Neurobiological substrates of nicotine addiction
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Tobacco smoking, which is attributed partly to the addictive properties of nicotine, continues to be a worldwide problem of drug abuse. Considering that the risk for developing diseases associated with tobacco smoking is reduced when smoking is stopped, there is much incentive to invest research resources in elucidating the neurobiological substrates of nicotine dependence and the factors that lead to relapse to assist in the development of treatments for dependence on nicotine. With the present grant, work initiated under Specific Aim 1 began the exploration and identification of the neuronal substrates of nicotine dependence by identifying brain sites where antagonism of nicotinic acetylcholine receptors (nAchRs) is sufficient to induce aspects of the nicotine withdrawal syndrome (i.e., precipitated withdrawal) in rats. Elevations in brain reward thresholds can be precipitated in nicotine-treated rats with a variety of nAchR antagonists injected systemically or into specific brain sites. These threshold elevations are similar to those seen during spontaneous nicotine withdrawal. We investigated the effects of the nAchR antagonist dihydro-?-erythroidine (DH?E) injected into limbic brain sites, such as the nucleus accumbens and the ventral tegmental area, on brain reward thresholds in nicotine- and saline-treated rats. The results indicated that administration of the nAchR antagonist into the ventral tegmental area, but not into the shell of the nucleus accumbens, was sufficient to induce the reward threshold elevations associated with spontaneous nicotine withdrawal. This experimental outcome indicated that there is decreased nAchR number/function with the development of nicotine dependence in the ventral tegmental area that may contribute to withdrawal symptomatology and relapse. Elevations in brain reward thresholds reflect "diminished interest or pleasure" in the rewarding electrical stimuli and are an operational measure of the depressive symptom of anhedonia that characterizes tobacco withdrawal. Studies under Specific Aim 2 develop and use new animal models of nicotine dependence to explore whether the adaptations that occur in the function of the cholinergic system with the development of nicotine dependence in specific brain sites (explored in Specific Aim 1) are long-lasting and persistent. These long-lasting adaptations in the function/number of nAchRs was revealed by administering the nAchR antagonist mecamylamme long after the overt somatic aspects of spontaneous nicotine withdrawal have subsided. Rats were allowed to become dependent through daily intravenous nicotine self-administration. Different groups of rats had different access conditions to nicotine (1-6 hr 5 days/week or daily). The results indicated that, although there was no escalation in nicotine intake, subjects that had access to nicotine for 6 hours/day or even 1 hour/day developed dependence faster and their dependence was longer lasting than that of rats that had limited access to nicotine 1 hr/day, 5 days/week. These results indicate that dependence is long lasting, and can be revealed when the nAchR system is probed. Such long lasting dependence may contribute to relapse to tobacco smoking.