CHOLINERGICS AND SENSORY GATING IN SCHIZOPHRENIA

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This is a resubmission of a previous application. This project is designed to assess the roles of muscarinic and nicotinic cholinergic mechanisms that modulate P50 auditory sensory gating in schizophrenia. We have previously combined recording the P50 waveform oft he auditory evoked potential (AEP) with a condition-testing paradigm used to assess the strength of inhibitory neuronal pathways. Normal controls show a significant decrement of the AEP P50 waveform in response to the second of two closely paired clicks. Both unmedicated and medicated schizophrenic subjects show less decrement, indicating, a deficit in inhibitory mechanisms involved in P50 auditory gating. About half of all first-degrees relatives of schizophrenic patients have as a trait, a similar deficit in P50 auditory sensory gating. By studying the P50 auditory sensory gating deficit in first degree relatives of identified patients, we can elucidate the mechanisms underlying the inherited deficits in P50 auditory sensory gating interference from the effects of neuroleptic and anticholinergic meditations that are commonly used to treat schizophrenic patients. In an animal model, blockade of nicotinic cholinergic neuronal transmission to the hippocampus impaired auditory sensory gating. This deficit was reversed by treatment with nicotine. In a preliminary study, we found that oral nicotine transiently enhanced P50 gating in first-degrees relatives with impaired P50 gating. In this study we will study 3 groups of subjects- normal controls with no family history of mental illness, nongating first-degrees relatives of schizophrenic patients, an schizophrenic patients. The first experiments will study the effects of 6 mg of oral nicotine on sensory gating. The second experiment will study the effects of 0.0006 mg/kg of scopolamine, a muscarinic antagonist, on P50 auditory gating before and after treatment. The third study will use mecamylamine, to assess the effect of antagonism of high affinity nicotinic receptors on P50 gating. In each study, auditory evoked potentials using the P50 conditioning- testing paradigm will be recorded prior to treatment and 30 minutes, 1 hour, and two hours after treatment. In the fourth study, we will ask normal controls and nongating first-degree relatives of schizophrenic patients to wear a nicotine patch. They will have their P50s recorded prior to wearing the patch and weekly thereafter for 4 weeks, in order to assess possible long-term desensitization of CNS nicotine receptors. Statistical analysis will be by MANOVA and separate analyses of group *tx*time interaction effects. In the fifth study, we will give normal controls and nongating first-degrees relatives of schizophrenic patients two doses of nicotine within two hours of each other to study possible short-term desensitization of nicotinic receptors. Individual effects on different EEG leads will be assessed by separate analyses of tx*time*lead effects.