P50 amplitude reduction: a nicotinic receptor-mediated deficit in first-degree relatives of schizophrenia patients.

RATIONALE: Impaired P50 gating is a putative index of genetically mediated nicotinic dysfunction in schizophrenia. However, assessment is confounded, in patients, by differential effects of smoking, symptoms, and treatment. OBJECTIVES: This double-blind placebo-controlled study was designed to tease apart the relationships among P50, acute and chronic nicotine exposure, and familial risk. METHODS AND RESULTS: Experiment 1: To assess the putative effects of genetic vulnerability without other confounds, 14 unaffected relatives of schizophrenia patients and 15 controls, all nonsmokers, were tested with/without 7 mg transdermal nicotine. Family members had reduced P50 amplitude to an initial auditory stimulus, but normal P50 gating. Nicotine decreased P50 amplitude in controls; family members had a mixed response: eight decreased and six increased P50 amplitude with nicotine. Experiment 2: To assess chronic nicotine use and short-term withdrawal as a model of nicotinic dysfunction, 26 healthy smokers (14 abstinent for >12 h) received 21 mg transdermal nicotine. Chronic nicotine use, alone, did not alter P50 amplitude or gating. Short-term withdrawal resulted in decreased P50 amplitude, with no effect on P50 gating. Nicotine increased P50 amplitude in abstinent smokers and decreased it in nonabstinent smokers. CONCLUSIONS: Familial vulnerability to schizophrenia reduces P50 amplitude. Nicotinic modulation of this deficit mirrors the effect of nicotine during smoking abstinence and suggests an "inverted-U" relationship between P50 amplitude and endogenous nicotinic activity. P50 amplitude may, therefore, be a sensitive marker of nicotinic dysfunction in individuals with familial risk for schizophrenia, which is mediated through mechanisms (e.g., α4ß2 receptors) that are distinct from those (e.g., α7 receptors) that mediate P50 gating.