Effects Of Dopamine Antagonists Research Articles

The Acute Pharmacological Manipulation of Dopamine Receptors Modulates Judgment Bias in Japanese Quail.

We have studied the effects of dopamine antagonists and agonists on Japanese quail behavior in the spatial judgment task. Twenty-four Japanese quail hens were trained in the spatial discrimination task to approach the feeder placed in the rewarded location (Go response, feeder containing mealworms) and to not approach the punished location (No-Go response, empty feeder plus aversive sound). In a subsequent spatial judgment task, the proportion of Go responses as well as approach latencies to rewarded, punished, and three ambiguous locations (near-positive, middle, near-negative, all neither rewarded nor punished) were assessed in 20 quail hens that successfully mastered the discrimination task. In Experiment 1, each bird received five treatments (0.1 and 1.0 mg/kg of dopamine D1 receptor antagonist SCH 23390, 0.05 and 0.5 mg/kg of dopamine D2 receptor antagonist haloperidol, and saline control) in a different order, according to a Latin square design. All drugs were administered intramuscularly 15 min before the spatial judgment test, with 2 days break between the treatments. Both antagonists caused a significant dose-dependent increase in the approach latencies as well as a decrease in the proportion of Go responses. In Experiment 2, with the design analogous to Experiment 1, the hens received again five treatments (1.0 and 10.0 mg/kg of dopamine D1 receptor agonist SKF 38393, 1.0 and 10.0 mg/kg of dopamine D2 receptor agonist bromocriptine, and saline control), applied intramuscularly 2 h before the test. The agonists did not have any significant effect on approach latencies and the proportion of Go responses in the spatial judgment task, as compared to the saline control, except for 10.0 mg/kg SKF 38393, which caused a decrease in the proportion of Go responses. The approach latency and the proportion of Go responses were affected by the cue location in both experiments. Our data suggest that the dopamine D1 and D2 receptor blockade leads to a decrease in the reward expectation and the negative judgment of stimuli. The effect of dopamine receptor activation is less clear. The results reveal that dopamine receptor manipulation alters the evaluation of the reward and punishment in the spatial judgment task.

The Single Dose Cocaine Reinstatement of Lever‐Pressing Behavior in Rats is Explained by The Compulsion Zone Theory

The compulsion zone theory of the cocaine self‐administration paradigm states that lever‐pressing behavior is induced when cocaine levels fall to or below the satiety threshold. Single injections of cocaine are known to reinstate lever‐pressing in rats trained to self‐administer cocaine. We investigated whether this phenomenon can be explained by the compulsion zone theory. Male Sprague‐Dawley rats (n = 5) were trained to self‐administer cocaine i.v. on an FR‐1 schedule. Once trained, these rats were administered a single dose of cocaine (2 – 12 µmol/kg, i.v.) in four daily sessions per week, and the time to lever‐pressing, the number of presses and the duration of pressing were recorded. The latency from the start of an injection to the resumption of lever pressing increased with the cocaine dose and ranged from approximately 2 min at 2 µmol/kg to more than 15 min at 12 µmol/kg. The D1 dopamine receptor antagonist SCH23390 (10‐30 nmol/kg i.v.) decreased the latency to reinstatement of lever pressing, following a dose of 12 µmol/kg cocaine. The increasing latency to lever‐pressing is consistent with the increasingly higher cocaine levels taking longer to fall to the satiety threshold, while the lower doses are immediately within the compulsion zone. An antagonist‐induced elevation of the satiety threshold explains the reduced latency to reinstatement. The number and duration of lever presses may reflect the time that the cocaine levels are within the compulsion zone. The cocaine satiety threshold model explains the dose‐dependent delay in reinstatement of lever‐pressing behavior and the effect of dopamine antagonists.

Prolactin, metabolic and immune parameters in naïve subjects with a first episode of psychosis

BackgroundProlactin (Prl) is a pleiotropic hormone initially described for its regulation of lactation in mammals but later associated with metabolic and immune homeostasis, stress, inflammatory response and human behavior. Its regulation through dopamine receptors highlights its importance in psychiatry mostly because hyperprolactinemia is a common secondary side effect of dopamine antagonists. Despite its undeciphered patho-physiological mechanisms, hyperprolactinemia in naïve psychosis patients has been widely described. Its consequences might underlie the increased morbidity and early mortality found in naïve subjects as described in the general population where prolactin values have been correlated with inflammatory, immune and metabolic parameters. MethodsWe aimed to evaluate the correlation between prolactin values and other biochemical parameters (C-reactive Protein-CrP, blood cell count, lipid and hepatic profile, fasting glucose) in a cohort of first episode psychosis naïve subjects (N = 491) stratified by sex. Regression analyses with confounders were performed to evaluate the association. FindingsPrl displayed significant correlations with C-Reactive Protein (CrP), Low-Density Lipoprotein (LDL), Aspartate Transaminase (AST) for females and High-Density Lipoprotein (HDL) and eosinophil count for males. However, and despite previous specific sex correlations, significant associations were described for CrP, HDL, LDL, AST and ALT without sex interaction and despite confounders such as age, Body Mass Index or smoking status. ConclusionsOur results show a specific relation of Prl with immune and metabolic parameters describing a heterogeneous pattern. Our results suggest that prolactin might underlie the excess of morbidity and early mortality in naïve patients through a specific pathway.

Antagonists D1 and D2 of Dopamine Receptors Determine Different Mechanisms of Neuroprotective Action in the Frog Vestibular.

The high functional plasticity of the glutamatergic synapse of the vestibular epithelium is supported by a delicate balance of excitatory and inhibitory interactions. One of the peptides co-localized with acetylcholine (ACh) in the efferent fibers is dopamine. Using external perfusion of the synaptic zone and multiunit recording of an afferent fibers activity the effect of dopamine antagonists on the background firing rate of the semicircular canal sensory fibers was studied on the isolated frog vestibular. The present research revealed that the dopamine receptor antagonist (D1) SCH-23390 significantly reduced the level of background activity at high concentrations. In contrast, D2 antagonist eticlopride caused positive-negative answer of the background activity of the sensory fibers in dose-depending manner. The data confirm the hypothesis that dopamine, being tonic released from the efferent fibers, realizes neuroprotective inhibitory control over the afferent glutamatergic synapse activity in the vestibular epithelium via D1 and D2 receptors.

Tardive Dyskinesia: New Treatments Available.

Tardive dyskinesia (TD), the choreoathetoid movements of fingers, arms, legs, and trunk and irregular stereotypical movements of the mouth, face, and tongue, has been the scourge of antipsychotic medications since the approval of chlorpromazine. TD tends to occur late in treatment and sometimes remains after discontinuation of the antipsychotic medication. With the recent approval of two medications, valbenazine (Ingrezza®) and deutetrabenazine (Austedo®), there are now treatments for this disfiguring consequence of dopamine-blocking medications. The current article distinguishes the movement disorder adverse effects of dopamine antagonists, explains the putative mechanism of action, and describes how best to treat TD with the new vesicular monamine transporter 2 (VMAT2) medications now approved by the U.S. Food and Drug Administration. [Journal of Psychosocial Nursing and Mental Health Services, 57(5), 11-14.].

Tiapride prevents the aversive but not the rewarding effect induced by parabrachial electrical stimulation in a place preference task

The parabrachial complex has been related to the processing of both rewarding and aversive signals. This pontine area is activated after the gastrointestinal administration of rewarding nutrients, in taste aversion learning, and in response to the reinforcing and aversive effects of some drugs of abuse. Electrical stimulation of this region can induce, in different animals, preference or aversion behaviors towards a place in a rectangular three-chamber maze task. This study examined the effect of tiapride, a D2/D3 receptor antagonist, on the aversive or rewarding effects induced by electrical stimulation of the external lateral parabrachial subnucleus (NLPBe). As previously observed, administration of tiapride interrupted the aversive effect induced by NLPBe electrical stimulation. However, in contrast to the effects of dopamine antagonists on other rewarding systems, tiapride did not impair the place preference induced by NLPBe stimulation, an activation effect that is subject to tolerance. Tiapride administration also appeared to have no effect on the horizontal motor activity (crossings) of the electrically stimulated animals. We discuss the specific relevance of parabrachial reward with respect to other reinforcing brain components or systems, especially in relation to the preference effect of drugs of abuse, such as opiates, after dopamine antagonist administration.

Differential effects of dopamine antagonists infused to the medial preoptic area on the sexual behavior of female rats primed with estrogen and progesterone

Dopamine (DA) in the medial preoptic area (mPOA) is important for the control of appetitive aspects of sexual behavior in the female rat. Recently, following infusions of DA agonists to the mPOA of females primed with estradiol benzoate (EB) alone, we found that the ratio of D1R/D2R activity within the mPOA determines the expression of appetitive behaviors (Graham and Pfaus, 2010). To further the knowledge of this mechanism, the present experiments examined the effects of intra-mPOA infusions of selective DA receptor antagonists. Ovariectomized, sexually-experienced rats primed with EB and progesterone (P) were implanted bilaterally with cannulae aimed at the mPOA and infused with 4 doses (0, 0.25, 1.0 and 4.0μg) of the nonselective D1R/D2R antagonist flupenthixol (FLU), and selective D1R or D2R antagonists, SCH 23390 (SCH) or raclopride (RAC), respectively, in a randomized order prior to tests of sexual behavior in bilevel chambers. The high dose of FLU significantly decreased solicitations, hops and darts, and pacing behavior. The high dose of SCH also significantly decreased solicitations. In contrast, the high dose of RAC produced an increase in pacing, and a trend toward an increase in solicitations but no other effect on sexual behavior. These results reinforce the idea that the ratio of D1R/D2R activity within the mPOA of female rats is critical for the expression of appetitive behaviors, and further that this ratio is altered by P which shifts the DA effect to a predominantly facilitative D1R activation.

Remapping-like changes in place field activity through dopaminergic action

Event Abstract Back to Event Remapping-like changes in place field activity through dopaminergic action Moritz Von Heimendahl1* and Michael Brecht1 1 Humboldt Universität, Bernstein Center for Compuational Neuroscience, Germany The phenomenon of hippocampal remapping has received sustained attention ever since its discovery. Remapping is striking because usually, most place cells in the rodent hippocampus show stable response properties over weeks and more. However, strong changes in the environment lead to global remapping, whereby most place cells change their firing fields drastically or shut down altogether, while new, previously silent cells become active. While the kind of environmental cues that elicit remapping have been studied in detail, it is still unclear what kind of internal signal prompts the otherwise so stable place representations to change all at once. Dopamine is often discussed as a potential novelty signal and here we investigated the effects of dopamine agonists on place cell activity. To this end, we recorded the spatial response properties of pyramidal cells in the dorsal hippocampus of rats while they freely explored an environment. Systemic injection of the nonspecific dopamine agonist apomorphine, but not of saline, led to changes in place field locations of many cells, similar to changes observed in global remapping. In further experiments, the dose-dependence, role of the specific receptor subtypes, and the effect of dopamine antagonists were examined. The finding that dopaminergic action induces remapping-like place field changes shows that global remapping can occur in the absence of environmental changes. Pharmacological manipulation opens up new avenues to analyze the mechanisms underlying global remapping. Acknowledgements This work was supported by Humboldt Universität zu Berlin, the Bernstein Center for Computational Neuroscience Berlin, the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung) (Förderkennzeichen 01GQ1001A), Neurocure, and a European Research Council grant (M.B.). We thank Brigitte Geue and Undine Schneeweiss for technical assistance. Keywords: Dopamine, Hippocampus, remapping Conference: Bernstein Conference 2012, Munich, Germany, 12 Sep - 14 Sep, 2012. Presentation Type: Poster Topic: Learning, plasticity, memory Citation: Von Heimendahl M and Brecht M (2012). Remapping-like changes in place field activity through dopaminergic action. Front. Comput. Neurosci. Conference Abstract: Bernstein Conference 2012. doi: 10.3389/conf.fncom.2012.55.00199 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: 11 May 2012; Published Online: 12 Sep 2012. * Correspondence: Dr. Moritz Von Heimendahl, Humboldt Universität, Bernstein Center for Compuational Neuroscience, Berlin, 10115, Germany, moritz@heimendahl.net 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 Moritz Von Heimendahl Michael Brecht Google Moritz Von Heimendahl Michael Brecht Google Scholar Moritz Von Heimendahl Michael Brecht PubMed Moritz Von Heimendahl Michael Brecht 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 antagonistic effects of a series of analogues of oxiperomide and spiroxatrine measured behaviourally in the rodent.

The activity spectra of oxiperomide, spiroxatrine and analogues were determined in two experimental models of abnormal peri-oral movements (induced by intrastriatal dopamine and subcutaneously administered 2-(NN-dipropyl)amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (NN-diPr-5,6-diOHATN) in the guinea-pig), and in a stereotypy test (induced by subcutaneous apomorphine in the guinea-pig); the ability of the test compounds to induce catalepsy or catatonia in the rat was also determined. The parent compounds oxiperomide and spiroxatrine possessed optimal activity in all tests, although responses to the series of compounds allowed clear differentiation between an ability to antagonize the peri-oral movements (dopamine- or NN-di Pr-5,6-diOHATN induced) and an ability to antagonize apomorphine stereotypy. However, all compounds that antagonized the abnormal peri-oral movements also caused catalepsy/catatonia. The results are considered in terms of the selection of suitable agent(s) for the treatment of peri-oral dyskinesias.

Dopaminergic mechanisms of reinstatement of MDMA‐seeking behaviour in rats

Animal models of drug-seeking suggest that exposure to cues associated with self-administered drugs and drug primes might precipitate relapse via activation of central dopaminergic substrates. The effects of priming injections of dopamine and 5-HT agonists on drug-seeking and effects of dopamine antagonists on methylenedioxymethamphetamine (MDMA)-produced potentiation of drug-seeking following extinguished MDMA self-administration were examined. Drug-seeking was produced by exposure to a light stimulus that had been paired with self-administered MDMA infusions and this effect was potentiated by experimenter-administered injections of the dopamine D(2) -like receptor agonist, quinpirole, the indirect agonist, amphetamine and the uptake inhibitor, GBR 12909. Drug-seeking was not elicited by the dopamine D(1) -like receptor agonist, SKF 81297 or the non-selective agonist, apomorphine. The 5-HT receptor agonists DOI or mCPP also failed to elicit drug-seeking. The 5-HT uptake inhibitor, clomipramine, attenuated drug-seeking produced by the MDMA-associated stimulus but failed to alter the potentiated response produced by GBR 12909. The D(1) receptor antagonist, SCH 23390 or the D(2) receptor antagonist, eticlopride attenuated the potentiation of drug-seeking produced by MDMA. These data provide evidence of dopaminergic mechanisms in drug-seeking following extinction of MDMA self-administration. Because tissue levels of 5-HT were significantly decreased following MDMA self-administration, we suggest that MDMA begins to preferentially activate dopaminergic substrates to potentiate the drug-seeking response.

Stimulant effects of adenosine antagonists on operant behavior: differential actions of selective A2A and A1 antagonists

Adenosine A(2A) antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone. The present studies were undertaken to investigate the potential for rate-dependent stimulant effects of both selective and nonselective adenosine antagonists. Six drugs were tested: two nonselective adenosine antagonists (caffeine and theophylline), two adenosine A(1) antagonists (DPCPX and CPT), and two adenosine A(2A) antagonists (istradefylline (KW6002) and MSX-3). Two schedules of reinforcement were employed; a fixed interval 240-s (FI-240 sec) schedule was used to generate low baseline rates of responding and a fixed ratio 20 (FR20) schedule generated high rates. Caffeine and theophylline produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec schedule but decreasing responding on the FR20 schedule. The A(2A) antagonists MSX-3 and istradefylline increased FI-240 sec lever pressing but did not suppress FR20 lever pressing in the dose range tested. In fact, there was a tendency for istradefylline to increase FR20 responding at a moderate dose. A(1) antagonists failed to increase lever pressing rate, but DPCPX decreased FR20 responding at higher doses. These results suggest that adenosine A(2A) antagonists enhance operant response rates, but A(1) antagonists do not. The involvement of adenosine A(2A) receptors in regulating aspects of instrumental response output and behavioral activation may have implications for the treatment of effort-related psychiatric dysfunctions, such as psychomotor slowing and anergia in depression.

Pisa Syndrome During Amisulpride Treatment

Back to table of contents Previous article Next article LETTERFull AccessPisa Syndrome During Amisulpride TreatmentTien-Chun Li M.D.Hsiu-Wen Chiu R.N.Hung-Hui Liu M.D.,Tien-Chun Li M.D.Search for more papers by this authorHsiu-Wen Chiu R.N.Search for more papers by this authorHung-Hui Liu M.D.Search for more papers by this author,Published Online:1 Jul 2010https://doi.org/10.1176/jnp.2010.22.3.352.e27AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Pisa syndrome, a movement disorder characterized by tonic, sustained lateral flexion with slight posterior rotation of the trunk, was first reported in 1972. 1 It appeared mainly subsequent to typical antipsychotics. Rare cases have been recently reported with atypical antipsychotics, cholinesterase inhibitors, and valproic acid. 2 Amisulpride, an atypical antipsychotic, induced fewer movement disorders. To our knowledge, there have been no reports of amisulpride-induced Pisa syndrome in the literature. This report presents a case of amisulpride induced Pisa syndrome. Case ReportA 26-year-old man was diagnosed with schizophrenia 5 years ago without history of major operations, neurological disorders, or drug abuse. Initial laboratory studies, including thyroid function test and serum electrolyte, were within normal ranges. He had been treated with risperidone, 6 mg/day, for the previous 6 months. He was admitted for disorganized speech, auditory hallucination, and persecutory delusions. On the first day, risperidone, 6 mg/day, was prescribed. The risperidone was tapered and stopped within 2 days for inadequate control of symptoms, whereas amisulpride, 800 mg/day, and valproic acid, 1,000 mg/day, were added on the second day. Two weeks later, he was observed walking with a tilt toward the left. Valproic acid levels were normal, and a physical examination revealed sustained tonic flexion of the trunk to the left side with slight backward rotation. No neurological deficits or mental status changes were noted. The differential diagnosis of catatonic presentation was ruled out. Trihexyphenidyl, 15 mg/day, was prescribed for acute dystonia. Diphenylhydramine, 100 mg/day, was also prescribed, but the symptoms did not improve after 1 week. Pisa syndrome was highly suspected, and amisulpride was tapered and stopped. Quetiapine was cross titrated to 800 mg/day to control his psychotic symptoms. The symptoms gradually resolved within 12 days.Discussion The incidence rates of Pisa syndrome were poorly established and seemed to be low. In 1991, a study by Yassa et al. 3 reported a rate of 8.3%. Similarly, a German study showed a lower rate of 0.037% in 2000. 4 It occurred mostly during the first month of treatment and responded to the discontinuation of antipsychotics. 5 In our case, it developed after 2 weeks of amisulpride administration and resolved with dose reduction. Risk factors were female gender, old age, organic brain disorder, and typical antipsychotics. 4 Our patient was a young man without organic brain disorder. The clinical characteristics suggested that the underlying pathophysiology might be drug-related. The pathophysiology was controversial. The common hypothesis was dopaminergic-cholinergic imbalance, an excess of cholinergic neurotransmission, and a decrease of dopaminergic neurotransmission. 6 Different antipsychotics had varying degrees of cholinergic and dopamine antagonistic effects. In our case, tapering off risperidone and switching to amisulpride resulted in this imbalance. Thus, switching of antipsychotics should be performed gradually, especially when the former antipsychotic has potent effects. The most effective treatment was either reduction or discontinuation of current medications. Delayed treatment may harm the rehabilitation of patients. Early detection of these symptoms would improve the patient’s quality of life even more. Department of Psychiatry, Beitou Armed Forces Hospital, Taipei, Taiwan

Interactions between adenosine and dopamine receptor antagonists with different selectivity profiles: Effects on locomotor activity

Forebrain dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation. Adenosine A 2A antagonists reverse many of the behavioral effects of DA antagonists, and A 2A receptors are co-localized with D 2 receptors on striatal medium spiny neurons. The present work was undertaken to determine if the ability of an A 2A antagonist, a non-selective adenosine antagonist, or an A 1 antagonist to reverse the locomotor effects of DA blockade in rats differed depending upon whether D 1 or D 2 family receptors were being antagonized. The adenosine antagonists MSX-3, caffeine, DPCPX and CPT were studied for their ability to reverse the locomotor suppression induced by the D 1 antagonist SCH 39166 (ecopipam) and the D 2 antagonist eticlopride. The D 1 and D 2 antagonists suppressed locomotion in all experiments. The adenosine A 2A receptor antagonist MSX-3 (0.5–2.0 mg/kg IP) significantly reversed the suppression of locomotion induced by eticlopride. The non-selective adenosine antagonist caffeine (5.0–20.0 mg/kg IP) also reversed the effect of eticlopride, though the effect was not as robust as that seen with MSX-3. The adenosine A 1 antagonists DPCPX (0.375–1.5 mg/kg) and CPT (3.0–12.0 mg/kg IP) were unable to reverse the locomotor impairment elicited by eticlopride. Furthermore, the attenuation of locomotion induced by the D 1 antagonist could only be reversed by the highest dose of MSX-3, but not by caffeine, DPCPX or CPT. DA and adenosine receptor antagonists interact in the regulation of locomotor activation, but the nature of this interaction appears to depend upon the receptor selectivity profiles of the specific drugs being tested.

Effects of dopamine antagonists on drug cue-induced reinstatement of nicotine-seeking behavior in rats

Dopaminergic neurotransmission has been implicated in associative learning processes related to drugs of abuse. However, it is not clear whether blockade of activation of dopamine receptors alters conditioned incentive properties of nicotine-associated cues. Using a response-reinstatement procedure, this study examined the effects of antagonists selective for the D1 and the D2 subtypes of dopamine receptors on cue-induced reinstatement of nicotine-seeking behavior. Male Sprague-Dawley rats were trained in 30 daily 1 h sessions to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed ratio 5 schedule and associate a conditioned stimulus (cue) with each nicotine delivery. After extinction of responding by withholding nicotine (saline substitution) and its cue, the reinstatement tests were conducted following subcutaneous administration of a D1 antagonist SCH23390 (0, 5, 10, 30 microg/kg) or a D2 antagonist eticlopride (0, 5, 10, 30 microg/kg) in different groups of animals. Both SCH23390 and eticlopride significantly attenuated the magnitude of cue-elicited reinstatement of nicotine-seeking responding. These results indicate that activation of dopaminergic D1 and D2 receptors may play a role in mediating the conditioned motivational effects of nicotine-associated cues as measured in the response-reinstatement procedure. These findings suggest that manipulation of dopaminergic neurotransmission at D1 and/or D2 receptors may prove to be a potential target for the development of pharmacotherapy for prevention of environmental nicotine cue-triggered smoking relapse.

Effects of dopamine antagonists on methamphetamine-induced dopamine release in high and low alcohol preference rats

The authors have previously shown that high alcohol preference rats (HAP) have a significantly higher sensitivity than low alcohol preference rats (LAP) for methamphetamine (MAP). In this study, changes in dopamine and serotonin release induced by MAP (1 mg/kg, intraperitoneally) after pre-treatment with D1 and D2 receptor antagonists were examined in the striatum of rats with different alcohol preferences to elucidate differences in receptor levels between the two rat strains. D1 receptor antagonist SCH23390 or D2 receptor antagonist haloperidol were administrated intracerebroventricularly 10 min before MAP stimulation. This study investigated the effect of methamphetamine-induced dopamine and serotonin release in striatum using microdialysis of freely moving rats coupled to ECD-HPLC. With haloperidol treatment both strains of rats showed a significantly greater maximum increase on MAP-induced dopamine release compared with respective control rats. However, after SCH23390 treatment only HAP rats showed a significantly greater increase in dopamine release compared with controls. SCH23390 blocks mainly D1 receptors only in the post-synaptic membrane, whereas haloperidol blocks D2 receptors in both the pre-synaptic and post-synaptic membranes. The MAP-induced increase in dopamine release following haloperidol pre-treatment was greater than SCH23390 pre-treatment in both strains. This result indicates that D2 receptors (autoreceptors) in the pre-synaptic membrane were blocked, leading to the elimination of the feedback function that regulates dopamine release. These data suggested that alcohol preference is associated with the action of MAP, and the dopaminergic mechanism, specifically the D1 system in the striatum, might have a different pathway dependent on alcohol preference.

Reproductive cycle in female Waigieu seaperch ( Psammoperca waigiensis) reared under different salinity levels and the effects of dopamine antagonist on steroid hormone levels

Waigieu seaperch ( Psammoperca waigiensis) is a tropical marine finfish species, which may inhabit wide range of salinity during the entire life cycle. Regardless of the wide salinity tolerance, little is known about how salinity may influence the reproductive endocrinology of this important tropical species. In the present study, we investigated the seasonal variations in steroid hormone levels, oocyte maturation (OM) and ovulation in fish reared under different salinity levels. In addition, we investigated the effects a dopamine antagonist (domperidone: DOM) during the peak spawning period. Mature brood fish at 3 years old were cultured in four different salinities of 5, 10, 20 and 30‰ (part per thousand, ppt) from March to December 2007. Blood samples were collected monthly and key steroid hormones (testosterone (T), 11-ketotestosterone (11-KT), 17β-estradiol (E2) and progesterone (P)) levels in female fish plasma were analyzed using enzyme immunoassay method. OM, ovulation and several reproductive performance indexes were evaluated twice per month during the breeding season. Plasma hormone analysis showed significant differences in fish groups cultured in different salinities during the seasonal cycle. The gonadosomatic index (GSI) gradually increased from March, peaking in July at 10 and 30‰, and then decreased thereafter until December. Plasma steroid levels (E2, T, 11-KT and P) were observed in variable concentrations during the spawning period and showed monthly fluctuations that were apparently salinity dependent during on and off-seasons. Interestingly, 11-KT levels were found in small amounts in female fish and peaked in September at salinities of 10 and 20‰. DOM exposure produced significant differences in steroid hormone levels that were apparently dependent on dose, exposure time and the individual hormone. The present study indicated that holding Waigieu seaperch brood fish in different salinities during the breeding season produced significant effects on gonadal development and spawning incidences. The first spawning was observed on 8th of April for all groups after 100% water exchange at night. No significant differences of absolute and relative fecundity were observed between groups. Fish held at 10 ppt salinity during the breeding season spawned naturally, but maturity and spawning rates were reduced and no hatching was observed at the same salinity. Fish holding at 5‰ resulted to 100% mortality in brood fish. This indicated that salinity limits for oocyte maturation or ovulation and subsequent reduction in spawning, but embryonic development requires a higher salinity. The effect of salinity on embryo development and hatching rate suggests that in breeding season the brood fish spawned in areas where the salinity and other parameters are favorable.

Rats Self-Administer Intravenous Nicotine Delivered in a Novel Smoking-Relevant Procedure: Effects of Dopamine Antagonists

Attempts to explain tobacco addiction have relied heavily on the assumption that each cigarette puff delivers a bolus of nicotine to the brain within seconds. However, nicotine transits from lungs to brain much more gradually than once thought. Nevertheless, animal self-administration studies continue to use rapid (e.g., <3-s) infusions, as well as high unit doses of nicotine (e.g., 15-30 microg/kg/infusion), each equivalent to one to two cigarettes. Here, we report that nicotine is self-administered across a range of infusion durations (3, 30, 60, and 120 s) in rats. Slow (30-s) infusions were preferred over fast (nominal 3-s) infusions and were self-administered across several reinforcement schedules, at doses as low as 3 microg/kg/infusion, equivalent to one to two puffs. A conventional "fast/high" self-administration procedure (3 s-30 microg/kg/infusion) was then compared with our new "slow/low" procedure (30 s-3 microg/kg/infusion) in rats trained on a progressive ratio schedule and acutely challenged with dopamine receptor antagonists. The D(1) antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) (6-25 microg/kg s.c.) reduced intake in both procedures and in rats self-administering cocaine (0.5 mg/kg/infusion). The D(2) antagonists spiperone (3-30 microg/kg s.c.) and sulpiride (5-20 mg/kg i.p.) increased intake of fast/high nicotine and cocaine, but markedly reduced intake of slow/low nicotine. In a final test, in which only infusion speed was varied, an acute spiperone challenge produced the same differential effect on nicotine self-administration. In conclusion, our new slow/low nicotine self-administration procedure, designed to better mimic smoking-associated nicotine intake, is pharmacologically distinct from the conventional fast delivery/high-dose procedure.

Acute and Chronic Ethanol Modulate Dopamine D2‐Subtype Receptor Responses in Ventral Tegmental Area GABA Neurons

Ventral tegmental area (VTA) gamma-aminobutyric acid (GABA) neurons appear to be critical substrates underlying the acute and chronic effects of ethanol on dopamine (DA) neurotransmission in the mesocorticolimbic system implicated in drug reward. VTA GABA neuron firing rate is reduced by acute ethanol and enhanced by DA via D2 receptor activation. The objective of this study was to evaluate the role of D2 receptors in acute ethanol inhibition of VTA GABA neuron activity, as well as the adaptation of D2 receptors by chronic ethanol consumption. Using electrophysiological methods, we evaluated the effects of intraperitoneal ethanol on DA activation of VTA GABA neurons, the effects of DA antagonists on ethanol inhibition of their firing rate, as well as adaptations in firing rate following chronic ethanol consumption. Using single cell quantitative RT-polymerase chain reaction (PCR), we evaluated the expression of VTA GABA neuron D2 receptors in rats consuming ethanol versus pair-fed controls. In acute ethanol studies, microelectrophoretic activation of VTA GABA neurons by DA was inhibited by acute intraperitoneal ethanol, and intravenous administration of the D2 antagonist eticlopride blocked ethanol suppression of VTA GABA neuron firing rate. In chronic ethanol studies, while there were no signs of withdrawal at 24 hours, or significant adaptation in firing rate or response to acute ethanol, there was a significant down-regulation in the expression of D2 receptors in ethanol-consuming rats versus pair-fed controls. Inhibition of DA activation of VTA GABA neuron firing rate by ethanol, as well as eticlopride block of ethanol inhibition of VTA GABA neuron firing rate, suggests an interaction between ethanol and DA neurotransmission via D2 receptors, perhaps via enhanced DA release in the VTA subsequent to ethanol inhibition of GABA neurons. Down-regulation of VTA GABA neuron D2 receptors by chronic ethanol might result from persistent DA release onto GABA neurons.

Cannabinoid CB1 antagonists and dopamine antagonists produce different effects on a task involving response allocation and effort-related choice in food-seeking behavior

Cannabinoid CB1 antagonists/inverse agonists suppress food-motivated behaviors and are being evaluated as potential appetite suppressants. It has been suggested that the effects of CB1 antagonism on food motivation could be related to actions on mesolimbic dopamine (DA). If this were true, then the effects of interference with cannabinoid CB1 transmission should closely resemble the effects of interference with DA transmission. To directly compare the effects of DA antagonists with those of CB1 antagonists/inverse agonists, the present studies employed a concurrent lever-pressing/chow-intake procedure. With this task, interference with DA transmission shifts choice behavior such that lever pressing for a preferred food is decreased but chow intake is increased. Rats treated with IP injections of the DA D1 antagonist SCH39166 (ecopipam; 0.05-0.2 mg/kg) or the D2 antagonist eticlopride (0.025-0.1 mg/kg) showed substantial decreases in lever pressing and concomitant increases in chow consumption. In contrast, IP administration of the CB1 neutral antagonist AM4113 (4.0-16.0 mg/kg) or the CB1 antagonist/inverse agonist AM251 (2.0-8.0 mg/kg) decreased operant responding for pellets, but there was no corresponding increase in chow intake. These effects of CB1 antagonists/inverse agonists were similar to those produced by the appetite suppressant fenfluramine and by prefeeding. In contrast, low doses of DA antagonists leave primary food motivation intact, but shift behaviors toward food reinforcers that can be obtained with lower response costs. These results suggest that the effects of interference with CB1 transmission are readily distinguishable from those of reduced DA transmission.

Coordinated Accumbal Dopamine Release and Neural Activity Drive Goal-Directed Behavior

Intracranial self-stimulation (ICSS) activates the neural pathways that mediate reward, including dopaminergic terminal areas such as the nucleus accumbens (NAc). However, a direct role of dopamine in ICSS-mediated reward has been questioned. Here, simultaneous voltammetric and electrophysiological recordings from the same electrode reveal that, at certain sites, the onset of anticipatory dopamine surges and changes in neuronal firing patterns during ICSS are coincident, whereas sites lacking dopamine changes also lack patterned firing. Intrashell microinfusion of a D1, but not a D2 receptor antagonist, blocks ICSS. An iontophoresis approach was implemented to explore the effect of dopamine antagonists on firing patterns without altering behavior. Similar to the microinfusion experiments, ICSS-related firing is selectively attenuated following D1 receptor blockade. This work establishes a temporal link between anticipatory rises of dopamine and firing patterns in the NAc shell during ICSS and suggests that they may play a similar role with natural rewards and during drug self-administration.