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Involvement of Nicotinic Receptor Mechanisms

Kristi A. Sacco, PsyD; Angelo Termine, BS; Aisha Seyal, BS; Melissa M. Dudas, BS; Jennifer C. Vessicchio, LCSW; Suchitra Krishnan-Sarin, PhD; Peter I. Jatlow, MD; Bruce E. Wexler, MD; Tony P. George, MD

Arch Gen Psychiatry. 2005;62:649-659.

Background  Cigarette smoking rates in schizophrenia are higher than in the general population.

Objectives  To determine whether cigarette smoking modifies cognitive deficits in schizophrenia and to establish the role of nicotinic acetylcholine receptors (nAChRs) in mediating cigarette smoking–related cognitive enhancement.

Design  Neuropsychological assessments were performed at smoking baseline, after overnight abstinence, and after smoking reinstatement across 3 separate test weeks during which subjects were pretreated in a counterbalanced manner with the nonselective nAChR antagonist mecamylamine hydrochloride (0, 5, or 10 mg/d).

Participants  Twenty-five smokers with schizophrenia and 25 control smokers.

Setting  Outpatient mental health center.

Main Outcome Measures  Visuospatial working memory (VSWM) and Continuous Performance Test (CPT) scores.

Results  In smokers with schizophrenia and control smokers, overnight abstinence led to undetectable plasma nicotine levels and an increase in tobacco craving. While abstinence reduced CPT hit rate in both groups, VSWM was only impaired in smokers with schizophrenia. Smoking reinstatement reversed abstinence-induced cognitive impairment. Enhancement of VSWM and CPT performance by smoking reinstatement in smokers with schizophrenia, but not the subjective effects of smoking, was blocked by mecamylamine treatment.

Conclusions  Cigarette smoking may selectively enhance VSWM and attentional deficits in smokers with schizophrenia, which may depend on nAChR stimulation. These findings may have implications for understanding the high rates of smoking in schizophrenia and for developing pharmacotherapies for cognitive deficits and nicotine dependence in schizophrenia.

Author Affiliations: Program for Research in Smokers with Mental Illness (PRISM) (Drs Sacco and George; Mr Termine; and Mss Seyal, Dudas, and Vessicchio), Division of Substance Abuse (Dr Krishnan-Sarin), Department of Psychiatry (Drs Sacco, Wexler, and George), Department of Laboratory Medicine (Dr Jatlow), Yale University School of Medicine, New Haven, Conn.

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