Vulnerability to nicotine abstinence-related social anxiety-like behavior: molecular correlates in neuropeptide Y, Y2 receptor and corticotropin releasing factor

Abstract

An outbred rat model of the novelty-seeking phenotype is used to study nicotine vulnerability, where experimentally naïve rats were phenotype screened as high or low responders (HRs or LRs, ranking in the upper or lower one-third of the population respectively) based on locomotor activity displayed in a novel environment. Following nicotine training and abstinence, HR animals pre-trained with nicotine showed expression of locomotor sensitization to nicotine challenge along with enhanced social anxiety-like behavior in the social interaction test compared to saline pre-trained controls. HR rats also showed a downregulation in neuropeptide Y (NPY) mRNA levels in the medial nucleus of amygdala and the CA1 field of the hippocampus, an upregulation in Y2 mRNA levels in the CA3 field of the hippocampus, and an upregulation in the corticotropin releasing factor (CRF) mRNA levels in the central nucleus of the amygdala. These findings implicate dysregulations in the NPY-CRF systems in the HR hippocampus and amygdala associated with the emergence of social anxiety-like behavior, and a novel Y2R-mediated pathway in nicotine relapse.

Figure 1

Total locomotor reactivity to 0.35 mg/kg dose of nicotine or saline training injections (A), a low dose nicotine challenge (B; 0.1 mg/kg; s.c), percent time spent interacting with the resident rat in the SI test (C) and percent time spent in the light compartment in the LDB (D) following 1 wk of injection free period. Group means±SEMs are plotted in line (A) and bar (B, C, D) graphs. * represents the significant effects in total locomotor reactivity to nicotine in HRs compared to saline-injected controls, whereas # represents significant effects in nicotine-injected LRs compared to saline-injected controls. Significance is set at p = 0.05.

Figure 2

Alterations in NPY mRNA expression in the MeA (A, B), CA1 field of the hippocampus (C, D); Y2R mRNA expression in the CA3 field of the hippocampus (E, F) and CRF mRNA expression in the CeA (G, H) in HRs pre-trained with nicotine or saline. Panels A, C, E and G show images of representative coronal hemisections of the amygdala and the hippocampus that were radioactively labeled with an antisense cRNA probe against NPY (A, C), Y2R (E) and CRF (G) mRNA, and exposed on an x-ray film. Means of quantification results for integrated densities ± SEMs are plotted with bar graphs (B, D, F, H; *: p ≤ 0.05). Scale bar = 250 µm.