Acute and subacute effects of risperidone and cocaine on accumbens dopamine and serotonin release using in vivo microvoltammetry on line with open-field behavior.

摘要

In vivo microvoltammetry was used to detect dopamine (DA) and serotonin (5-HT) release from nucleus accumbens (NAcc) of freely moving, male, Sprague-Dawley laboratory rats, while animals' locomotor (forward ambulations) and stereotypic behavior (fine movements of sniffing and grooming) were monitored at the same time with infrared photobeams. Monoamine release mechanisms were determined by using a depolarization blocker (gamma-butyrolactone, gammaBL). Miniature carbon sensors (BRODERICK PROBES(R) microelectrodes) smaller than a human hair were used in conjunction with a semidifferential electrochemical circuit to detect release of each monoamine in separate signals and within seconds. The purpose was to evaluate the neuropharmacology of the 5-HT(2)/DA(2) antagonist risperidone in its current therapeutic role as an atypical antipsychotic medication as well as in its potential role as pharmacotherapy for cocaine psychosis and withdrawal symptoms. Acute (single drug dose) and subacute (24-h follow-up studies in the same animal, no drug administration) studies were performed for each treatment group. The hypothesis for the present studies is derived from a growing body of evidence that cocaine-induced psychosis and schizophrenic psychosis share similar neurochemical and behavioral manifestations. Results showed that (1) Acute administration of risperidone (2 mg/kg sc) significantly increased DA and 5-HT release in NAcc above baseline (habituation) values (P<.001) while locomotion and stereotypy were virtually unaffected. In subacute studies, DA release did not differ from baseline (P>.05), whereas 5-HT release was significantly increased above baseline (P<.001). Locomotion increased over baseline but not to a significant degree, while stereotypy was significantly increased above baseline (P<.05). (2) Acute administration of cocaine (10 mg/kg ip) significantly increased both DA and 5-HT release above baseline (P<.001), while locomotion and stereotypy were significantly increased over baseline (P<.001). In subacute studies, DA decreased significantly below baseline (P<.001) and significant decreases in 5-HT release occurred at 15, 20, 50 and 55 min (P<.05). Behavior increased above baseline but did not reach a statistically significant degree. (3) Acute administration of risperidone/cocaine (2 mg/kg sc and 10 mg/kg ip, respectively) showed a significant block of the cocaine-induced increase in DA release in the first hour (P<.001) and 5-HT release in both hours of study (P<.001). Cocaine-induced locomotion and stereotypy were blocked simultaneously with the monoamines (P<.001). In subacute studies, DA and 5-HT release returned to baseline while locomotion and stereotypy increased insignificantly above baseline. Thus, (a) these studies were able to tease out pharmacologically the critical differences between presynaptic and postsynaptic responses to drug treatment(s) and these differences may lead to more effective therapies for schizophrenic and/or cocaine psychosis. (b) Taken together with other data, these acute studies suggest that risperidone may possibly act via inhibition of presynaptic autoreceptors to produce the observed increases in accumbens DA and 5-HT release, whereas cocaine may be acting at least in part via serotoninergic modulation of DA postsynaptically. The subacute data suggest that pharmacokinetics may play a role in risperidone's action and that neuroadaptation may play a role in the mechanism of action of cocaine. Finally, the ability of risperidone to block cocaine-induced psychostimulant neurochemistry and behavior during acute studies while diminishing the withdrawal symptoms of cocaine during subacute studies suggests that risperidone may be a viable pharmacotherapy for cocaine psychosis and withdrawal.