No abstract

Sex-differences exist in tobacco smoking behaviors. Nicotine, the primary addictive ingredient in tobacco smoke indirectly affects γ-amino butyric acid (GABA) function. Previous studies reported sex by smoking interactions in brain GABA levels. The goal of the present study was to evaluate if there is a sex by smoking interaction at the GABAA-benzodiazepine receptors (GABAA-BZRs), as well as relationships between GABAA-BZR availability and behavioral variables before and after 1wk of smoking cessation. Twenty six women (8 nonsmokers, age 36.0 ± 13.4y; 19 smokers, age 34.6 ± 8.9y) and twenty five men (8 nonsmokers, age 37.9 ± 13.8y; 17 smokers, 34.1 ± 12.4y) were imaged using [123I]iomazenil and single photon emission computed tomography (SPECT). Smokers were imaged at baseline 7h after the last cigarette. A significantly great number of men were able to abstain from smoking for 1 week (p=0.003). There were no significant differences in nicotine dependence and cigarette craving, mood or pain sensitivity between male and female smokers. There was a significant effect of sex across all brain regions (frontal, parietal, anterior cingulate, temporal and occipital cortices, and cerebellum; p<0.05), with all women (smokers and nonsmokers combined) having a higher GABAA-BZR availability than all men. There was a negative correlation between GABAA-BZR availability and craving (p≤;0.02) and pain sensitivity (p=0.04) in female but not male smokers. This study provides further evidence of a sex-specific regulation of GABAA-BZR availability in humans and demonstrates the potential for GABAA-BZRs to mediate tobacco smoking craving and pain symptoms differentially in female and male smokers.

Introduction In vivo imaging biomarkers of various HIV neuropathologies, including dopaminergic dysfunction, are still lacking. Towards developing dopaminergic biomarkers of brain involvement in HIV, we assessed the pre and postsynaptic components of the dopaminergic system in the HIV-1 transgenic rat (Tg), a well-characterized model of treated HIV+ patients, using small-animal PET imaging. Methods 15–18 month-old Tg and wild type (WT) rats were imaged with both [18F]-FP-CMT, a dopamine transporter (DAT) ligand (n=16), and [18F]-Fallypride, a D2/D3 dopamine receptor (D2/D3DR) ligand (n=16). 5–8 month-old Tg and WT rats (n=18) were also imaged with [18F]-FP-CMT. A subset of animals was imaged longitudinally at 7 and 17 months of age. Multiplex immunohistochemistry staining for DAT, tyrosine hydroxylase, D2DR, D3DR, GFAP, Iba1 and NeuN was performed on a subgroup of the scanned animals. Results [18F]-FP-CMT and [18F]-Fallypride binding potential (BPND) values were significantly lower in 15–18 month-old Tg compared to age-matched WT rats (p< 0.0001 and 0.001, respectively). [18F]-FP-CMT BPND values in 5–8 month-old rats, however, were not significantly different. Longitudinal age-related decrease in [18F]-FP-CMT BPND was exacerbated in the Tg rat. Immunohistochemistry showed decreased staining of dopaminergic markers in Tg rats. Rats with higher serum gp120 had lower mean BPND values for both ligands. Conclusions We found presynaptic and postsynaptic dopaminergic dysfunction/loss in older Tg compared to WT rats. We believe this to be related to neurotoxicity of viral proteins present in the Tg rats’ serum and brain. Advances in Knowledge Our findings confirm prior reports of neurobehavioral abnormalities suggestive of dopaminergic dysfunction in this model. They also suggest similarities between the Tg rat and HIV+ patients as far as dopaminergic dysfunction. Implications for patient Care The Tg rat, along with the above-described quantitative PET imaging biomarkers, can have a role in the evaluation of HIV neuroprotective therapies prior to human translation.

Personality traits contribute to variation in human behavior, including the propensity to take risk. Extant work targeted risk-taking processes with an explicit manipulation of reward, but it remains unclear whether personality traits influence simple decisions such as speeded versus delayed responses during cognitive control. We explored this issue in an fMRI study of the stop signal task, in which participants varied in response time trial by trial, speeding up and risking a stop error or slowing down to avoid errors. Regional brain activations to speeded versus delayed motor responses (risk-taking) were correlated to novelty seeking (NS), harm avoidance (HA) and reward dependence (RD), with age and gender as covariates, in a whole brain regression. At a corrected threshold, the results showed a positive correlation between NS and risk-taking responses in the dorsomedial prefrontal, bilateral orbitofrontal, and frontopolar cortex, and between HA and risk-taking responses in the parahippocampal gyrus and putamen. No regional activations varied with RD. These findings demonstrate that personality traits influence the neural processes of executive control beyond behavioral tasks that involve explicit monetary reward. The results also speak broadly to the importance of characterizing inter-subject variation in studies of cognition and brain functions.