Examination of the neurochemical mechanisms that mediate nicotine withdrawal in adolescent and adult rats
Introduction: The mechanisms that mediate nicotine withdrawal are presently unclear and age group differences in the neurochemical effects of withdrawal have been largely unexplored. Previous studies in our laboratory demonstrated that adult rats display a decrease in extracellular levels of dopamine in the nucleus accumbens (NAcc) during nicotine withdrawal and this decrease is reduced in adolescent rats (Natividad et al., 2010). The goal of this dissertation was to examine whether these age group differences in dopamine during withdrawal are mediated via excitatory and inhibitory mechanisms that modulate dopamine in the cell body region of the ventral tegmental area (VTA). Methods: Adolescent and adult rats (n=7-14) were prepared with subcutaneous pumps that delivered an equivalent dose of nicotine. On day 13 of nicotine exposure, the rats were implanted with microdialysis probes into the NAcc and the ipsilateral VTA. Dialysates collected from the NAcc were assayed for dopamine and the results were previously published (Natividad et al., 2010). The data presented here reflect dialysates collected from the VTA of the same rats. On day 14 of nicotine exposure, extracellular levels of glutamate and gamma-aminobutyric acid (GABA) in the VTA were monitored following administration of escalating doses of the nicotinic receptor antagonist mecamylamine to precipitate withdrawal. To examine whether mecamylamine alone produced neurochemical changes, a group of drug-naïve adolescent and adult rats (n=6 per group) received a sham surgery and were then monitored for extracellular levels of dopamine in the NAcc following the same dose regimen of mecamylamine. Results: Naïve rats of both age groups did not exhibit any alterations in NAcc dopamine levels following mecamylamine administration, suggesting that our pharmacological tool to precipitate withdrawal alone does not alter neurochemical measures. In adult rats, nicotine withdrawal produced a decrease in VTA glutamate levels (44% maximal decrease) and an increase in GABA levels (38% increase), consistent with an overall inhibition of dopamine cell activity. In contrast, adolescents did not exhibit significant changes in either VTA glutamate or GABA levels during nicotine withdrawal. In order to examine the relationship between NAcc dopamine and VTA amino acid transmission, regression analyses were performed for each age group before and after withdrawal. Following mecamylamine, decreases in dopamine were positively correlated with decreases in glutamate in adults, whereas adolescents did not exhibit any significant correlation. The relationship between dopamine and glutamate was significantly stronger in adult versus adolescent rats. Similarly, decreases in dopamine were negatively correlated with increases in GABA in adults, whereas adolescents did not exhibit any significant correlation. The relationship between dopamine and GABA was also significantly stronger in adult versus adolescent rats. Discussion: Overall, the results revealed that adults display a decrease in dopamine during nicotine withdrawal. This effect appears to be related to a decrease in excitatory and an increase in inhibitory mechanisms that modulate dopamine transmission in the cell body region of the VTA. On the other hand, adolescents appear to be resistant to these neurochemical changes that follow nicotine withdrawal. Specifically, adolescents do not exhibit deficits in VTA glutamate and elevations in VTA GABA that contribute to the decreases in NAcc dopamine during withdrawal in adults. Taken together, these results indicate that adolescents display resistance to withdrawal-related neurochemical processes that inhibit mesolimbic dopamine function in adults experiencing nicotine withdrawal. The findings provide a potential mechanism involving VTA amino acid neurotransmission that may begin to explain age group differences in nicotine withdrawal.
Natividad, Luis Alberto, "Examination of the neurochemical mechanisms that mediate nicotine withdrawal in adolescent and adult rats" (2012). ETD Collection for University of Texas, El Paso. AAI3512018.