title: Nicotine and clozapine selectively reverse a PCP-induced deficit of PPI in BALB/cByJ but not NMRI mice: comparison with risperidone.
abstract: 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 (0.03-1mg/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 [(125)I]alpha-bungaratoxin binding in the hippocampus and poor inhibitory gating of auditory evoked potentials (AEPs), a model related to PPI. At 1mg/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, 1mg/kg nicotine inhibited in vivo [(3)H]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.
authors.affiliation: NeuroSearch A/S, 93 Pederstrupvej, Ballerup, DK-2750, Denmark.
authors.forename: J T
authors.initials: JT
authors.lastname: Andreasen
authors.forename: K K
authors.initials: KK
authors.lastname: Andersen
authors.forename: E Ø
authors.initials: EØ
authors.lastname: Nielsen
authors.forename: L
authors.initials: L
authors.lastname: Mathiasen
authors.forename: N R
authors.initials: NR
authors.lastname: Mirza
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006213:Hallucinogens / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009433:Neural Inhibition / Q000187:drug effects*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D018967:Risperidone / Q000494:pharmacology*; D013045:Species Specificity
chemical_list: D014150:Antipsychotic Agents; D006213:Hallucinogens; D018722:Nicotinic Agonists; D009538:Nicotine; D010622:Phencyclidine; D003024:Clozapine; D018967:Risperidone