A role for glutamate in subjective response to smoking and its action on inhibitory control

Rationale Our previous study using memantine in smokers suggests that there may be a differential role for N-methyl-D-aspartate (NMDA) receptors in the subjective and cognitive effects of smoking. Objectives This study was designed to investigate if D-cycloserine (DCS) would modulate the subjective and cognitive effects of limited smoking. Methods Forty-eight habitual smokers abstinent for a minimum of 2 h were randomly allocated to receive either placebo or 50 mg DCS (double-blind) and were subsequently required either to smoke half of one cigarette or to remain abstinent. Subjective and physiological effects of DCS were measured at baseline, 90 min postcapsule, and again after the partial-smoking manipulation, while the effects on sustained attention (rapid visual information processing test-RVIP) and cognitive flexibility (intraextra dimensional set-shift test-IED) were evaluated only after the partial-smoking manipulation. Results DCS alone did not produce significant subjective effects other than an increase in ratings of Stimulated. In combination with partial smoking, however, DCS blocked the smoking-induced increase in Stimulated and the decrease in Relaxed ratings. Furthermore, in combination with smoking, DCS reduced the number of false alarms during the RVIP test (an index of inhibitory control) and produced a small increase in diastolic blood pressure. DCS failed to modulate IED performance. Conclusions These findings provide further evidence of a role for glutamate release in the subjective effects of smoking but not the effects on attention and cognitive flexibility. Furthermore, our results indicate that glutamate release may also be involved in the effect of smoking on inhibitory control.