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 [I-125]alpha-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 (T-1/2, C-max T-max 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 [H-3]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. alpha(7) 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 alpha(7) 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. (c) 2005 Elsevier B.V. All rights reserved.