The duration of nicotine withdrawal-associated deficits in contextual fear conditioning parallels changes in hippocampal high affinity nicotinic acetylcholine receptor upregulation

Abstract

A predominant symptom of nicotine withdrawal is cognitive deficits, yet understanding of the neural basis for these deficits is limited. Withdrawal from chronic nicotine disrupts contextual learning in mice and this deficit is mediated by direct effects of nicotine in the hippocampus. Chronic nicotine treatment upregulates nicotinic acetylcholine receptors (nAChR); however, it is unknown whether upregulation is related to the observed withdawal-induced cognitive deficits. If a relationship between altered learning and nAChR levels exists, changes in nAChR levels after cessation of nicotine treatment should match the duration of learning deficits. To test this hypothesis, mice were chronically administered 6.3 mg/kg/day (freebase) nicotine for 12 days and trained in contextual fear conditioning on day 11 or between 1 to 16 days after withdrawal of treatment. Changes in [125I]-epibatidine binding at cytisine-sensitive and cytisine-resistant nAChRs and chronic nicotine-related changes in α4, α7, and β2 nAChR subunit mRNA expression were assessed. Chronic nicotine had no behavioral effect but withdrawal produced deficits in contextual fear conditioning that lasted 4 days. Nicotine withdrawal did not disrupt cued fear conditioning. Chronic nicotine upregulated hippocampal cytisine-sensitive nAChR binding; upregulation continued after cessation of nicotine administration and the duration of upregulation during withdrawal paralleled the duration of behavioral changes. Changes in binding in cortex and cerebellum did not match behavioral changes. No changes in α4, α7, and β2 subunit mRNA expression were seen with chronic nicotine. Thus, nicotine withdrawal-related deficits in contextual learning are time-limited changes that are associated with temporal changes in upregulation of high-affinity nAChR binding.

Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: contributions to development and maintenance of addiction

“…In addition to these general symptoms, cognitive deficits such as difficulty concentrating (Pomerleau et al 2000), disrupted working memory (Jacobsen et al 2005;Mendrek et al 2006), verbal memory problems (Jacobsen et al 2005), increased response time (Snyder et al 1989;Bell et al 1999), and problems in paired-associate learning (Kleinman et al 1973) were observed during nicotine withdrawal. In line with these reports, animal studies also showed that while chronic nicotine did not have any effect on hippocampus-dependent contextual and trace fear conditioning, nicotine withdrawal impaired hippocampal learning and memory (Davis et al 2005;Davis and Gould 2009;Raybuck and Gould 2009;Gould et al 2012Gould et al , 2014aPortugal et al 2012a, b;. Overall, human and animal studies demonstrate hippocampus-dependent learning and memory enhancement during initial nicotine exposure and cognitive deficits during nicotine withdrawal.…”

Activation ofα4β2*/α6β2* Nicotinic Receptors Alleviates Anxiety during Nicotine Withdrawal Without Upregulating Nicotinic Receptors

“…Previous studies suggest that the upregulated pool of nAChRs arising from long-term exposure to nicotine may drive elements of the nicotine withdrawal syndrome (Turner et al, 2011;Gould et al, 2012), and this protracted upregulation of nAChRs has been correlated with reduced ability to maintain abstinence in the clinical population (Staley et al, 2006). Therefore, to determine whether ABT-089 reduced anxiety during nicotine withdrawal in the NIH via maintenance of upregulated nAChRs, we quantified [ 3 H]EB binding density after long-term ABT-089 administration during nicotine withdrawal.…”

Nicotine Addiction and Psychiatric Disorders

“…There is also evidence suggesting that during chronic nicotine administration, hippocampal nAChRs desensitize and upregulate and the resulting hypersensitive cholinergic system may be responsible for the effects of nicotine withdrawal on hippocampus-dependent learning (Dani & Heinemann, 1996; Gould et al, 2012; Marks, Grady, & Collins, 1993; Wilkinson & Gould, 2013). In support, Gould et al (2012) found that chronic nicotine increased nAChR binding in the hippocampus and the duration of nAChR upregulation paralleled the duration of withdrawal deficits in hippocampus-dependent learning. Also supporting the role of hypersensitive nAChRs in the withdrawal effects, Wilkinson and Gould (2013) found that reintroducing acute nicotine into the system during nicotine withdrawal lead to an even greater enhancement of the contextual fear conditioning compared to the effects of acute nicotine in previously nicotine naïve mice.…”