Sex Differences in the Mechanisms that Modulate the Neurochemical Effects of Nicotine
Prior behavioral studies in our laboratory revealed that overexpression of the stress peptide, corticotrophin-releasing factor (CRF), in the mesocorticolimbic reward pathway enhanced the reinforcing effects of nicotine. The latter effect was greater in female versus male rats, suggesting that females are uniquely susceptible to the effects of stress on nicotine reinforcement. The goal of this dissertation was to examine the neurochemical mechanisms by which overexpression of CRF in the nucleus accumbens (NAc), a terminal region of the mesocorticolimbic pathway, modulates the behavioral effects of nicotine. Specifically, we examined whether nicotine-induced dopamine levels are altered by CRF overexpression via excitatory (glutamate) and/or inhibitory (γ-aminobutyric acid; GABA) amino acid control of dopamine release in the NAc of female versus male rats. The animals first received intra-NAc infusion of a viral vector (AAV2/5-CRF) to overexpress CRF mRNA in one hemisphere. In the contralateral NAc, a control viral vector (AAV2/5-GFP) was infused. Three weeks later, the rats were implanted with dialysis probes in the NAc of each hemisphere. The following day, dialysate samples were collected during baseline and then following administration of two doses of nicotine (0.3 and 0.6 mg/kg/expressed as base). Dopamine, GABA, and glutamate levels were assessed using liquid chromatography-mass spectrometry procedures. The results revealed that during baseline, there were no sex differences in any of our neurochemical measures following intra-NAc infusion of the control virus. Our statistical analysis revealed that only glutamate levels were significantly altered by CRF overexpression in the NAc. Specifically, in males, overexpression of CRF produced an increase in NAc glutamate levels during baseline and following nicotine administration. However, in females, overexpression of CRF produced a decrease in NAc glutamate levels during baseline and following nicotine administration. These data suggest that stress systems promote excitatory glutamatergic regulation of the NAc in a sex-dependent manner. Future studies are needed to examine the role of different glutamate receptors in the NAc in modulating the behavioral effects of nicotine in female versus male rats.
Uribe, Kevin Patrick, "Sex Differences in the Mechanisms that Modulate the Neurochemical Effects of Nicotine" (2020). ETD Collection for University of Texas, El Paso. AAI28258523.