Effect of antipsychotic drugs on extracellular serotonin levels in rat medial prefrontal cortex and nucleus accumbens

Abstract

Amperozide, clozapine, olanzapine and risperidone are more potent serotonin (5-hydroxytryptamine, 5-HT) 2A receptor antagonists than dopamine D 2-like receptor antagonists. Haloperidol and S(−)-sulpiride are potent or selective dopamine D 2-like receptor antagonists and lack 5-HT 2A receptor antagonist properties. We studied the effect of these five proven antipsychotic drugs and one putative (amperozide) antipsychotic drug on extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens of awake, freely-moving rats, using in vivo microdialysis with dual probe implantation. Risperidone (1 mg/kg) and clozapine (20 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens, respectively. Amperozide (2 and 10 mg/kg) significantly increased extracellular 5-HT levels in both regions. Olanzapine (1 and 10 mg/kg), S(−)-sulpiride (10 and 25 mg/kg), haloperidol (0.1 and 1 mg/kg) and the selective 5-HT 2A receptor antagonist MDL-100,907 (1 mg/kg) had no significant effect on extracellular 5-HT levels in either region. Thus, the ability to increase extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens by these antipsychotic drugs is not directly related to their affinity for 5-HT 2A receptors since olanzapine and MDL-100,907 had no significant effect on extracellular 5-HT levels. A variety of mechanisms other than those involving 5-HT 2A receptors, e.g., reuptake inhibition (amperozide) and blockade of α 2-adrenoceptors (clozapine), may contribute to the ability to increase extracellular 5-HT levels in the brain. The increase in extracellular 5-HT levels in the medial prefrontal cortex or nucleus accumbens following amperozide, clozapine, or risperidone administration may not be related to the effect on psychotic symptoms but could be related to effects on other types of psychopathology such as depression, negative symptoms, or cognition.