Unique Clinical Profiles Research Articles

Regional specific effects of clozapine and haloperidol on GABA and dopamine release in rat basal ganglia

γ-Aminobutyric acid (GABA) and dopamine release were measured concomitantly in rat dorsolateral striatum, fundus striati (a ventral region of striatum) and globus pallidus following s.c. administration of haloperidol or clozapine. Release was measured by microdialysis in halothane-anesthetized rats. Clozapine (5.0 mg/kg) increased GABA release in the fundus striati and haloperidol (0.5 mg/kg) increased GABA release in the globus pallidus. In contrast, clozapine (2.5–40 mg/kg) failed to increase GABA release in the globus pallidus and haloperidol (0.1–2.0 mg/kg) failed to increase GABA release in the fundus. Thus, haloperidol and clozapine are clearly distinguished by their effects on GABA release in the fundus striati and globus pallidus (both drugs increased GABA release in the dorsolateral striatum). Dopamine release was increased by haloperidol and clozapine in the two regions of the striatum. However, except in the fundus striati where clozapine-induced inceases in dopamine and GABA occurred in parallel, both drugs were more potent in releasing dopamine than GABA. Drug-induced increases in GABA and dopamine release were reversed by addition of 1 μM tetrodotoxin to the perfusion medium. These data suggest that (1) regional differences in the effects of haloperidol and clozapine on GABA release in the basal ganglia may parallel the unique clinical profiles of these drugs; and (2) increases in dopamine release may occur independently of a GABAergic component in the dorsolateral striatum following low doses of haloperidol and clozapine and in the fundus striati following all effective doses of haloperidol.

Second-Generation Antidepressants

The host of newly developed antidepressant drugs offer important clinical advantages to some patients, although their promises of improved therapeutic efficacy and reduced adverse effects compared with conventional treatments are not fully realized. Increased biochemical specificity and unique mechanistic or clinical profiles render these compounds valuable in research into the pathophysiology of affective disorders and mode of action of antidepressant agents.