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

Abstract

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 (intra-extra 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.

Fig. 1

Effects of drug (DCS) or placebo (PL) on Nic-VAS ratings of a “Stimulated” and b “Relaxed” at predrug baseline (t1), presmoking (t2), and postsmoking measurement point (t3). NS nonsmoking group, S partial-smoking group (the two groups underwent identical protocol until the partial-smoking manipulation which occurred after t2). ‡p < 0.05, ‡‡p < 0.01 (t1 vs. t2; paired t test within DCS group), *p < 0.05 (t2 vs. t3; paired t test within PL-S and DCS-S groups)

Fig. 2

a Number of false alarms and b mean response times (log) on the rapid visual information processing (RVIP) test following partial smoking (S) or the nonsmoking (NS) manipulations in participants who underwent the drug (DCS) or the placebo (PL) treatment. *p ≤ 0.05 (independent t test vs. DCS-S groups), †p < 0.05 (main effect of drug group PL vs. DCS)