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The NMDA receptor antagonist ketamine can induce a rapid improvement in depressive symptoms that often endures for days after a single intravenous dose. The pharmacodynamic basis for this effect is poorly understood. Using a proton magnetic resonance spectroscopy ([ 1 H]-MRS) method that previously detected a normalization of amino acid neurotransmitter (AANt) content after chronic treatment with conventional antidepressant treatments, we examined whether the acute action of ketamine is associated with alterations in AANt content as well. Ten subjects with major depressive disorder (MDD) received saline, then ketamine in a fixed order, one week apart, under single-blind conditions. Each infusion was associated with three [ 1 H] MRS scans (baseline, 3 hours and 48 hours post-infusion) that measured glutamate, GABA and glutamine within the occipital cortex. Rating scales were administered before, during and after each infusion. The rapid (1 hour) and sustained (at least 7 days) antidepressant effect we observed after ketamine infusion was not associated with either baseline measures of, or changes in, occipital AANt content. Dissociative symptoms were not correlated with changes in depression scores. While our results indicate that changes in occipital AANt content are not a correlate of ketamine's antidepressant action, this may only apply to the regional and temporal windows of our MRS measurements.

BackgroundCigarette smoking is the main cause of preventable death in developed countries. While the direct positive behavioral reinforcing effect of nicotine has historically been considered the primary mechanism driving the development of TUD, accumulating contemporary research suggests that the cognitive-enhancing effects of nicotine may also significantly contribute to the initiation and maintenance of TUD, especially in individuals with pre-existing cognitive deficits.MethodsWe provide a selective overview of recent advances in understanding nicotine’s effects on cognitive function, a discussion of the role of cognitive function in vulnerability to TUD, followed by an overview of the neurobiological mechanisms underlying the cognitive effects of nicotine.ResultsPreclinical models and human studies have demonstrated that nicotine has cognitive-enhancing effects. Attention, working memory, fine motor skills and episodic memory functions are particularly sensitive to nicotine’s effects. Recent studies have demonstrated that the α4, β2, and α7 subunits of the nicotinic acetylcholine receptor (nAChR) participate in the cognitive-enhancing effects of nicotine. Imaging studies have been instrumental in identifying brain regions where nicotine is active, and research on the dynamics of large-scale networks after activation by, or withdrawal from, nicotine hold promise for improved understanding of the complex actions of nicotine on human cognition.ConclusionBecause poor cognitive performance at baseline predicts relapse among smokers who are attempting to quit smoking, studies examining the potential efficacy of cognitive-enhancement as strategy for the treatment of TUD may lead to the development of more efficacious interventions.

Nicotine dependence is a serious public health concern. Optimal treatment of nicotine dependence will require greater understanding of the mechanisms that contribute to the maintenance of smoking behaviors. A growing literature indicates sex and menstrual phase differences in responses to nicotine. The aim of this study was to assess sex and menstrual phase influences on a broad range of measures of nicotine response including subjective drug effects, cognition, physiological responses, and symptoms of withdrawal, craving, and affect. Using a well-established intravenous nicotine paradigm and biochemical confirmation of overnight abstinence and menstrual cycle phase, analyses were performed to compare sex (age 18-50 years; 115 male and 45 female) and menstrual cycle phase (29 follicular and 16 luteal) effects. Females had diminished subjective drug effects of, but greater physiological responses to, nicotine administration. Luteal-phase females showed diminished subjective drug effects and better cognition relative to follicular-phase women. These findings offer candidate mechanisms through which the luteal phase, wherein progesterone is dominant relative to estradiol, may be protective against vulnerability to smoking.