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1.  Genetic Background Influences the Effects of Withdrawal from Chronic Nicotine on Learning and High-Affinity Nicotinic Acetylcholine Receptor Binding in the Dorsal and Ventral Hippocampus 
Psychopharmacology  2012;225(1):201-208.
The effects of nicotine on cognitive processes may play an important role in nicotine addiction. Nicotine withdrawal impairs hippocampus-dependent learning and genetic factors influence this effect. However, the neural changes that contribute to these impairments are unknown. Chronic nicotine upregulates hippocampal nicotinic acetycholine receptors (nAChRs), which may contribute to cognitive deficits when nicotine administration ceases. If nAChR upregulation underlies withdrawal-deficits in learning, then strains of mice exhibiting withdrawal-deficits in hippocampus-dependent learning should also show upregulation of hippocampal nAChRs.
Here, we examined the effects of nicotine withdrawal on fear conditioning and [3H]epibatidine binding in the dorsal and ventral hippocampus in two inbred mouse strains and their F1 hybrids.
Male C57BL/6NTac, 129S6/SvEvTac, and B6129SF1/Tac mice were administered chronic nicotine (18 mg/kg/d) for 12 days through osmotic pumps and then were trained and tested in fear conditioning 24 hours after cessation of nicotine treatment.
Nicotine withdrawal impaired hippocampus-dependent contextual conditioning in C57BL/6NTac mice but not 129S6/SvEvTac or B6129SF1/Tac mice; no changes were observed in hippocampus-independent cued fear conditioning. Upregulated [3H]epibatidine binding was found in the dorsal, but not ventral, hippocampus of C57BL/6NTac mice and in the ventral hippocampus of B6129SF1/Tac mice after chronic nicotine.
Upregulation of high-affinity binding sites in the dorsal hippocampus of C57BL/6NTac mice, the only strain that exhibited nAChR upregulation in this region and withdrawal-deficits in contextual conditioning, suggests that upregulation of high-affinity binding sites in the dorsal hippocampus mediates, in part, nicotine withdrawal-deficits in contextual conditioning and genetic background modulates these effects.
PMCID: PMC3755015  PMID: 22836371
Nicotine; addiction; genetics; learning; withdrawal; acetylcholine
2.  Effects of chronic low- and high-dose nicotine on cognitive flexibility in C57BL/6J mice 
Behavioural brain research  2012;238:134-145.
The addictive nature of nicotine remains a global health problem. Despite the availability of treatments for smoking cessation, relapse to smoking after quit attempts still remains very high. Here, we evaluated the effects of chronic nicotine in male C57BL/6J mice in an operant cognitive flexibility task that required the animals to progress sequentially through multiple phases including visual discrimination, strategy shifting and response reversal. As frontostriatal circuits involving discrete regions of dorsal striatum contribute directly to decision-making processes, and BDNF modulates synaptic plasticity and learning, we also assessed the effects of nicotine on striatal BDNF expression. Osmotic minipumps containing either of the two doses of nicotine (low: 6.3 mg/kg/day; high: 18 mg/kg/day) or saline (control) were implanted for chronic delivery that lasted 4 weeks. Nicotine-treated mice exhibited greater response accuracy during visual discrimination. Neither dose of nicotine affected learning of new egocentric response strategy during set-shifting. However, higher but not lower dose of nicotine impaired reversal learning by increasing perseverative responding to the previously non-reinforced stimulus. Furthermore, this effect was associated with reduced BDNF levels in the dorsal striatum. Collectively, these findings suggest that higher relapse rates often observed in high nicotine-dependent smokers may be attributed to impairments in inhibitory control processes. Moreover, striatal BDNF may play a critical role in nicotine-induced alterations in cognitive flexibility.
PMCID: PMC3513643  PMID: 23103711
Nicotine; addiction; cognitive flexibility; BDNF; mice
3.  Targeted Deletion of the Mouse α2 Nicotinic Acetylcholine Receptor Subunit Gene (Chrna2) Potentiates Nicotine-Modulated Behaviors 
Baseline and nicotine-modulated behaviors were assessed in mice harboring a null mutant allele of the nicotinic acetylcholine receptor (nAChR) subunit gene α2 (Chrna2). Homozygous Chrna2−/− mice are viable, show expected sex and Mendelian genotype ratios, and exhibit no gross neuroanatomical abnormalities. A broad range of behavioral tests designed to assess genotype-dependent effects on anxiety (elevated plus maze and light/dark box), motor coordination (narrow bean traverse and gait), and locomotor activity revealed no significant differences between mutant mice and age-matched wild-type littermates. Furthermore, a panel of tests measuring traits, such as body position, spontaneous activity, respiration, tremors, body tone, and startle response, revealed normal responses for Chrna2-null mutant mice. However, Chrna2−/− mice do exhibit a mild motor or coordination phenotype (a decreased latency to fall during the accelerating rotarod test) and possess an increased sensitivity to nicotine-induced analgesia in the hotplate assay. Relative to wild-type, Chrna2−/− mice show potentiated nicotine self-administration and withdrawal behaviors and exhibit a sex-dependent enhancement of nicotine-facilitated cued, but not trace or contextual, fear conditioning. Overall, our results suggest that loss of the mouse nAChR α2 subunit has very limited effects on baseline behavior but does lead to the potentiation of several nicotine-modulated behaviors.
PMCID: PMC3831006  PMID: 23637165
4.  Strain-dependent Effects of Acute, Chronic, and Withdrawal from Chronic Nicotine on Fear Conditioning 
Behavior genetics  2011;42(1):133-150.
The effects of nicotine on cognitive processes such as learning and memory may play an important role in the addictive liability of tobacco. However, it remains unknown whether genetic variability modulates the effects of nicotine on learning and memory. The present study characterized the effects of acute, chronic, and withdrawal from chronic nicotine administration on fear conditioning, somatic signs, and the elevated plus maze in 8 strains of inbred mice. Strain-dependent effects of acute nicotine and nicotine withdrawal on contextual fear conditioning, somatic signs, and the elevated plus maze were observed, but no association between the effects of acute nicotine and nicotine withdrawal on contextual fear conditioning were observed, suggesting that different genetic substrates may mediate these effects. The identification of genetic factors that may alter the effects of nicotine on cognition may lead to more efficacious treatments for nicotine addiction.
PMCID: PMC3788685  PMID: 21822688
Nicotine; Genetics; Addiction; Anxiety; Learning; Withdrawal
5.  The Duration of Nicotine Withdrawal-Associated Deficits in Contextual Fear Conditioning Parallels Changes in Hippocampal High Affinity Nicotinic Acetylcholine Receptor Upregulation 
Neuropharmacology  2012;62(5-6):2118-2125.
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.
PMCID: PMC3278577  PMID: 22285742
Nicotine; Addiction; Acetylcholine; Learning; Withdrawal; Receptor Binding
6.  Comparison of the Performance of DBA/2 and C57BL/6 Mice in Transitive Inference and Foreground and Background Contextual Fear Conditioning 
Behavioral Neuroscience  2012;126(2):249-257.
DBA/2 mice have altered hippocampal structure and perform poorly in several hippocampus-dependent contextual/spatial learning tasks. The performance of this strain in higher cognitive tasks is less studied. Transitive inference is a hippocampus-dependent task that requires an abstraction to be made from prior rules to form a new decision matrix; performance of DBA/2 mice in this task is unknown, whereas contextual fear conditioning is a hippocampus-dependent task in which DBA/2 mice have deficits. The present study compared DBA/2J and C57BL/6J inbred mice in two different contextual fear conditioning paradigms and transitive inference to test if similar deficits are seen across these hippocampus-dependent tasks. For background fear conditioning, mice were trained with two paired presentations of an auditory conditioned stimulus (CS, 30 second, 85 dB white noise) paired with an unconditioned stimulus (US, 2 second, 0.57 mA foot shock), the context was a continuous background CS. Mice were tested for contextual learning 24 hours later. Foreground fear conditioning differed in that no auditory CS was presented. For transitive inference, separate mice were trained to acquire a series of overlapping odor discrimination problems and tested with novel odor pairings that either did or did not require the use of transitive inference. DBA/2 mice performed significantly worse than the C57BL/6 in both foreground and background fear conditioning and transitive inference. These results demonstrate that the DBA/2 mice have deficits in higher-cognitive processes and suggest that similar substrates may underlie deficits in contextual learning and transitive inference.
PMCID: PMC3314134  PMID: 22309443
hippocampus; learning; fear conditioning; genetics; schizophrenia
7.  Nicotinic Receptors in the Dorsal and Ventral Hippocampus Differentially Modulate Contextual Fear Conditioning 
Hippocampus  2012;22(8):1681-1690.
Nicotine administration alters various forms of hippocampus-dependent learning and memory. Increasing work has found that the dorsal and ventral hippocampus differentially contribute to multiple behaviors. Thus, the present study examined whether the effects of nicotine in the dorsal and ventral hippocampus have distinct influences on contextual fear learning in male C57BL/6J mice. Direct infusion of nicotine into the dorsal hippocampus resulted in an enhancement of contextual fear learning, whereas nicotine infused into the ventral hippocampus resulted in deficits. Nicotine infusions into the ventral hippocampus did not alter hippocampus-independent cued fear conditioning or time spent in the open arm of the elevated plus maze, a measure of anxiety, suggesting the effects are due to alterations in contextual learning and not other general processes. Finally, results from using direct infusions of MLA, a low-affinity α7 nicotinic acetylcholine receptor (nAChR) antagonist, in conjunction with systemic nicotine, provide evidence that α7-nAChRs in the ventral hippocampus mediate the detrimental effect of ventral hippocampal nicotine on contextual fear learning. These results suggest that with systemic nicotine administration, competition exists between the dorsal and ventral hippocampus for behavioral control over contextual learning.
PMCID: PMC3343189  PMID: 22271264
Acetylcholine; learning; nicotine; low-affinity nAChRs; mouse
8.  The effects of galantamine on nicotine withdrawal-induced deficits in contextual fear conditioning in C57BL/6 mice 
Behavioural brain research  2011;223(1):53-57.
Current smoking cessation are relatively ineffective at maintaining abstinence during withdrawal. Nicotine withdrawal is associated with a variety of symptoms including cognitive deficits and targeting these deficits may be a useful strategy for maintaining abstinence. Galantamine is an acetylcholinesterase inhibitor and allosteric modulator of nicotinic acetylcholine receptors (nAChRs) with cognitive enhancing effects that may alleviate cognitive deficits associated with nicotine withdrawal. The effects of galantamine on nicotine withdrawal-induced deficits in contextual fear conditioning in C57BL/6 mice were examined. An initial acute dose-response experiment revealed that 0.5 and 1 mg/kg galantamine had no effect on fear conditioning. To determine if galantamine would reverse nicotine withdrawal-related deficits in contextual fear conditioning, mice were implanted with osmotic mini-pumps that delivered chronic saline or 6.3 mg/kg/d nicotine for 12 days and then pumps were removed. Training and testing of fear conditioning occurred 24 and 48 hours later, respectively. Nicotine withdrawal disrupted contextual fear conditioning, which was reversed with 1 but not 0.5 mg/kg galantamine. Across all conditions in both studies 2 mg/kg galantamine led to high levels of freezing that were likely due to nonspecific effects. The ability of galantamine to reverse nicotine withdrawal-deficits in contextual conditioning is likely mediated through enhanced levels of acetylcholine via inhibition of acetylcholinesterase, potentiation of hippocampal α4β2* nAChRs, or both. The present study suggests that acetylcholinesterase inhibitors and/or drugs that act as allosteric modulators of nAChRs might be targets for smoking cessation aids because they may alleviate withdrawal symptoms such as cognitive deficits that can lead to relapse.
PMCID: PMC3111856  PMID: 21514327
Nicotine; withdrawal; learning and memory; acetylcholine; addiction; cognition
9.  Developmental Effects of Acute, Chronic, and Withdrawal from Chronic Nicotine on Fear Conditioning 
Pre-adolescence and adolescence are developmental periods associated with increased vulnerability for tobacco addiction, and exposure to tobacco during these periods may lead to long-lasting changes in behavioral and neuronal plasticity. The present study examined the short- and long-term effects of nicotine and nicotine withdrawal on fear conditioning in pre-adolescent, adolescent, and adult mice, and potential underlying substrates that may mediate the developmental effects of nicotine, such as changes in nicotinic acetylcholine receptor (nAChR) binding, CREB expression, and nicotine metabolism. Age-related differences existed in sensitivity to the effects of acute nicotine, chronic nicotine and nicotine withdrawal on contextual fear conditioning (no changes in cued fear conditioning were seen); younger mice were more sensitive to the acute effects and less sensitive to the effects of nicotine withdrawal 24 hours post treatment cessation. Developmental differences in nAChR binding were associated with the effects of nicotine withdrawal on contextual learning. Developmental differences in nicotine metabolism and CREB expression were also observed, but were not related to the effects of nicotine withdrawal on contextual learning 24 hours post treatment. Chronic nicotine exposure during pre-adolescence or adolescence, however, produced long-lasting impairments in contextual learning that were observed during adulthood, whereas adult chronic nicotine exposure did not. These developmental effects could be related to changes in CREB. Overall, there is a developmental shift in the effects of nicotine on hippocampus-dependent learning and developmental exposure to nicotine results in adult cognitive deficits; these changes in cognition may play an important role in the development and maintenance of nicotine addiction.
PMCID: PMC3358528  PMID: 22521799
Hippocampus; Adolescent; Addiction; Learning; Acetylcholine
10.  Hippocampal nAChRs Mediate Nicotine Withdrawal-Related Learning Deficits 
Nicotine modulation of learning may contribute to its abuse liability. The role of hippocampal nicotinic acetylcholine receptors (nAChRs) in the effects of acute, chronic and withdrawal from chronic nicotine on learning was assessed via intrahippocampal drug infusion in mice. Acute dorsal hippocampal nicotine infusion enhanced contextual fear conditioning. Conversely, chronic intrahippocampal infusion of a matched dose had no effect, and withdrawal from chronic infusion impaired learning. Thus, hippocampal functional adaptation, evidenced by learning deficits during abstinence, occurs with the transition from acute to chronic nicotine exposure. To investigate which hippocampal nAChRs mediate these adaptations, C57BL/6, β2 nAChR subunit knockout (KO), and wildtype (WT) mice treated chronically with systemic nicotine received intrahippocampal dihydro-β-erythroidine (a high affinity nAChR antagonist). Intrahippocampal dihydro-β-erythroidine precipitated learning deficits in all but the KO mice. Therefore, the action of nicotine at hippocampal β2* nAChRs mediates adaptations in hippocampal function that underlie withdrawal deficits in contextual fear conditioning.
PMCID: PMC2777542  PMID: 19278836
nicotine; withdrawal; hippocampus; learning; nicotinic acetylcholine receptors; dihydro-β-erythroidine; addiction; cognition
11.  Nicotine acts in the anterior cingulate, but not dorsal or ventral hippocampus, to reverse ethanol-induced learning impairments in the plus-maze discriminative avoidance task 
Addiction biology  2011;16(1):176-188.
The current study examines the role of the dorsal and ventral hippocampus, and anterior cingulate in the interactive effects of ethanol and nicotine on learning, anxiety, and locomotion in the plus-maze discriminative avoidance task, which allows dissociation of drug effects on each behavior.
At training, time spent in each of the arms of the elevated plus-maze was recorded for five minutes. Each time that the mouse entered the aversive enclosed arm, a light and white noise were turned on. At testing, no cues were turned on and time spent in each arm was recorded for three minutes. The effects of systemic ethanol (1.0 or 1.4 g/kg) and nicotine (0.35 μg/0.50 μl/side) infused into the anterior cingulate, dorsal and ventral hippocampus were examined, as were the interactive effects of systemic ethanol (1.0 g/kg) and nicotine (0.09 mg/kg) with the high-affinity nicotinic receptor antagonist dihydro-beta-erythroidine (DHβE) (18.0 μg/0.50 μl/side) infused into the anterior cingulate.
Ethanol dose-dependently decreased anxiety, increased locomotion, and decreased learning. Anterior cingulate-infused nicotine decreased anxiety and reversed ethanol-associated learning deficits. Anterior cingulate-infused DHβE blocked reversal of ethanol-induced learning deficits by systemic nicotine. Dorsal hippocampus-infused nicotine reversed ethanol-induced anxiolysis and hyper-locomotion (1.4 g/kg) but produced no behavioral changes in ethanol-naïve mice. Ventral hippocampus-infused nicotine enhanced anxiolysis associated with 1.4 g/kg ethanol, but had no other effects.
The anterior cingulate is necessary and sufficient for nicotine reversal of ethanol-induced learning deficits. In addition, the anterior cingulate, dorsal hippocampus, and ventral hippocampus may mediate drug-induced changes in anxiety.
PMCID: PMC2925056  PMID: 20331558
nAChR; Learning; Anxiety; Motor Behavior; Alcohol
12.  The GSK3 Signaling Pathway Is Activated by Cocaine and Is Critical for Cocaine Conditioned Reward in Mice 
PLoS ONE  2014;9(2):e88026.
The Akt - GSK3 signaling pathway has been recently implicated in psychostimulant-induced behavioral and cellular effects. Here, the ability of cocaine to regulate the activity of Akt and GSK3 was investigated by measuring the phosphorylation states of the two kinases. The anatomical specificity of the response was determined, as was the contributions of dopamine and NMDA receptors to the actions of cocaine. As GSK3 activity was found to be increased by cocaine, subsequent experiments investigated the importance of GSK3 activation in cocaine conditioned reward. Adult male CD-1 mice were injected with cocaine or saline, and levels of phosphorylated Akt and GSK3α/β were measured 30 minutes later. Acute administration of cocaine significantly decreased the phosphorylation of Akt-Thr308 (pAkt-Thr308) and GSK3β in the caudate putamen and nucleus accumbens core, without altering pAkt-Ser473 and pGSK3α. To investigate the role of dopamine and NMDA receptors in the regulation of Akt and GSK3 by cocaine, specific receptor antagonists were administered prior to cocaine. Blockade of dopamine D2 receptors with eticlopride prevented the reduction of pAkt-Thr308 produced by cocaine, whereas antagonists at dopamine D1, dopamine D2 or glutamatergic NMDA receptors each blocked cocaine-induced reductions in pGSK3β. The potential importance of GSK3 activity in the rewarding actions of cocaine was determined using a cocaine conditioned place preference procedure. Administration of the selective GSK3 inhibitor, SB 216763, prior to cocaine conditioning sessions blocked the development of cocaine place preference. In contrast, SB 216763 did not alter the acquisition of a contextual fear conditioning response, demonstrating that SB 216763 did not globally inhibit contextual learning processes. The results of this study indicate that phosphorylation of GSK3β is reduced, hence GSK3β activity is increased following acute cocaine, an effect that is contingent upon both dopaminergic and glutamatergic receptors. Further, GSK3 activity is required for the development of cocaine conditioned reward.
PMCID: PMC3913742  PMID: 24505362
13.  The enhancement of contextual fear conditioning by ABT-418 
Behavioural pharmacology  2010;21(3):246-249.
Activation of nicotinic acetylcholine receptors (nAChRs) is known to modulate various forms of learning and memory, including contextual fear conditioning. Although numerous studies have shown that high-affinity β2-containing nAChRs are necessary for the nicotine-induced enhancement of contextual fear conditioning, it is unknown whether other high-affinity nAChR agonists are capable of enhancing this learning. To examine this issue, ABT-418, a high-affinity nAChR agonist with greater selectivity for high-affinity receptors than nicotine, was administered before acquisition and/or recall of contextual fear memories. ABT-418 enhanced acquisition of contextual fear memories in a dose-dependent manner.
PMCID: PMC3042125  PMID: 20400893
ABT-418; acetylcholine; learning; memory; mouse; nicotinic acetylcholine receptors; nicotine
14.  Nicotine and Extinction of Fear Conditioning 
Neuroscience  2009;165(4):1063.
Despite known health risks, nicotine use remains high, especially in populations diagnosed with mental illnesses, including anxiety disorders and Post-Traumatic Stress Disorder (PTSD). Smoking in these populations may relate to the effects of nicotine on emotional memories. The current study examined the effects of nicotine administration on the extinction of conditioned fear memories.
C57BL/6J mice were trained with 2 white noise conditioned stimulus (CS; 30 s, 85 dB)-foot shock (2 s, 0.57 mA) pairings. Extinction sessions consisted of 6 presentations of the CS (60 s) across multiple days. Mice were either tested in an AAA design, in which all stages occurred in the same context, or in an ABA design to identify if context changes alter extinction. Saline or nicotine was administered 5 minutes before training and/or extinction.
In the AAA design, nicotine administration before training did not alter extinction. Nicotine administered prior to extinction sessions enhanced extinction and nicotine administered before training and extinction decreased extinction. In the ABA design, nicotine administered before extinction enhanced extinction and blocked context renewal of conditioned fear, while nicotine administered during training and extinction did not alter extinction but enhanced the context renewal of conditioned fear.
Nicotine has a differential effect on extinction of fear conditioning depending on when it is administered. Administration during extinction enhances extinction whereas administration during training and extinction may strengthen contextual fear memories and interfere with extinction.
PMCID: PMC2814978  PMID: 19931599
Addiction; Learning; Extinction; PTSD; Anxiety; Acetylcholine
15.  The effects of acute, chronic, and withdrawal from chronic nicotine on novel and spatial object recognition in male C57BL/6J mice 
Psychopharmacology  2011;217(3):353-365.
Spatial and novel object recognition learning is different from learning that uses aversive or appetitive stimuli to shape acquisition because no overt contingencies are needed. While this type of learning occurs on a daily basis, little is known about how nicotine administration affects it.
To determine the effects of acute, chronic, and withdrawal from chronic nicotine on two related but distinct incidental learning tasks, novel and spatial object recognition.
In C57BL/6J mice, the effects of acute (0.045–0.18 mg/kg), chronic (6.3 mg/kg/day), and withdrawal from chronic nicotine on novel and spatial object recognition were examined.
With a 48-h delay between training and testing, acute nicotine enhanced spatial (difference score, saline=3.34 s, nicotine=7.71 s, p=0.029) but resulted in a deficit in novel object recognition (difference score, saline=8.76 s, nicotine= 4.48 s, p=0.033). Chronic nicotine resulted in a strong trend towards a deficit in spatial object recognition (difference score, saline=4.01 s, nicotine=1.81 s, p=0.059) but had no effect on novel object recognition, and withdrawal from chronic nicotine disrupted spatial object recognition (difference score, saline=3.00 s, nicotine=0.17 s, p=0.004) but had no effect on novel object recognition.
The effects of nicotine on spatial object recognition shift from enhancement to deficit as administration changes from acute to chronic and withdrawal. These effects were specific for spatial object recognition, which may be due to differing underlying neural substrates involved in these tasks. Understanding how nicotine alters learning has implications for understanding diseases associated with altered cholinergic function.
PMCID: PMC3161157  PMID: 21487656
Acetylcholine; Learning and memory; Hippocampus; Addiction; Mice; Rodent; Object-place memory; Nicotine; Object recognition; Spatial memory
16.  Addiction and Cognition 
The brain regions and neural processes that underlie addiction overlap extensively with those that support cognitive functions, including learning, memory, and reasoning. Drug activity in these regions and processes during early stages of abuse foster strong maladaptive associations between drug use and environmental stimuli that may underlie future cravings and drug-seeking behaviors. With continued drug use, cognitive deficits ensue that exacerbate the difficulty of establishing sustained abstinence. The developing brain is particularly susceptible to the effects of drugs of abuse; prenatal, childhood, and adolescent exposures produce long-lasting changes in cognition. Patients with mental illness are at high risk for substance abuse, and the adverse impact on cognition may be particularly deleterious in combination with cognitive problems related to their mental disorders.
PMCID: PMC3120118  PMID: 22002448
17.  Involvement of Hippocampal Jun-N terminal Kinase Pathway in the Enhancement of Learning and Memory by Nicotine 
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 changes in behavior. The present study is the first to explore how nicotine interacts with learning to alter gene transcription, 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 in the presence of nicotine whereas neither learning alone nor nicotine administration alone had 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 prior to conditioning and inhibition of JNK during consolidation prevented the nicotine-induced enhancement of contextual fear conditioning. These data suggest that nicotine and learning interact to alter hippocampal JNK1 gene expression and related signaling processes, thus resulting in strengthened contextual memories.
PMCID: PMC2794924  PMID: 19776730
Hippocampus; acetylcholine; MAPK; addiction; learning; gene transcription
18.  Learning and Nicotine Interact to Increase CREB Phosphorylation at the jnk1 Promoter in the Hippocampus 
PLoS ONE  2012;7(6):e39939.
Nicotine is known to enhance long-term hippocampus dependent learning and memory in both rodents and humans via its activity at nicotinic acetylcholinergic receptors (nAChRs). However, the molecular basis for the nicotinic modulation of learning is incompletely understood. Both the mitogen activated protein kinases (MAPKs) and cAMP response element binding protein (CREB) are known to be integral to the consolidation of long-term memory and the disruption of MAPKs and CREB are known to abrogate some of the cognitive effects of nicotine. In addition, the acquisition of contextual fear conditioning in the presence of nicotine is associated with a β2-subunit containing nAChR-dependent increase in jnk1 (mapk8) transcription in the hippocampus. In the present study, chromatin immunoprecipitation (ChIP) was used to examine whether learning and nicotine interact to alter transcription factor binding or histone acetylation at the jnk1 promoter region. The acquisition of contextual fear conditioning in the presence of nicotine resulted in an increase in phosphorylated CREB (pCREB) binding to the jnk1 promoter in the hippocampus in a β2-subunit containing nAChR dependent manner, but had no effect on CREB binding; neither fear conditioning alone nor nicotine administration alone altered transcription factor binding to the jnk1 promoter. In addition, there were no changes in histone H3 or H4 acetylation at the jnk1 promoter following fear conditioning in the presence of nicotine. These results suggest that contextual fear learning and nicotine administration act synergistically to produce a unique pattern of protein activation and gene transcription in the hippocampus that is not individually generated by fear conditioning or nicotine administration alone.
PMCID: PMC3386232  PMID: 22761932
19.  The hippocampus and cingulate cortex differentially mediate the effects of nicotine on learning versus on ethanol-induced learning deficits via different effects at nicotinic receptors 
The current study examined the effects of nicotine infusion into the dorsal hippocampus or anterior cingulate on fear conditioning and on ethanol-induced deficits in fear conditioning, and whether these effects involved receptor activation or inactivation.
Conditioning consisted of two white noise (30 seconds, 85 dB)–foot shock (2 seconds, 0.57 mA) pairings. Saline or ethanol was administered to C57BL/6 mice 15 minutes before training and saline or nicotine was administered 5 minutes before training or before training and testing. The ability of the high-affinity nicotinic acetylcholinergic receptor (nAChR) antagonist dihydro-beta-erythroidine (DHβE) to modulate the effects of ethanol and nicotine was also tested; saline or DHβE was administered 25 (injection) or 15 (infusion) minutes before training or before training and testing.
Infusion of nicotine into the hippocampus enhanced contextual fear conditioning but had no effect on ethanol-induced learning deficits. Infusion of nicotine into the anterior cingulate ameliorated ethanol-induced deficits in contextual and cued fear conditioning but had no effect on learning in ethanol-naïve mice. DHβE blocked the effects of nicotine on ethanol-induced deficits; interestingly, DHβE alone and co-administration of sub-threshold doses of DHβE and nicotine also ameliorated ethanol-induced deficits but failed to enhance learning. Finally, DHβE failed to ameliorate ethanol-induced deficits in β2 nAChR subunit knockout mice.
These results suggest that nicotine acts in the hippocampus to enhance contextual learning, but acts in the cingulate to ameliorate ethanol-induced learning deficits through inactivation of high-affinity β2 subunit-containing nAChRs.
PMCID: PMC2770339  PMID: 19404242
Alcohol; Addiction; Learning and Memory; Hippocampus; Anterior Cingulate
20.  Nicotine Withdrawal Disrupts Contextual Learning but Not Recall of Prior Contextual Associations: Implications for Nicotine Addiction 
Interactions between nicotine and learning could contribute to nicotine addiction. Although previous research indicates that nicotine withdrawal disrupts contextual learning, the effects of nicotine withdrawal on contextual memories acquired before withdrawal are unknown. The present study investigated whether nicotine withdrawal disrupted recall of prior contextual memories by examining the effects of nicotine withdrawal on recall of nicotine conditioned place preference (CPP) and contextual fear conditioning. C57BL/6J mice trained in CPP exhibited a significant preference for an initially non-preferred chamber that was paired with 0.35 mg/kg nicotine. Following CPP, mice were implanted with mini-osmotic pumps containing 6.3 mg/kg/d nicotine or saline. Pumps were removed twelve days later and nicotine CPP was retested 24 hours later. Mice withdrawn from chronic nicotine exhibited CPP, suggesting that older drug-context associations are not disrupted by nicotine withdrawal. One hour later, the same mice were trained in contextual and cued fear conditioning; nicotine withdrawal disrupted contextual but not cued fear conditioning. A subsequent experiment demonstrated that nicotine withdrawal did not disrupt recall of contextual or cued fear conditioning when acquisition occurred before nicotine withdrawal. These data suggest that nicotine withdrawal disrupts new contextual learning, but does not alter contextual learning that occurred before withdrawal.
PMCID: PMC2777668  PMID: 19028516
Nicotine; Withdrawal; Learning; Reward; Addiction; Hippocampus
21.  Genetic Variability in Nicotinic Acetylcholine Receptors and Nicotine Addiction: Converging Evidence from Human and Animal Research 
Behavioural brain research  2008;193(1):1-16.
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.
PMCID: PMC2602830  PMID: 18571741
Genetics; Nicotine; Addiction; Withdrawal; Acetylcholine; Mice
22.  Sensorimotor Gating Deficits in Transgenic Mice Expressing a Constitutively Active Form of Gsα 
Neuropsychopharmacology  2004;29(3):494-501.
Schizophrenia is a complex disorder characterized by wide-ranging cognitive impairments, including deficits in learning as well as sensory gating. The causes of schizophrenia are unknown, but alterations in intracellular G-protein signaling pathways are among the molecular changes documented in patients with schizophrenia. Using the CaMKIIα promoter to drive expression in neurons within the forebrain, we have developed transgenic mice that express a constitutively active form of Gsα (Gsα*), the G protein that couples receptors such as the D1 and D5 dopamine receptors to adenylyl cyclase. We have also generated mice in which the CaMKIIα promoter drives expression of a dominant-negative form of protein kinase A, R(AB). Here, we examine startle responses and prepulse inhibition of the startle reflex (PPI) in these Gsα* and R(AB) transgenic mice. Gsα* transgenic mice exhibited selective deficits in PPI, without exhibiting alterations in the startle response, whereas no deficit in startle or PPI was found in the R(AB) transgenic mice. Thus, overstimulation of the cAMP/PKA pathway disrupts PPI, but the cAMP/PKA pathway may not be essential for sensorimotor gating. Gsα* transgenic mice may provide an animal model of certain endophenotypes of schizophrenia, because of the similarities between them and patients with schizophrenia in G-protein function, hippocampus-dependent learning, and sensorimotor gating.
PMCID: PMC3348581  PMID: 14694347
G proteins; protein kinase A; startle response; prepulse inhibition; schizophrenia; animal model
23.  Nicotine Enhances Context Learning but not Context-Shock Associative Learning 
Behavioral neuroscience  2008;122(5):1158-1165.
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 we made use of the context pre-exposure 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.
PMCID: PMC2559949  PMID: 18823171
Nicotine; Hippocampus; Fear Conditioning; Addiction; Acetylcholine; Memory
24.  Acute Ethanol Has Biphasic Effects on Short- and Long-Term Memory in Both Foreground and Background Contextual Fear Conditioning in C57BL/6 Mice 
Ethanol is a frequently abused, addictive drug that impairs cognitive function. Ethanol may disrupt cognitive processes by altering attention, short-term memory, and/ or long-term memory. Interestingly, some research suggests that ethanol may enhance cognitive processes at lower doses. The current research examined the dose-dependent effects of ethanol on contextual and cued fear conditioning. In addition, the present studies assessed the importance of stimulus salience in the effects of ethanol and directly compared the effects of ethanol on short-term and long-term memory.
This study employed both foreground and background fear conditioning, which differ in the salience of contextual stimuli, and tested conditioning at 4 hours, 24 hours, and 1 week in order to assess the effects of ethanol on short-term and long-term memory. Foreground conditioning consisted of 2 presentations of a foot shock unconditioned stimulus (US) (2 seconds, 0.57 mA). Background conditioning consisted of 2 auditory conditioned stimulus (30 seconds, 85 dB white noise)–foot shock (US; 2 seconds, 0.57 mA) pairings.
For both foreground and background conditioning, ethanol enhanced short-term and long-term memory for contextual and cued conditioning at a low dose (0.25 g/kg) and impaired short-term and long-term memory for contextual and cued conditioning at a high dose (1.0 g/kg).
These results suggest that ethanol has long-lasting, biphasic effects on short-term and long-term memory for contextual and cued conditioning. Furthermore, the effects of ethanol on contextual fear conditioning are independent of the salience of the context.
PMCID: PMC2744497  PMID: 17760787
Alcohol; Learning; Mice; NMDA Receptors; Addiction; Hippocampus
25.  Nicotine Withdrawal Disrupts Both Foreground and Background Contextual Fear Conditioning but not Pre-Pulse Inhibition of the Acoustic Startle Response in C57BL/6 Mice 
Behavioural brain research  2008;190(2):174-181.
Nicotine withdrawal is associated with multiple symptoms such as anxiety, increased appetite, and disrupted cognition in humans. Although animal models have provided insights into the somatic and affective symptoms of nicotine withdrawal, less research has focused on the effects of nicotine withdrawal on cognition. Therefore, in this study, C57BL/6 mice were used to test the effects of withdrawal from chronic nicotine on foreground and background contextual fear conditioning, which present the context as a primary or secondary stimulus, respectively. Mice withdrawn from 12 days of chronic nicotine (6.3 mg/kg/day) or saline were trained and tested in either foreground or background contextual fear conditioning; nicotine withdrawal-associated deficits in contextual fear conditioning were observed in both conditions. Mice were also tested for the effects of withdrawal on pre-pulse inhibition of the acoustic startle reflex (PPI), a measure of sensory gating, and on the acoustic startle reflex. Mice withdrawn from 12 days of chronic nicotine (6.3 or 12.6 mg/kg/day) or saline underwent one 30-minute PPI and startle session; no effect of withdrawal from chronic nicotine on PPI or startle was observed for either dose at 24 hours after nicotine removal. Therefore, mice were tested at different time points following withdrawal from 12.6 mg/kg/day chronic nicotine (8, 24, and 48 hours after nicotine removal). No effect of withdrawal from chronic nicotine was observed at any time point for PPI. Overall, these results demonstrate that nicotine withdrawal disrupts two methods of contextual learning but not sensory gating in C57BL/6 mice.
PMCID: PMC2409068  PMID: 18367257
learning; nicotine; withdrawal; addiction; sensory gating; acetylcholine

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