Nicotine and clozapine selectively reverse a PCP-induced deficit of PPI in BALB/cByJ but not NMRI mice: Comparison with risperidone

Schizophrenic patients have deficits in prepulse inhibition (PPI) that may be alleviated by smoking/nicotine. The effect of nicotinic agents on PPI in rodents is equivocal and few studies in mice have been reported. Thus, we assessed nicotine's (0.03–1 mg/kg) effect on PPI in five mouse strains with no effects. We next determined if nicotine would reverse a phencyclidine (PCP)-induced deficit of PPI in BALB/cByJ and NMRI mice. BALB/cByJ mice have a low density of [125I]α-bungaratoxin binding in the hippocampus and poor inhibitory gating of auditory evoked potentials (AEPs), a model related to PPI. At 1 mg/kg, nicotine selectively reversed the PCP-induced deficit of PPI in BALB/cByJ mice. The pharmacokinetic profile of nicotine (T1/2, Cmax, Tmax and AUC) was identical in both strains, obviating this as a factor for the strain-dependent effect observed. Moreover, 1 mg/kg nicotine inhibited in vivo [3H]epibatidine binding with the same time-course in both strains, indicating no difference in brain “kinetics”. Since high doses of nicotine were effective in BALB/cByJ mice a role for low-affinity nicotinic receptors, e.g. α7 receptors, is plausible. Clozapine, but not risperidone, also only reversed the PCP deficit of PPI in BALB/cByJ. Clozapine and nicotine also enhance inhibitory gating of AEPs in DBA/2 mice, and clozapine's effect is antagonized by an α7 antagonist. Our data and previous evidence possibly suggest a role for low-affinity nicotinic receptors in the effects of clozapine and nicotine. Furthermore, BALB/cByJ mice may represent a model to test the effects of nicotinic agents acting at low-affinity nicotinic receptors.