CLOZAPINE ATTENUATES THE DISCRIMINATIVE STIMULUS PROPERTIES OF (-)-NICOTINE

Rats were trained to discriminate 1.9 mu mol/kg (-)-nicotine (0.3 mg/k g) from saline in a standard two-bar operant conditioning paradigm wit h food reinforcement. The effect of neuronal nicotinic acetylcholine r eceptor (nAChR) agonists and antagonists were verified, and the partic ipation of dopaminergic receptors subtypes in the expression of the (- )-nicotine cue was investigated with cis-flupentixol (D1-D2 antagonist ), haloperidol(D2 antagonist) and clozapine (D4 antagonist). The stere oselectivity of the behavioral response was indicated by the 10-fold l ess sensitivity to (+)-nicotine in (-)-nicotine-trained rats. (+/-)-An abasine and (-)-cytisine exhibited partial agonist profiles at the 1.9 mu mol/kg dose while (-)-lobeline was devoid of any effect in doses u p to 19 mu mol/kg. (-)-Lobeline did not show antagonist properties in this paradigm. The nicotinic channel blockers mecamylamine, chlorisond amine and hexamethonium were inactive on their own but mecamylamine an d chlorisondamine were able to block the effect of (-)-nicotine. Cloza pine attenuated the (-)-nicotine cue while cis-flupentixol and haloper idol were ineffective. Similar doses of cis-flupentixol significantly blocked the locomotor stimulant effect of (-)-nicotine in rats indicat ing that blockade of dopaminergic receptors was achieved at the doses used in the drug discrimination studies. These data suggest that the d iscriminative stimulus properties of (-)-nicotine are mediated through neuronal nAChRs and involves the activation of dopaminergic receptors of the D4 subtype.