Reward Sensitization: Effects of Repeated Nicotine Exposure and Withdrawal in Mice

Abstract

Tobacco dependence is an addiction with high rates of relapse, resulting in multiple quit attempts in individuals who are trying to stop smoking. How these multiple cycles of smoking and withdrawal contribute to nicotine dependence, long-term alterations in brain reward systems, and nicotine receptor regulation is unknown. Therefore, to evaluate how multiple exposures of nicotine and withdrawal periods modulate rewarding properties of nicotine, we used intracranial self-stimulation to measure alterations in the threshold of brain stimulation reward. In addition, we employed the conditioned place preference (CPP) paradigm to evaluate positive context conditioning following each withdrawal period and measured levels of neuronal nicotinic receptors in cortex, striatum, and hippocampus. We found that repeated nicotine exposure and withdrawal enhanced brain stimulation reward and reward sensitivity to acute injections of nicotine. This increased reward was reflected by enhanced CPP to nicotine. Chronic nicotine is known to up-regulate nAChRs (nicotinic acetylcholine receptors) and we found that this up-regulation was maintained for up to 8 days of withdrawal in the striatum and in the hippocampus, but not in the cortex, of animals exposed to multiple nicotine exposure and withdrawal periods. These results demonstrate that repeated exposures to nicotine, followed by withdrawal, induce a persistent increase in both brain reward function and sensitivity to the hedonic value of nicotine and long-lasting up-regulation of neuronal nicotinic receptors. Together, these data suggest that a continuing increase in brain reward function and enhanced sensitivity to nicotine reward following repeated withdrawal periods may be one reason why smokers relapse frequently.

Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons

“…During a single withdrawal episode, 3 H nicotine binding sites increase in cerebral cortex and midbrain (35). In contrast, repeated cycles of nicotine treatment and withdrawal result in progressive up-regulation of 3 H epibatidine sites in striatum and hippocampus but not in the cortex (36). Given these studies, and the cell-specific response we have demonstrated here, it would be interesting to compare cytisine-resistant radioligand binding studies under a variety of withdrawal conditions to distinguish the responses of α4β2* and α3β4* receptors.…”

Nicotine Dependence Reveals Distinct Responses from Neurons and Their Resident Nicotinic Receptors in Medial Habenula

“…Mice received a mean dose of 1 mg/kg per hour of nicotine for 14 days. The nicotine dose used in this study to develop physical dependence was chosen based on the results obtained in previous studies (Matta et al, 2007;Hilario et al, 2012;Shih et al, 2014). This dose yields plasma levels of ∼0.3 mM, a concentration similar to that observed in human smokers consuming an average of 17 cigarettes a day (Matta et al, 2007).…”

Genetic deletion of the adenosine A2A receptor prevents nicotine-induced upregulation of α7, but not α4β2* nicotinic acetylcholine receptor binding in the brain

“…The prolonged exposure to nicotine has been consistently shown to increase nAChR binding, both in cigarette smokers (Mukhin et al, 2008;Staley et al, 2006) and in animal models of nicotine intake (Marks et al, 1983;Schwartz and Kellar, 1983). This neurochemical adaptation has been associated with several nicotine-induced behaviours, including self-administration (Metaxas et al, 2010), reward sensitisation (Hilario et al, 2012), locomotor activity tolerance (McCallum et al, 2006), and nicotine withdrawal (Gould et al, 2012).…”