Although control subjects will inhibit the evoked electrophysiological response to the second of paired auditory stimuli, schizophrenics are unable to do so. Inhibitory pathways in the hippocampus, which can be modulated through alpha7 nicotinic cholinergic receptors, are insufficiently activated in schizophrenia patients. This results in an inability to appropriately inhibit the response to repetitive sensory stimuli. Clozapine, unlike typical antipsychotics, is able to normalize this deficit in sensory inhibition. The mechanism of this normalization is unknown, but its elucidation would allow better understanding of clozapine?s efficacy. We propose that clozapine-induced increases in cholinergic neurotransmission are responsible for the increased inhibition of response. This hypothesis will be tested in DBA/2 mice, a mouse model of the deficit which shares both phenotypic and genotypic attributes with the deficit observed in schizophrenia. After construction of a dose response curve for the effects of clozapine on sensory inhibition we will carry out mechanistic studies. The first of these will determine how the normalizing effects of clozapine on sensory inhibition are affected by pretreatment of the mice with various nicotinic antagonists, to infer if (and which) nicotinic receptors are involved in mediating the effects of clozapine. In the final aim, the techniques of hippocampal in vivo microdialysis and single unit recording will be used to determine if clozapine increases the release of acetylcholine and/or increases the activity of septohippocampal cholinergic neurons.
| Simosky, Johanna K; Stevens, Karen E; Adler, Lawrence E et al. (2003) Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism. Psychopharmacology (Berl) 165:386-96 |
