agents on DDAVP-induced locomotor stimulation were studied in rats. The catecholamine depleting agent reserpine (5 mg/kg), administered alone or together with the catecholamine synthesis inhibitor alpha-methyltyrosine (250 mg/kg), completely prevented the locomotor stimulatory effect of DDAVP. The dopamine D1 receptor antagonist Sch-23390 (0.01 and 0.03 mg/kg) significantly antagonized the DDAVP-induced locomotor stimulation when administered in the higher dose, that also produced a significant reduction of locomotor activity per se, whereas the dopamine D2 receptor antagonist raclopride (0.08 and 0.16 mg/kg) had no significant effect. The two dopamine blockers administered together produced a significant, dose-dependent reduction of DDAVP-induced locomotor stimulation, while controls were not significantly affected. Also the alpha-adrenoceptor antagonist phenoxybenzamine decreased the DDAVP-induced locomotor stimulation in a dose (20 mg/kg) that did not influence locomotor activity in controls, and, finally, administration of Sch-23390, raclopride and phenoxybenzamine antagonised the DDAVP-induced effect in a dose combination that failed to influence locomotor activity per se. In vivo microdialysis experiments in awake, freely moving rats indicated that DDAVP increases dopamine overflow in the nucleus accumbens, a brain area of importance for initiation of locomotor activity, by approximately 25%, as compared to baseline levels. Taken together, these results indicate that the central stimulatory action of DDAVP involves granula-mediated dopamine release and subsequent activation of dopamine D1 and D2 receptors, and that alpha-adrenoceptors possibly also are involved.