A comparison of the acute effects of zotepine and other antipsychotics on rat cortical dopamine release, in vivo

The acute effects of systemic administration of the antipsychotic drug, zot epine, on extracellular dopamine (DA) in the frontal cortex of freely-movin g rats were stud led using in vivo microdialysis and compared with the acti ons of clozapine, olanzapine and haloperidol. Treatment with zotepine (1.0 mg/kg, i.p.) resulted in a prolonged elevation of cortical DA levels for up to 180 min post-drug. A maximal rise of +333% was observed at 120 min post-zotepine treatment. Clozapine (10.0 mg/kg, i. p.) also evoked a rise in extracellular DA which was similar in duration (2 00 min) to that resulting from treatment with zotepine. A maximal rise of 223% was observed at 100 min post-clozapine treatment. Olanzapine (1.0 mg/k g, i.p.) resulted in an immediate increase in DA levels which was maximal 4 0 min post-treatment (+280%) with levels returning to pre-injection values by 100 min after dosing. In contrast, haloperidol (0.1 mg/kg, i.p.) had no measurable influence on cortical DA levels. Local perfusion with the NA upt ake inhibitor, nisoxetine (10 mu M), resulted in an increase in cortical DA levels which was maximal alt 100 min post-onset of perfusion (+257% above baseline). Administration of zotepine (1.0 mg/kg, i.p.) during nisoxetine p erfusion elevated DA levels to a maximum of +301% above baseline, 60 min po st-zotepine. These results show that acute administration of each of three drugs with an atypical antipsychotic profile causes an elevation of cortical DA in freel y-moving rats at doses relevant to those derived from animal models which p redict antipsychotic activity. As a dysfunction in cortical DA is thought t o be involved in both the negative symptoms of schizophrenia and cognitive deficits in schizophrenic patients, it is possible that zotepine's ability to elevate cortical DA levels may underlie its effectiveness in successfull y treating these components of schizophrenia. Furthermore, the ability of z otepine to elevate cortical DA is more likely to derive from its inhibition of the NA transporter rather than DA receptor blockade in this region.