Thalamic glutamate decreases with cigarette smoking

Abstract

Rationale: Findings from animal studies and human PET imaging indicate that nicotine and cigarette smoking affect glutamate (Glu) and related neurochemical markers in the brain and imply that smoking reduces extracellular Glu. As Glu release is mediated by nicotinic acetylcholine receptors (nAChRs), which are present at high concentrations in the thalamus, we examined the effects of smoking on thalamic Glu.

Objective: To determine the effects of tobacco smoking on thalamic glutamate levels.

Methods: Thalamic Glu levels were measured in vivo in 18 smokers and 16 nonsmokers using proton magnetic resonance spectroscopic imaging ((1)H MRSI) at 1.5 T.

Results: Mean Glu levels did not differ significantly between the subject groups. However, within smokers, Glu levels were negatively correlated with self-reports of both cigarettes/day over the last 30 days (r = -0.64, p = 0.006) and pack-years of smoking (r = -0.66, p = 0.005).

Conclusions: Consistent with expectations based on preclinical studies, within smokers, cigarettes/day and pack-years are associated with reduced Glu in thalamus, a brain region rich in nAchRs. These results encourage work on candidate glutamatergic therapies for smoking cessation and suggest a noninvasive metric for their action in the brain.

Fig. 1

¹H MRSI spectrum (a) acquired from right mesial thalamus of subject (PRESS, 1.5 T, repetition time/echo-time = 1500/30 ms). Glutamate and overlapping glutamine (together “Glx”) present as the shoulder in the 2.3-2.4 ppm range. Axial-oblique (b) and sagittal (c) MRI of the brain depicting 9-mm thick MRSI slab of 11×11-mm² voxels. The PRESS volume (white; ~8×10 voxels) was aligned parallel to the genu-splenium line and fit to the subject. It sampled bilateral thalamus, and environs. The blue square in (b-c) denotes voxel yielding MR spectrum in (a).

Fig. 2

¹H MRSI raw (light jagged black trace), LCModel fit (red), and baseline (smooth black) spectra for a representative voxel acquired as in Fig. 1. Principal resonances are labelled for N-acetyl-asparatate (NAA) and N-acetyl-aspartyl-glutamate (NAAG), glutamate (Glu) and glutamine (Gln), creatine (Cr) and phosphocreatine (PCr), choline-compounds (Cho), and myo-inositol (mI). Both Glu and Glx were fit by LCModel with < 20% standard deviation.

Fig. 3

Left: Negative correlation (2-way Spearman) of glutamate (Glu) levels in thalamus (average of left and right) with cigarettes per day over last 30 days. Note: There are data overlapping from two participants at the points (15,7.2) and (20,6.6), each marked by “2”, for a total of 17 observations and 15 degrees-of-freedom. Right: Correlation with pack-years (2-way Spearman, participant age partialled out). Individual smokers represented by green triangles. Metabolite levels in Institutional Units (IU) corrected for voxel CSF content. Higher levels of tobacco use are associated with lower thalamic Glu. Similar results were observed for Glx (Glx = Glu + glutamine).