Clozapine attenuates N-methyl-d-aspartate receptor complex-mediated responses in vivo: tentative evidence for a functional modulation by a noradrenergic mechanism

Recent studies revealed a role for dopamine and noradrenaline in the etiology of ischemia-induced neuronal cell death. In the present investigation, the modulation by clozapine, an atypical antipsychotic agent that interacts with adrenergic receptors, of N-methyl-d-spartate (NMDA) receptor complex-mediated events were studied by examining its effects on levels of cGMP in the cerebellum. Clozapine decreased basal levels of cGMP in the cerebellum and antagonized harmalinemethamphet-amine, pentylenetetrazol- and d-serine-induced increases in levels of cGMP with ED₅₀ values of 3.9, 2.36, 2.13 and 2.1 mg kg (i.p.). However, clozapine (1.25-25 mg kg) did not attenuate the quisqualate-induced increases in levels of cGMP, indicating a specific modulation of events modulated by the NMDA receptor complex. Antagonists of dopamine (D₂), serotonin (5-HT)-5-HT₁, 5-HT₂ and 5-HT₃ haloperidol, propranolol, ritanserin, ICS 205-930 [(3-tropanyl-indole-3-carboxylate methiodide)] respectively, did not reverse the response to harmaline. However, WB-4101 [2(2,6-dimethoxy-phenoxyethyl)aminomethyl-1,4-benzodioxane HCl], an alpha₁-adrenergic antagonist, reversed harmaline-, d-serine-, PTZ- and MA-induced increases in levels of cGMP, indicating an adrenergic modulation of the events mediated by the NMDA receptor complex. Intracerebellar and intracerebroventricular administration of clozapine and intracerebellar administration of WB-4101 reversed the d-serine-induced response, indicating a central locus of action. These results indicated that clozapine modulates levels of cGMP predominantly through its interactions with central adrenergic receptors.