Risperidone: regional effects in vivo on release and metabolism of dopamine and serotonin in the rat brain

Abstract

The antipsychotic drug risperidone shows high affinity for both central serotonin (5-HT)2A and dopamine (DA)-D2 receptors in vivo. By employing microdialysis in freely moving rats, the effects of acute risperidone administration on regional brain DA and 5-HT release and metabolism were compared with the corresponding effects of the atypical antipsychotic drug clozapine as well as amperozide, the selective DA-D2 receptor antagonist raclopride and the selective 5-HT2A/5-HT2C receptor antagonist ritanserin. Risperidone (0.2 or 2.0 mg/kg, SC) was found to increase DA release and metabolism to about the same extent in three major projection areas of the mesotelencephalic dopaminergic system, i.e. the nucleus accumbens (NAC), the medial prefrontal cortex (MPC) and the lateral striatum (STR). In contrast, clozapine and amperozide (both 10.0 mg/kg, SC), as well as raclopride (2.0 mg/kg, SC), were all found differentially to affect DA release and metabolism in the three projections areas. Specifically, clozapine and amperozide enhanced DA release in the MPC to a greater extent than in the NAC or the STR, whereas raclopride instead preferentially increased DA release in the NAC and the STR but not in the MPC. Ritanserin (3.0 mg/kg, SC) did not exert any major effects on DA metabolism in the three areas studied. In contrast to the regionally rather homogenous activation of brain DA systems caused by risperidone, the drug was found to enhance brain 5-HT metabolism preferentially in the MPC, as indicated by the elevated extracellular concentration of 5-hydroxyindoleacetic acid (5-HIAA) in this region. A similar elevation of the 5-HIAA level in the MPC was observed after amperozide and, to some extent, after clozapine and ritanserin administration. The risperidone-induced (2.0 mg/kg, SC) elevation of 5-HIAA concentrations in the frontal cortex was found to be paralleled by an increased 5-HT release in this brain area. Consequently, our findings demonstrate a pharmacological profile of risperidone, as reflected in brain DA metabolism, in between that of clozapine and the DA-D2 antagonists. The preferential activation of 5-HT release and metabolism in frontal cortical areas might be of particular relevance for the ameliorating effect of risperidone on negative symptoms in schizophrenia, especially when associated with depression.

Evidence for the Preferential Involvement of 5-HT2A Serotonin Receptors in Stress- and Drug-Induced Dopamine Release in the Rat Medial Prefrontal Cortex

“…This effect may have been mediated, at least partially, by blockade of local 5-HT2A receptors, since cortical M100907 induced a similar effect. It is unknown whether cortical risperidone infusion, as used in the current work, would increase 5-HT levels in the mPFC as has been Serotonin-2A receptors and prefrontocortical dopamine release EA Pehek et al shown with systemic risperidone treatment (Ichikawa et al, 1998;Hertel et al, 1996; although see Zhang et al, 2000;Ojima et al, 2004). If so, other non-5-HT2 serotonin receptors could be implicated in this stress effect of risperidone.…”

“…Indeed, this combination of properties may explain why the systemic administration of higher doses (1 mg/kg) of risperidone produces increases in mPFC DA efflux (Hertel et al, 1996;Kuroki et al, 1999;Zhang et al, 2000). Lower doses of risperidone (0.004 mg/ kg), like M100907, do not alter cortical DA efflux (Westerink et al, 1998(Westerink et al, , 2001).…”

Disruption of the Prepulse Inhibition of the Startle Reflex in Vasopressin V1b Receptor Knockout Mice: Reversal by Antipsychotic Drugs

“…Hence, risperidone and clozapine may be able to increase DA release in the medial prefrontal cortex. Apparently consistent with this possibility, a recent study proposed that risperidone and clozapine could increase DA release in the medial prefrontal cortex (Hertel et al, 1996;Kuroki et al, 1999;Ichikawa et al, 2001). Moreover, these effects of atypical antipsychotics are through D2 and 5-HT2A receptors blockade (Ichikawa et al, 2001).…”

Increase of Dialysate Dopamine in the Bed Nucleus of Stria Terminalis by Clozapine and Related Neuroleptics

“…The present study shows that clozapine and other putative atypical neuroleptics dose-dependently increase extracellular DA in the BNST; whereas, haloperidol and Clozapine increased DA in dialysates from BNST at doses lower than those effective in raising DA concentration in dialysate from the prefrontal cortex (Nomikos et al 1994;Volontè et al 1997); risperidone raised DA in the BNST only at doses about twofold higher than those active in increasing dialysate DA in the prefrontal cortex (Hertel et al 1996;Volontè et al 1997). Olanzapine, BIMG 80, and amperozide, instead, were equipotent in increasing DA in dialysates from the BNST and from prefrontal cortex (Nomikos et al 1994, Volontè et al 1997, Xi-Ming et al 1998).…”

“…Therefore, an increase of DA transmission onto specific DA receptor subtypes might be instrumental for the antipsychotic effects of atypical neuroleptics. Similar considerations have been applied to the increase of DA release in the prefrontal cortex, which apparently behaves in a manner similar to the BNST in response to atypical neuroleptics (Andersson et al 1995;Hertel et al 1996;Volontè et al 1997). It is notable, however, that typical neuroleptics increase, although to a lesser extent, extracellular DA in the prefrontal cortex whereas, they are without effect in the BNST.…”