Role of neuronal nicotinic receptors in the effects of nicotine and ethanol on contextual fear conditioning

Kenney

Neurobiology of Learning and Memory

2008

Acute nicotine enhances contextual fear conditioning, whereas withdrawal from chronic nicotine produces impairments. However, the nicotinic acetylcholine receptors (nAChR) that are involved in nicotine withdrawal deficits in contextual fear conditioning are unknown. The present study used genetic and pharmacological techniques to investigate the nAChR subtype(s) involved in the effects of nicotine withdrawal on contextual fear conditioning. β2 or α7 nAChR subunit knockout (KO) and corresponding wild-type (WT) mice were withdrawn from 12 days of chronic nicotine treatment (6.3 mg/kg/day), and trained with 2 conditioned stimulus (CS; 85 dB white noise) -unconditioned stimulus (US; 0.57mA footshock) pairings on day 13. On day 14, mice were tested for contextual and cued freezing. β2 KO mice did not show nicotine withdrawal-related deficits in contextual fear conditioning, in contrast to WT mice and α7 KO mice. A follow-up study investigated if nicotine withdrawal disrupts acquisition or recall of contextual fear conditioning. The high affinity nAChR antagonist dihydro-beta-erythroidine (DHβE; 3 mg/kg) was administered prior to training or testing to precipitate withdrawal in chronic nicotine-treated C57BL/6 mice. Deficits in contextual fear conditioning were observed in chronic nicotine-treated mice when DHβE was administered prior to training, but not when administered at testing. These results indicate that β2-containing nAChRs, such as the α4β2 receptor, mediate nicotine withdrawal deficits in contextual fear conditioning. In addition, nicotine withdrawal selectively affects acquisition but not recall or expression of the learned response.

Section: Discussionsupporting

confidence: 80%

β2 subunit containing acetylcholine receptors mediate nicotine withdrawal deficits in the acquisition of contextual fear conditioning

Kenney

Neurobiology of Learning and Memory

2008

“…Research from our lab has demonstrated that β2 KO mice show no enhancement of trace cued conditioning by acute nicotine, whereas WT littermates do [34]. Similarly, acute nicotine enhances contextual conditioning in β2 WT mice but not in KO mice, suggesting that the effects of acute nicotine on hippocampus-dependent learning likely require α4β2* nAChRs [186]. Furthermore, nicotine withdrawal-related deficits in contextual conditioning are present in β2 subunit WT mice but not in KO mice [133].…”

Section: The β2 Nachr Subunitmentioning

confidence: 89%

“…Consistent with these data, research in mice has demonstrated that nicotine alters contextual learning. In mice trained to form an association between an auditory conditioned stimulus (CS) and a footshock unconditioned stimulus (US; cued conditioning), and an association between the training context CS and the US (contextual conditioning), acute nicotine enhances contextual conditioning, but has no effect on cued conditioning [30,32,31,56,55,186]. However, contextual conditioning is not altered by a dose of chronic nicotine that produces the same plasma nicotine levels as the acute dose that produces enhancement, suggesting the development of tolerance [30].…”

Section: Nicotinic Acetylcholine Receptors: Animal Researchmentioning

confidence: 99%

“…Research examining the rewarding properties of nicotine has found that both α7 KO and WT mice can develop nicotine CPP, suggesting that α7 nAChRs are not critical for the effects of nicotine on reward [181]. The enhancing effects of acute nicotine on contextual conditioning and trace cued conditioning are also normal in α7 KO mice, but only when a lower footshock US intensity is used [34,186]. At higher footshock intensities, both α7 KO and WT mice do not show enhancement of contextual conditioning by acute nicotine [186].…”

Section: The α7 Nachr Subunitmentioning

confidence: 99%

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Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

Behavioural Brain Research

2008

Tobacco smoking is a leading preventable cause of death in the United States and produces a major health and economic burden. Although the majority of smokers want to quit, few are successful. These data highlight the need for additional research into the neurobiology of tobacco dependence. Addiction to nicotine, the main psychoactive component of tobacco, is influenced by multiple factors that include individual differences in genetic makeup. Twin studies have demonstrated that genetic factors can influence vulnerability to nicotine addiction, and subsequent research has identified genes that may alter sensitivity to nicotine. In humans, genome-wide and candidate gene association studies have demonstrated that genes encoding nicotinic acetylcholine receptor (nAChR) proteins are associated with multiple smoking phenotypes. Similarly, research in mice has provided evidence that naturally occurring variability in nAChR genes is associated with changes in nicotine sensitivity. Furthermore, the use of genetic knockout mice has allowed researchers to determine the nAChR genes that mediate the effects of nicotine, whereas research with knockin mice has demonstrated that changes to nAChR genes can dramatically alter nicotine sensitivity. This review will examine the genetic factors that alter susceptibility to nicotine addiction, with an emphasis on the genes that encode nAChR proteins.

“…One ideal animal model for examining the effects of nicotine withdrawal on learning and memory is Pavlovian fear conditioning, in which subjects form an association between a context and a footshock (contextual fear conditioning), and an association between an auditory stimulus and a footshock (cued fear conditioning). Previous studies have shown that acute nicotine enhanced contextual fear conditioning but had no effect on cued fear conditioning in mice (Davis et al, 2005;Davis et al, 2006;Gould and Higgins, 2003;Gould and Wehner, 1999;Wehner et al, 2004). In contrast, withdrawal from chronic nicotine produced impairments in contextual fear conditioning but not cued fear conditioning (Davis and Gould, 2007;Davis et al, 2005).…”

Section: Introductionmentioning

confidence: 97%

Bupropion dose-dependently reverses nicotine withdrawal deficits in contextual fear conditioning

Pharmacology Biochemistry and Behavior

2007

Bupropion, a norepinephrine and dopamine reuptake inhibitor and nicotinic acetylcholine receptor antagonist, facilitates smoking cessation and reduces some symptoms of nicotine withdrawal. However, the effects of bupropion on nicotine withdrawal-associated deficits in learning remain unclear. The present study investigated whether bupropion has effects on contextual and cued fear conditioning following withdrawal from chronic nicotine or when administered alone. Bupropion was administered alone for a range of doses (2.5, 5, 10, 20 or 40 mg/kg), and dose-dependent impairments in contextual and cued fear conditioning were observed (20 or 40 mg/kg). Follow-up studies investigated if bupropion disrupted acquisition or expression of fear conditioning. Bupropion (40 mg/kg) administration on training day only produced deficits in contextual fear conditioning. Alternatively, bupropion (20 or 40 mg/kg) administration during testing dose-dependently produced deficits in contextual and cued fear conditioning. To test the effect of bupropion on nicotine withdrawal, mice were withdrawn from 12 days of chronic nicotine (6.3 mg/kg/day) or saline treatment. Withdrawal from chronic nicotine disrupted contextual fear conditioning; however, 5 mg/ kg bupropion reversed this deficit. Overall, these results indicate that a low dose of bupropion can reverse nicotine withdrawal deficits in contextual fear conditioning, but that high doses of bupropion produce deficits in fear conditioning.