Effects of risperidone on glutamate receptor subtypes in developing rat brain

Levels of ionotropic glutamate (Glu) N-methyl-d-aspartic acid (NMDA), 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA), and kainic acid (KA) receptors in forebrain regions of juvenile rats (age 42 days) were quantified after 3 weeks of treatment with three different doses of risperidone (0.3, 1.0 and 3.0 mg/kg) and compared findings to those in adult rats treated with risperidone (3.0 mg/kg/day) previously. Risperidone (at 0.3 mg/kg/day) did not alter levels of three ionotropic Glu receptors in all brain regions examined. Risperidone (at 1.0 and 3.0 mg/kg/day) significantly decreased NMDA binding in caudate-putamen of juvenile and adult animals. In contrast, the same two doses of risperidone decreased NMDA receptors in nucleus accumbens of juveniles and not adults. Risperidone (at 1.0 and 3.0 mg/kg/day) increased AMPA receptors in medial prefrontal cortex and caudate-putamen of juvenile animals, whereas risperidone (at 3.0 mg/kg) increased AMPA receptors in caudate-putamen and hippocampus of adults. Kainate receptors were not altered by any dose of risperidone in any brain region examined in developing and mature animals. The findings indicate that risperidone exerts dose-dependent effects on Glu receptor subtypes in developing animals, and that Glu receptor responses to repeated administration of risperidone are different in juvenile animals than adults.     

Nicotine and epibatidine alter differently nomifensine-elevated dopamine output in the rat dorsal and ventral striatum

We studied the effects of nicotine and epibatidine given in combination with dopamine uptake inhibitor, nomifensine, on striatal extracellular dopamine and its metabolites by using brain microdialysis in freely moving rats. Nomifensine (3 mg/kg) elevated extracellular dopamine in the caudate-putamen, and clearly more in the nucleus accumbens. In the caudate-putamen, nicotine (0.5 mg/kg) and epibatidine (0.6 microg/kg but not 3.0 microg/kg) enhanced nomifensine's effect on dopamine. The effect of nomifensine on accumbal dopamine was enhanced by nicotine, but inhibited by epibatidine at 0.6 microg/kg. The larger dose of epibatidine had no effect. Thus, the effects of the smaller epibatidine dose (0.6 microg/kg) on the dopamine output in the caudate-putamen but not in the accumbens resemble those of nicotine 0.5 mg/kg. Discrepancies in the effects of epibatidine and nicotine are most probably due to differences in their affinities to nicotinic receptor subtypes regulating dopamine release. Further, different responses to low concentrations of epibatidine between the brain areas suggest that there are differences in the nicotinic regulation of nigrostriatal and mesolimbic dopaminergic pathways.     

In vitro and in vivo receptor binding and effects on monoamine turnover in rat brain regions of the novel antipsychotics risperidone and ocaperidone.

Risperidone and ocaperidone are new benzisoxazol antipsychotics with particularly beneficial effects in schizophrenia. We report a comprehensive study on the in vitro and in vivo receptor binding profile of the new compounds, compared with haloperidol, and on the drug effects on monoamine and metabolite levels in various brain areas. The in vitro receptor binding and monoamine uptake inhibition profiles, comprising 29 receptors and four monoamine uptake systems, revealed that ocaperidone and risperidone bound primarily, and with the highest affinity thus far reported, to serotonin 5HT2 receptors (Ki values of 0.14 and 0.12 nM, respectively). Further, the drugs bound at nanomolar concentrations to the following receptors (Ki values, in nM, for ocaperidone and risperidone, respectively): alpha 1-adrenergic (0.46 and 0.81), dopamine D2 (0.75 and 3.0), histamine H1 (1.6 and 2.1), and alpha 2-adrenergic (5.4 and 7.3). In contrast, haloperidol showed nanomolar affinity for D2 receptors (1.55) and haloperidol-sensitive sigma sites (0.84) only. The in vitro binding affinity of ocaperidone, risperidone, and haloperidol for D2 receptors was exactly the same when measured in membranes from rat striatum, nucleus accumbens, tuberculum olfactorium, and human kidney cells expressing the cloned human D2 receptor (long form). In vivo binding in rats, using intravenous administration of [3H]spiperone, revealed very potent occupation by ocaperidone and risperidone of 5HT2 receptors in the frontal cortex (ED50 of 0.04-0.03 mg/kg); in this respect, they were 6, 30, and 100 times more potent than ritanserin, haloperidol, and clozapine, respectively. Ocaperidone occupied D2 receptors in the striatum and the nucleus accumbens with similar potency as did haloperidol (ED50 of 0.14-0.16 mg/kg). Risperidone revealed biphasic inhibition curves in the latter brain areas, indicating that [3H] spiperone labeled both 5HT2 receptors (occupied by risperidone at less than 0.04 mg/kg) and D2 receptors (risperidone ED50 of approximately 1 mg/kg). In the tuberculum olfactorium, 5HT2 and D2 receptors were also distinguished with risperidone. The ED50 values for occupation of the latter were for ocaperidone and risperidone 2 times lower and for haloperidol 2 times higher than in the striatum. Ocaperidone, risperidone, and haloperidol readily increased the levels of the dopamine metabolites 3,4-dihydroxybenzene acetic acid and homovanillic acid in the striatum, the nucleus accumbens, the tuberculum olfactorium, and, to some extent, the frontal cortex. Dose-response curve shapes were markedly different; with ocaperidone maximal levels were reached at 0.16 mg/kg and maintained to 10 mg/kg; with risperidone the levels tended to increase continuously up to 10 mg/kg. Haloperidol produced dome-shaped curves (maximum at 0.16-0.63 mg/kg).(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparison of the effects of nicotine and epibatidine on the striatal extracellular dopamine

We compared the effects of nicotine and epibatidine on striatal extracellular dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), by microdialysis in freely moving rats. Nicotine (0.5 mg/kg) elevated dopamine in the caudate-putamen and somewhat more in the nucleus accumbens. Epibatidine at 0.3 microg/kg reduced, and at 0.6 and 1.0 microg/kg increased, dopamine in the caudate-putamen; 2.0 and 3.0 microg/kg had no effect. Accumbal dopamine epibatidine elevated only at 3.0 microg/kg. Thus, in contrast to nicotine, epibatidine increased dopamine output in the caudate-putamen at smaller doses than in the accumbens. Both epibatidine and nicotine enhanced accumbal dopamine metabolism clearly more than that in the caudate-putamen. Also epibatidine was found to elevate 5-hydroxyindoleacetic acid (5-HIAA) in the nucleus accumbens at smaller doses than in the caudate-putamen. Similarly to what has been reported concerning nicotine, the dose-response curve of epibatidine to increase the dopamine output in the caudate-putamen was bell-shaped and clearly differed from that in the accumbens. These findings indicate that the nicotinic mechanisms controlling dopamine release and metabolism in the nigrostriatal and mesolimbic dopaminergic pathways differ fundamentally.     

Effects of repeated risperidone exposure on serotonin receptor subtypes in developing rats

Risperidone is an atypical antipsychotic drug that is widely prescribed to young patients with different psychotic disorders. The long-term effects of this antipsychotic agent on neuronal receptors in developing brain remain unclear and require further investigation. In this study, we examined the effects of long-term treatment of risperidone on two serotonin receptor subtypes in brain regions of juvenile rat. Levels of 5-HT_1A and 5-HT_2A receptors in forebrain regions of juvenile rats were quantified after 3 weeks of treatment with three different doses of risperidone (0.3, 1.0 and 3.0 mg/kg). Findings were compared to previously reported changes in 5-HT receptors after risperidone treatment (3.0 mg/kg) in adult rat brain. The three doses of risperidone selectively and dose-dependently increased levels of 5-HT_1A receptors in medial–prefrontal and dorsolateral–frontal cortices of juvenile animals. The higher doses (1.0 and 3.0 mg/kg) of risperidone also increased 5-HT_1A receptor binding in hippocampal CA₁ region of juvenile but not adult rats. In contrast, the three doses of risperidone significantly reduced 5-HT_2A labeling in medial–prefrontal and dorsolateral–frontal cortices in juvenile as well as in adult animals in an equipotent fashion. 5-HT_1A and 5-HT_2A receptors in other forebrain regions were not altered by repeated risperidone treatment. These findings indicate that there are differential effects of risperidone on 5-HT_1A and 5-HT_2A receptors in juvenile animals, and that the 5-HT system in developing animals is more sensitive than adults to the long-term effects of risperidone.     

Acute administration of nicotine increases the in vivo extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat: Comparison with caudate-putamen

Using in vivo dialysis and voltammetry, the effect of acute administration of (−)-nicotine (0.8 mg/kg free base, s.c.) on extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid and ascorbic acid in the nucleus accumbens and caudate-putamen of chloral hydrateanaesthetised rats has been examined. Nicotine stimulated release of dopamine only in the nucleus accumbens, measured using dialysis. After a short time delay levels of 3,4-dihydroxyphenylacetic acid in both the nucleus accumbens and caudate-putamen also increased. In both regions, 5-hydroxyindoleacetic acid was unaffected by nicotine. Using voltammetry the effect of nicotine on extracellular levels of 3,4-dihydroxyphenylacetic acid and ascorbic acid was examined. An increase in 3,4 dihydroxyphenylacetic acid was observed in both regions after nicotine. This increase was blocked by pretreatment with the central nicotinic receptor antagonist mecamylamine (5 mg/kg). Nicotine increased the level of ascorbic acid in the nucleus accumbens and caudate-putamen; while in animals pretreated with mecamylamine, nicotine decreased levels of ascorbate.These results show that acute administration of nicotine stimulated release of dopamine in the nucleus accumbens and increased the levels of DOPAC and ascorbic acid in the nucleus accumbens and caudate-putamen. This effect is probably mediated by nicotinic receptors as it was antagonised by mecamylamine.     

Acute administration of nicotine increases the in vivo extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat: comparison with caudate-putamen

Using in vivo dialysis and voltammetry, the effect of acute administration of (−)-nicotine (0.8 mg/kg free base, s.c.) on extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid and ascorbic acid in the nucleus accumbens and caudate-putamen of chloral hydrateanaesthetised rats has been examined. Nicotine stimulated release of dopamine only in the nucleus accumbens, measured using dialysis. After a short time delay levels of 3,4-dihydroxyphenylacetic acid in both the nucleus accumbens and caudate-putamen also increased. In both regions, 5-hydroxyindoleacetic acid was unaffected by nicotine. Using voltammetry the effect of nicotine on extracellular levels of 3,4-dihydroxyphenylacetic acid and ascorbic acid was examined. An increase in 3,4 dihydroxyphenylacetic acid was observed in both regions after nicotine. This increase was blocked by pretreatment with the central nicotinic receptor antagonist mecamylamine (5 mg/kg). Nicotine increased the level of ascorbic acid in the nucleus accumbens and caudate-putamen; while in animals pretreated with mecamylamine, nicotine decreased levels of ascorbate.

These results show that acute administration of nicotine stimulated release of dopamine in the nucleus accumbens and increased the levels of DOPAC and ascorbic acid in the nucleus accumbens and caudate-putamen. This effect is probably mediated by nicotinic receptors as it was antagonised by mecamylamine.     

Effects of trimethyltin on dopaminergic and serotonergic function in the central nervous system

The effects of trimethyltin (TMT) administration on regional concentrations of dopamine (DA), serotonin (5-HT), and their metabolites were determined. Acute administration of 3 or 7 mg/kg TMT (as the chloride) to adult male Long-Evans rats caused alterations in both dopaminergic and serotonergic function in brain at 7 days posttreatment. Dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations were decreased in the nucleus accumbens of rats treated with 7 mg/kg, with a trend occurring with the 3-mg/kg dose group. Conversely, concentrations of DA or DOPAC were not altered in striatum, olfactory tubercle, septum, or amygdala/pyriform cortex. Administration of 3 mg/kg TMT decreased the concentration of serotonin in striatum and nucleus accumbens, and increased the concentration of 5-hydroxyindoleacetic acid (5-HIAA) in hippocampus. The 7-mg/kg dose resulted in increased concentrations of 5-HIAA in striatum, nucleus accumbens, septum, amygdala/pyriform cortex, and hippocampus, and also decreased the concentration of 5-HT only in amygdala/pyriform cortex. The ratio of 5-HIAA to 5-HT (an indirect estimate of serotonin turnover) was increased in all brain regions of rats treated with 7 mg/kg, and in nucleus accumbens and amygdala/pyriform cortex of rats treated with 3 mg/kg. Conversely, no alteration in the DOPAC to DA ratio was found in any region of brain in rats killed at 7 days, nor was there a change in dopamine receptors (as measured by [³H]spiperone binding) in rats treated with 7 mg/kg TMT and killed 7 days following exposure. Thus, the acute sequelae of TMT neurotoxicity appears to involve primarily serotonergic systems, and these effects may be related to the behavioral effects resulting from TMT administration.     

Pharmacological reactivity to cocaine in adult rats undernourished at perinatal age: behavioral and neurochemical correlates

The influence of neuronal alterations induced by early undernutrition on the stimulant effect of cocaine was assessed in adult rats submitted to a protein deprivation schedule at perinatal age. To evaluate the sensitization phenomenon induced by repeated cocaine administration, different groups of control (C) and deprived (D) rats received a daily injection of cocaine (5, 10 or 15 mg/kg, i.p.) for 16 days. Behavioral parameters were assessed every two days in an open-field. Dose-response curves obtained with different doses of cocaine used revealed a shift to the left in the locomotor activity curves of D rats compared to controls. Thus, D animals showed a clear behavioral sensitization to the lower dose of cocaine, whereas this phenomenon was only observed in C rats for the higher dose used. To correlate this differential development of sensitization with neurochemical parameters, we assessed extracellular dopamine (DA) levels in nucleus accumbens (core and shell) and in the dorsal caudate-putamen, using a microdialysis technique. A challenge with cocaine in cocaine pre-exposed animals produced a different increase in DA output only in nucleus accumbens "core" of D animals. Comparable DA levels were observed in nucleus accumbens shell and in dorsal caudate-putamen of both groups. These results demonstrate that D rats had a lower threshold developing a progressive behavioral sensitization following repeated cocaine administration, as well as higher responsiveness of the nucleus accumbens (core) expressed by increased DA release.     

Aripiprazole, a novel antipsychotic drug, preferentially increases dopamine release in the prefrontal cortex and hippocampus in rat brain

Aripiprazole,7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-carbostycil (OPC-14597), a novel atypical antipsychotic drug, is a dopamine D2 receptor partial agonist with functional 5-HT2A receptor antagonist, and 5-HT1A receptor partial agonist properties as well. Other atypical antipsychotic drugs, e.g. clozapine, but not typical antipsychotic drugs, e.g. haloperidol, produce significant increases in dopamine and acetylcholine release in the medial prefrontal cortex in rats, effects believed to be related to the ability to improve cognitive function. The increase in the medial prefrontal cortex dopamine release by the atypical antipsychotic drugs has been shown to be partially inhibited by N-[2[4-)2-methoxyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635), a selective 5-HT1A receptor antagonist. Aripiprazole, 0.1 and 0.3 mg/kg, significantly increased dopamine release in the hippocampus. Moreover, aripiprazole, 0.3 mg/kg, slightly but significantly increased dopamine release in the medial prefrontal cortex but not in the nucleus accumbens. These increases were significantly inhibited by WAY100635. By contrast, aripiprazole, 3.0 mg/kg and 10 mg/kg, significantly decreased dopamine release in the nucleus accumbens but not the medical prefrontal cortex. However, aripiprazole 10 mg/kg significantly decreased dopamine release in the both regions. Aripiprazole had no effect on acetylcholine release in the medial prefrontal cortex, hippocampus, or nucleus accumbens at any dose, except for 3.0 mg/kg, which decreased acetylcholine release in the nucleus accumbens only. Aripiprazole, 0.3 mg/kg, transiently potentiated haloperidol (0.1 mg/kg)-induced dopamine release in the medial prefrontal cortex but inhibited that in the nucleus accumbens. The present study demonstrated that aripiprazole, at low doses of 0.1 and 0.3 mg/kg, increases dopamine release in the medial prefrontal cortex and hippocampus. It also suggests that the function of both the medial prefrontal cortex and hippocampus may contribute to the ability of aripiprazole to improve negative symptom and cognition.     

Variations in the behavioral responses to apomorphine in different strains of rats

The present experiments compared patterns of locomotor activity during repeated acclimation sessions and determinations of locomotion and stereotypy elicited by administration of the direct dopamine receptor agonist apomorphine in five inbred strains of rats: the results suggest that each strain can be differentiated phenotypically according to these behavioral responses. Brown Norway rats demonstrated the greatest locomotion during acclimation sessions. Low doses of apomorphine (0.1 and 0.32mg/kg) produced a flat body posture in Lewis animals. A higher dose of apomorphine (1.0mg/kg) markedly increased locomotion in Fisher rats. Buffalo animals showed licking during control sessions and the greatest increase in gnawing at higher doses of apomorphine. DA rats were less responsive than the other strains of apomorphine. Between-strains autoradiographic determination of dopamine receptor densities revealed several differences in D1 receptors labeled by (3)H-SCH 23390 and D2/D3 receptors labeled by (125)I-NCQ 298 in the caudate-putamen and nucleus accumbens. However, the heterogeneity of dopamine receptor densities was not sufficient to explain the strain-specific behavioral responses. These experiments demonstrate variations in behavioral and neurochemical characteristics of inbred strains of rats which could be used to model genetically determined differences in dopamine-mediated behavioral responses.     

Increased levels of proneurotensin/neuromedin N mRNA in rat striatum and nucleus accumbens induced by 7-OH-DPAT and nafadotride.

The D3 dopamine receptor has been proposed as a potential antipsychotic site. In this study, the effects of the D3-preferring compounds 7-OH-DPAT and nafadotride on levels of proneurotensin/neuromedin N (proNT/N) were assessed. Adult, male, Sprague-Dawley rats were injected subcutaneously (s.c.) with the agonist 7-OH-DPAT (0.1 mg/kg) or antagonist nafadotride (1 mg/kg) at doses previously shown to produce negligible occupancy of D2 receptors in vivo. As a positive control, an additional group of animals was treated with haloperidol (3 mg/kg, s.c.). ProNT/N mRNA levels were determined by in situ hybridization. 7-OH-DPAT increased proNT/N mRNA in the nucleus accumbens shell. Nafadotride increased proNT/N mRNA levels in the nucleus accumbens shell and dorsomedial caudate nucleus to levels comparable to those produced by haloperidol. Nafadotride also increased proNT/N mRNA in the anterior and dorsal caudate but to a lesser extent than haloperidol. These data indicate that 7-OH-DPAT and nafadotride increase proNT/N mRNA levels in brain areas affected by antipsychotic drugs and suggest that the D3 receptor may regulate proNT/N mRNA expression in the nucleus accumbens shell.     

Biochemical evidence that the atypical antipsychotic drugs clozapine and risperidone block 5-HT(2C) receptors in vivo

Clozapine and risperidone are two atypical antipsychotic drugs which bind, among other receptors, to 5-HT(2C) receptor subtypes. They inhibit the basal inositol phosphate production in mammalian cells expressing rat or human 5-HT(2C) receptors. This biochemical effect is indicative of inverse agonist activity at these receptors. There is evidence that 5-HT(2C) receptors are involved in the control of the activity of central dopaminergic system. Therefore, the effects of clozapine (5 mg/kg ip), risperidone (0.08 mg/kg ip) and of the typical antipsychotic haloperidol (0.1 mg/kg ip) were studied on the extracellular concentration of dopamine (DA) in the nucleus accumbens of chloral hydrate-anesthetized rats, using intracerebral microdialysis. When injected alone, clozapine, risperidone and haloperidol caused only small variations in DA efflux. However, clozapine and risperidone completely prevented the inhibitory action of RO 60-0175 (1 mg/kg ip), a 5-HT(2C) receptor agonist, on DA release. On the other hand, haloperidol did not affect RO 60-0175-induced decrease in DA release. Taken together, these data indicate that clozapine and risperidone, unlike haloperidol, are capable of blocking 5-HT(2C) receptors in the nucleus accumbens. It is concluded that the experimental model presented in this study might represent a simple and useful in vivo biochemical method to test the effect of putative atypical antipsychotic drugs on 5-HT(2C) receptors.     

Chronic treatments with haloperidol and clozapine alter the level of NMDA-R1 mRNA in the rat brain: an in situ hybridization study

The aim of the present study was to examine the influence of 3-month administration of the typical neuroleptic haloperidol (1 mg/kg/day) and the atypical one clozapine (30 mg/kg/day) on the expression of the NMDA-R1 mRNA in different brain structures using in situ hybridization in rats. A long-term treatment with haloperidol decreased the NMDA-R1 mRNA level in intermediate and caudal parts of the caudate-putamen and in more caudally localized regions of parietal and frontal cortices, but increased it in the CA1 region of the hippocampus. No significant changes in the nucleus accumbens, insular cortex, CA3 and dentate gyrus of the hippocampus were found after haloperidol administration. Clozapine did not influence the NMDA-R1 mRNA expression in the hippocampus, as well as in the intermediate and caudal regions of the caudate-putamen, but significantly increased it in the rostral region of the latter structure, in the nucleus accumbens and insular cortex. The present study suggests that both these neuroleptics influence the expression of the mRNA of the NMDA-R1 subunit in brain structures which are thought to be important for development of psychotic symptoms.     

Evaluation of the histamine H1-antagonist-induced place preference in rats

The place preferences by some histamine H1 antagonists, such as tripelennamine, optical isomers of chlorpheniramine (dl-, d- and l-forms) and pyrilamine, in rats were evaluated with the conditioned place preference paradigm. In the present study, tripelennamine and all of the optical isomers of chlorpheniramine, but not pyrilamine, produced a significant place preference. The degree of the place preference induced by optical isomers of chlorpheniramine (6.0 mg/kg) did not correlate with the H1-antagonistic potency of these drugs, suggesting that H1-antagonist-induced place preferences are not mediated by H1-receptor blockade. The tripelennamine (3.0 mg/kg)- and dl-chlorpheniramine (6.0 mg/kg)-induced place preferences were completely abolished by pretreatment with the dopamine D1-receptor antagonist SCH23390 (0.05 mg/kg). Furthermore, the doses of H1 antagonists that induced a place preference significantly reduced the levels of DOPAC, which may be mediated by inhibition of dopamine uptake, in the limbic forebrain (including the nucleus accumbens and olfactory tubercle). These results suggest that some H1 antagonists induce rewarding effects, which may be mediated by the activation of dopamine D1 receptors, followed by the inhibition of dopamine uptake.     

Effects of amphetamine on serotoninergic and GABAergic expression of developing brain

Roles of age and withdrawal were explored in mechanisms underlying the action of amphetamine (Amph), by monitoring the serotonergic and GABAergic expression in key brain regions of the rat. Postnatal 21 and 60 day-old male rats were intraperitoneally injected with D-Amph, 5 mg/kg, or saline, three times daily for 14 days and then withdrawn from Amph for 0 or 14 days; these animals received single injections on day 15 (W0d) or day 29 (W14d). Following Amph injections, though both age groups exhibited hyperlocomotion, stereotypy and behavioral sensitization, the juvenile showed 100-300% longer latencies to reach and 30%-42% shorter duration of maximal behavioral scores than the adult from day 2-29. Immunocytochemical analysis revealed down-regulation of 42-76% in 5-hydroxytryptamine (HT) immunoreactive processes in motor and somatosensory cortices, and hippocampus of both ages after Amph exposure at W0d. At W14d, the 5-HT resembled saline-control in the Amph-treated juvenile, whereas remained weakened in the adult. By contrast, densities of GAD67 (glutamic acid decarboxylase)-boutons were up-regulated by 35-545% in the neocortical areas, nucleus accumbens, caudate-putamen and hippocampus of all Amph-administered rats. After 14 days withdrawal, the juvenile recovered the decreased 5-HT fibers, but not the increased GABAergic, indicating unique roles of the two systems in response to Amph.     

Dopamine D2 receptors and ingestive behavior: brainstem mediates inhibition of intraoral intake and accumbens mediates aversive taste behavior in male rats

RATIONALE: One of the factors that terminate the ingestion of an intraorally infused solution of sucrose may be an increase in the perceived aversiveness of its taste. OBJECTIVES: We tested the hypothesis that dopamine D(2), as opposed to D(1), receptors in the brainstem or nucleus accumbens inhibit intraoral intake by enhancing the aversiveness of the taste of the infused solution. METHODS: Male rats were infused intraorally with a 2 M sucrose solution (1 ml/min) and intake and the display of gapes and chin rubs, i.e. taste-related aversive behavior, was measured. Gapes and chin rubs were also measured in rats during and 40 s after brief intraoral infusion (1 ml/min during 20 s) of a 0.3 mM solution of quinine HCl. The full D(1) receptor agonist dihydrexidine (0.1-3.0 mg/kg) and antagonist SCH-23390 (0.03-0.1 mg/kg), the D(2) receptor agonist quinpirole (0.3 mg/kg) and antagonist raclopride (1.7 mg/kg) were injected IP. Quinpirole (14-55 microg) and raclopride (5 microg) were also infused into the fourth brain ventricle. In addition, quinpirole (2 or 10 microg) was infused into the shell region of the nucleus accumbens. RESULTS: IP dihydrexidine and quinpirole inhibited the intraoral intake of sucrose and pretreatment with raclopride, but (in the case of dihydrexidine) not SCH-23390, attenuated this effect. Injection of quinpirole into the fourth ventricle produced raclopride-reversible inhibition of intraoral intake but did not stimulate the display of gapes and chin rubs. Infusion of quinpirole into the shell region of the nucleus accumbens had the opposite effects. The intake of sucrose was suppressed by the addition of quinine HCl but this suppression was unaffected by dopamine agonist or antagonist treatment. CONCLUSIONS: It is suggested that brainstem dopamine D(2) receptors mediate suppression of consummatory ingestive behavior and that D(2) receptors in the shell region of the nucleus accumbens mediate the display of gapes and chin rubs, but that neither of these D(2) receptor populations mediate the hedonic evaluation of taste.     

Chronic lithium chloride administration to unanesthetized rats attenuates brain dopamine D2-like receptor-initiated signaling via arachidonic acid.

We studied the effect of lithium chloride on dopaminergic neurotransmission via D2-like receptors coupled to phospholipase A2 (PLA2). In unanesthetized rats injected i.v. with radiolabeled arachidonic acid (AA, 20:4 n-6), regional PLA2 activation was imaged by measuring regional incorporation coefficients k* of AA (brain radioactivity divided by integrated plasma radioactivity) using quantitative autoradiography, following administration of the D2-like receptor agonist, quinpirole. In rats fed a control diet, quinpirole at 1 mg/kg i.v. increased k* for AA significantly in 17 regions with high densities of D2-like receptors, of 61 regions examined. Increases in k* were found in the prefrontal cortex, frontal cortex, accumbens nucleus, caudate-putamen, substantia nigra, and ventral tegmental area. Quinpirole, 0.25 mg/kg i.v. enhanced k* significantly only in the caudate-putamen. In rats fed LiCl for 6 weeks to produce a therapeutically relevant brain lithium concentration, neither 0.25 mg/kg nor 1 mg/kg quinpirole increased k* significantly in any region. Orofacial movements following quinpirole were modified but not abolished by LiCl feeding. The results suggest that downregulation by lithium of D2-like receptor signaling involving PLA2 and AA may contribute to lithium's therapeutic efficacy in bipolar disorder.     

Antagonistic interaction between adenosine A2A and dopamine D2 receptors modulates the social recognition memory in reserpine-treated rats

Increasing evidence suggests that antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the basal ganglia are involved in the control of motor activity. However, there are few studies investigating this interaction in other brain regions and its role in additional functions. In the present study, we evaluated whether reserpine-treated rats (1.0 mg/kg, i.p.) exhibit altered social recognition memory abilities. The effects of acute administration of the dopamine receptor agonists 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3 benzazepine (SKF 38393, dopamine D(1) receptor agonist) and quinpirole (dopamine D(2) receptor agonist), together with the adenosine receptor antagonists caffeine (non-selective), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, adenosine A(1) receptor antagonist) and 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385, adenosine A(2A) receptor antagonist), were also investigated. Twenty-four hours after treatment, reserpine-treated rats exhibited a significant disruption in the ability to recognize a juvenile rat after a short period of time. These animals did not show any motor deficit. The social recognition disruption induced by reserpine was reversed by acute treatment with quinpirole (0.05-0.1 mg/kg, i.p.), caffeine (10.0-30.0 mg/kg, i.p.) or ZM241385 (0.5-1.0 mg/kg, i.p.), but not with SKF 38393 (0.5-3.0 mg/kg, i.p.) or DPCPX (0.5-3.0 mg/kg, i.p.). Moreover, a synergistic response was observed following the co-administration of 'non-effective' doses of ZM241385 (0.1 mg/kg, i.p.) and quinpirole (0.01 mg/kg, i.p.). These results reinforce and extend the notion of antagonistic interactions between adenosine and dopamine receptors, and demonstrate, for the first time, that the blockade of adenosine A(2A) receptors and the activation of dopamine D(2) receptors can reverse the social recognition deficits induced by reserpine in rats.     

Amphetamine-induced effects on neuropeptide Y in the rat brain

Repeated (+)-amphetamine sulfate (AMPH) administration (5 mg/kg sc twice daily for 6 days and once on day 7) markedly and reversibly decreased (until 96 h after the final dose) neuropeptide Y-like immunoreactivity (NPY-LI) in the rat striatum (caudate-putamen) and nucleus accumbens, and had no effect on NPY-LI in the hippocampus. No significant alterations were detected in the hybridization signal of NPY mRNA4 and 24 h after the end of AMPH treatment. A single dose of AMPH (5 mg/kg sc) administered to rats 4 and 24 h prior to sacrifice had no effect on NPY-LI in the brain structures studied. Moreover, AMPH injected 8 days after the last dose of repeated AMPH administration did not change NPY-LI up to 72 h. The minimal dose of haloperidol, the strong mixed dopaminergic D2/D1 receptor antagonist, (0.75 mg/kg injected ip 30 min before each of the multiple AMPH administrations) that was sufficient to completely block stereotypy and hyperlocomotion elicited by multiple AMPH administrations enhanced the AMPH-induced decrease in the striatal and accumbens NPY-LI. Our results suggest that NPY neurons in the striatum, nucleus accumbens and hippocampus are not directly involved in the acute behavioral response to AMPH (stereotypy and hyperlocomotion) as well as in the initiation and expression of AMPH-induced behavioral sensitization.