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

Abstract

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 β2 or α7 nAChR subunit knockout (KO) and corresponding wild-type (WT) mice were withdrawn from 12 days of chronic nicotine treatment (6.3 mg/kg/day), and trained with 2 conditioned stimulus (CS; 85 dB white noise) -unconditioned stimulus (US; 0.57mA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.

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

“…It is important to note that these plasma nicotine levels were within the range observed in smokers [5,64]. Additionally, withdrawal from chronic nicotine disrupts contextual but not cued conditioning [2,33,30,132,133], and this impairment in contextual learning can be ameliorated by nicotine replacement and by the smoking cessation drugs bupropion and varenicline [30,132,135]. Together, these data suggest that associations between stimuli and the effects of nicotine in humans may contribute to nicotine addiction, and these effects can be modeled in mice by studying the effects of nicotine on contextual learning.…”

“…Although these data suggest that α7 nAChRs mediate some aspects of nicotine withdrawal, other research has found that withdrawal-associated changes in contextual learning and anxiety are not affected by the deletion of the α7 subunit. Specifically, α7 KO and WT mice both exhibit nicotine withdrawal-related deficits in contextual conditioning [133]. Furthermore, withdrawal-associated increases in anxiety, as measured by decreased time in the open arms of the elevated plus maze, were present in both KO and WT mice [77].…”

“…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]. Taken together, these data reveal that β2-containing nAChRs are required for the enhancing effects of nicotine on hippocampus-dependent learning, as well as for the disruption of learning that occurs during nicotine withdrawal.…”

“…Mice withdrawn from nicotine spend less time on the open arms relative to saline controls, indicating increased anxiety [28,77]. Furthermore, nicotine withdrawal-related deficits in contextual learning have been evaluated in mice [33,30,132,133]. Withdrawal-related decreases in the brain reward system in humans has been modeled using the intracranial self stimulation (ICSS) procedure, in which rats press a lever to deliver electrical stimulation to reward-related brain areas.…”

Nicotine withdrawal disrupts both foreground and background contextual fear conditioning but not pre-pulse inhibition of the acoustic startle response in C57BL/6 mice

“…Although animal models have been used to examine the somatic and affective symptoms of nicotine withdrawal, less research has focused on the effects of nicotine withdrawal on learning and memory. One behavioral paradigm that has been used to examine the effects of nicotine on learning and memory is contextual fear conditioning [see 31 for review], and studies have consistently shown that acute nicotine enhances contextual conditioning, chronic nicotine does not alter contextual conditioning and nicotine withdrawal disrupts contextual conditioning [16,13,15,32,64,65].…”