Sex, GABA, and nicotine: the impact of smoking on cortical GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopy

Abstract

Background: Given that nicotine modulates amino acid neurotransmission, we sought to examine the impact of nicotine on cortical gamma-aminobutyric acid (GABA) levels in male and female smokers.

Methods: Healthy nicotine-dependent men (n = 10) and women (n = 6) underwent proton magnetic resonance spectroscopy (1H-MRS) to measure occipital cortex GABA concentrations. A subset of the smoking men (n = 5) underwent 1H-MRS scans before and after 48 hours of smoking abstinence, whereas each of the women were scheduled to undergo pre- and postabstinence scans during the follicular and luteal phases of one menstrual cycle. Healthy nonsmoking men (n = 7) and women (n = 13) underwent 1H-MRS for comparison.

Results: Short-term abstinence had no significant effect on cortical GABA concentrations in either men or women. There was, however, a significant effect of sex, diagnosis (smoker/nonsmoker), and menstrual cycle phase on cortical GABA levels, such that female smokers experienced a significant reduction in cortical GABA levels during the follicular phase and no cyclicity in GABA levels across the menstrual cycle, whereas cortical GABA levels were similar in smoking and nonsmoking men.

Conclusions: Taken together with previous 1H-MRS data showing abnormalities in occipital cortex GABA concentrations in several affective disorders, our preliminary finding that nicotine modulation of GABA levels varies by sex provides a further rationale for investigating the impact of nicotine on central GABAergic function as a potential risk factor for women to experience depressive symptoms during smoking cessation.

Figure 1

Scout image of voxel in occipital cortex. Gradient-echo scout images of the subject's brain were obtained for subject positioning, and a 1.5 × 3 × 3-cm³ voxel centered on the midline of the occipital cortex, 2 cm deep from the dura, was chosen for magnetic resonance spectroscopy.

Figure 2

Occipital cortex γ-aminobutyric acid (GABA) levels measured by proton magnetic resonance spectroscopy in male and female smokers and nonsmokers. Cortical GABA levels were obtained from 10 men. GABA levels from 5 of the 10 men with pre- and postabstinence scans were averaged. Follicular- and luteal-phase GABA levels for 6 female smokers represent the average of the pre- and postabstinence scans. GABA levels were obtained in 4 of the 6 women during the follicular phase and from 5 of the 6 women during the luteal phase. Two-way analysis of variance of sex and smoking effects on GABA levels revealed a significant sex × smoking interaction (p < .0001). Cortical GABA levels did not differ significantly between smoking and nonsmoking men (p = .2). Mixed-model analysis showed a significant menstrual cycle phase × smoking interaction (p = .0001).

Figure 3

Representative γ-aminobutyric acid (GABA) spectra in smoking and nonsmoking women. Representative spectra from a nonsmoking woman (left) and a smoking woman (right), for comparison of GABA in the follicular phase (top) and the midluteal phase (bottom). For each phase of the menstrual cycle, a subspectrum from the J-editing sequence is shown so that the creatine (Cr) resonance can be compared with the GABA resonance at 3.0 ppm, which is shaded grey. Cho, choline.