Search

Acute nicotine enhances hippocampus-dependent learning. Identifying how acute nicotine improves learning will aid in understanding how nicotine facilitates the development of maladaptive memories that contribute to drug-seeking behaviors, help development of medications to treat disorders associated with cognitive decline, and advance understanding of the neurobiology of learning and memory. The effects of nicotine on learning may involve recruitment of signaling through the c-Jun N-terminal kinase family (JNK 1–3). Learning in the presence of acute nicotine increases the transcription of mitogen-activated protein kinase 8 (MAPK8, also known as JNK1), likely through a CREB-dependent mechanism. The functional significance of JNK1 in the effects of acute nicotine on learning, however, is unknown. The current studies undertook a backward genetic approach to determine the functional contribution JNK1 protein makes to nicotine-enhanced contextual fear conditioning. JNK1 wildtype (WT) and knockout (KO) mice were administered acute nicotine prior to contextual and cued fear conditioning. 24 h later, mice were evaluated for hippocampus-dependent (contextual fear conditioning) and hippocampus-independent (cued fear conditioning) memory. Nicotine selectively enhanced contextual conditioning in WT mice, but not in KO mice. Nicotine had no effect on hippocampus-independent learning in either genotype. JNK1 KO and WT mice given saline showed similar levels of learning. These data suggest that JNK1 may be recruited by nicotine and is functionally necessary for the acute effects of nicotine on learning and memory. [ABSTRACT FROM AUTHOR]

Despite intense scrutiny over the past 20 years, the reasons for the high addictive liability of nicotine and extreme rates of relapse in smokers have remained elusive. One factor that contributes to the development and maintenance of nicotine addiction is the ability of nicotine to produce long-lasting modifications of behavior, yet little is known about the mechanisms by which nicotine alters the underlying synaptic plasticity responsible for behavioral changes. This study is the first to explore how nicotine interacts with learning to alter gene transcription, which is a process necessary for long-term memory consolidation. Transcriptional upregulation of hippocampal jun-N terminal kinase 1 (JNK1) mRNA was found in mice that learned contextual fear conditioning (FC) in the presence of nicotine, whereas neither learning alone nor nicotine administration alone exerted an effect. Furthermore, the upregulation of JNK1 was absent in β2 nicotinic receptor subunit knockout mice, which are mice that do not show enhanced learning by nicotine. Finally, hippocampal JNK activation was increased in mice that were administered nicotine before conditioning, and the inhibition of JNK during consolidation prevented the nicotine-induced enhancement of contextual FC. These data suggest that nicotine and learning interact to alter hippocampal JNK1 gene expression and related signaling processes, thus resulting in strengthened contextual memories. [ABSTRACT FROM AUTHOR]

Nicotine has been found to enhance learning in a variety of tasks, including contextual fear conditioning. During contextual fear conditioning animals have to learn the context and associate the context with an unconditioned stimulus (footshock). As both of these types of learning co-occur during fear conditioning, it is not clear whether nicotine enhances one or both of these types of learning. To tease these two forms of learning apart, the authors made use of the context preexposure facilitation effect (CPFE). Acquisition of the CPFE requires that contextual and context-shock learning occurs on separate days, allowing for their individual manipulation. Nicotine (0.09 mg/kg) administered prior to contextual learning and retrieval enhanced the CPFE whereas administration prior to context-shock learning and retrieval had no effect. Thus, nicotine enhances contextual learning but not context-shock associative learning. Finally, the results are discussed in terms of a theory of how nicotine could alter hippocampal-cortical-amygdala interactions to facilitate contextual learning. [ABSTRACT FROM AUTHOR]

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 (6.3mg/kg/day), and trained with 2 conditioned stimulus (CS; 85dB 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-β-erythroidine (DHβE; 3mg/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. [Copyright &y& Elsevier]

Nicotine is known to enhance learning and memory in hippocampus-dependent tasks such as contextual fear conditioning. The present study was designed to directly examine whether the hippocampus plays a role in mediating this enhancement and which nicotinic acetylcholine receptor (nAChR) subtypes localized to the hippocampus are critical for enhanced learning. Contextual fear conditioning consisted of two white noise conditioned stimuli presentations, each coterminating with a 2 s, 0.57 mA footshock separated by a 120 s intertrial interval. Nicotine (0.09, 0.18, and 0.35 µg per side) was bilaterally infused into the dorsal hippocampus before training and testing. Infusions of nicotine into the dorsal hippocampus produced a dose-dependent enhancement of contextual fear conditioning. To determine which nAChRs are critical to the enhancing effect of nicotine, the preferential α4β2 nAChR antagonist, dihydro-β-erythroidine (DHβE) (6.00 and 18.00 µg per side), or the preferential α7 nAChR antagonist, methyllycaconitine (MLA) (13.50 and 27.00 µg per side), was bilaterally infused into the dorsal hippocampus before systemic injections of nicotine (0.09 mg/kg). DHβE infusions dose-dependently blocked the enhancement of contextual fear conditioning by nicotine, where as MLA infusions yielded an intermediate effect. In addition, neither DHβE nor MLA had an effect on contextual fear conditioning in the absence of systemic nicotine. The present results suggest a critical role for α4β2 nAChRs in the dorsal hippocampus for mediating the enhancing effect of nicotine on contextual fear conditioning. [ABSTRACT FROM AUTHOR]

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 withdrawal-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 6.3mg/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. [Copyright &y& Elsevier]