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Substance use disorder (SUD) is a behavioral disorder characterized by volitional drug consumption. Mouse models of SUD allow for the use of molecular, genetic, and circuit-level tools, providing enormous potential for defining the underlying mechanisms of this disorder. However, the relevance of results depends on the validity of the mouse models used. Self-administration models have long been the preferred preclinical model for SUD as they allow for volitional drug consumption, thus providing strong face validity. While previous work has defined the parameters that influence intravenous cocaine self-administration in other species-such as rats and primates-many of these parameters have not been explicitly assessed in mice. In a series of experiments, we showed that commonly used mouse models of self-administration, where behavior is maintained on a fixed-ratio schedule of reinforcement, show similar levels of responding in the presence and absence of drug delivery-demonstrating that it is impossible to determine when drug consumption is and is not volitional. To address these issues, we have developed a novel mouse self-administration procedure where animals do not need to be pretrained on sucrose and behavior is maintained on a variable-ratio schedule of reinforcement. This procedure increases rates of reinforcement behavior, increases levels of drug intake, and results in clearer delineation between drug-reinforced and saline conditions. Together, these data highlight a major issue with fixed-ratio models in mice that complicates subsequent analysis and provide a simple approach to minimize these confounds with variable-ratio schedules of reinforcement. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A large body of work has focused on understanding stimulus-driven behavior, sex differences in these processes, and the neural circuits underlying them. Many preclinical mouse models present rewarding or aversive stimuli in isolation, ignoring that ethologically, reward seeking requires the consideration of potential aversive outcomes. In addition, the context (or reinforcement schedule under) in which stimuli are encountered can engender different behavioral responses to the same stimulus. Thus, delineating neural control of behavior requires a dissociation between stimulus valence and stimulus-driven behavior. We developed the Multidimensional Cue Outcome Action Task (MCOAT) to dissociate motivated action from cue learning and valence in mice. First, mice acquire positive and negative reinforcement in the presence of discrete discriminative stimuli. Next, discriminative stimuli are presented concurrently allowing for parsing innate behavioral strategies based on reward seeking and avoidance. Lastly, responding in the face of punishment is assessed, thus examining how positive and negative outcomes are relatively valued. First, we identified sex-specific behavioral strategies, showing that females prioritize avoidance of negative outcomes over seeking positive, while males have the opposite strategy. Next, we show that chemogenetically inhibiting D1 medium spiny neurons (MSNs) in the nucleus accumbens—a population that has been linked to reward-driven behavior—reduces positive and increases negative reinforcement learning rates. Thus, D1 MSNs modulate stimulus processing, rather than motivated responses or the reinforcement process itself. Together, the MCOAT has broad utility for understanding complex behaviors as well as the definition of the discrete information encoded within cellular populations.

BackgroundThe inability to predict when aversive stimuli will and will not occur in is a hallmark of anxiety and stress disorders. Dopamine release in the nucleus accumbens (NAc) is sufficient and necessary for aversive learning and has been linked to both anxiety and stress disorder symptomatology. Thus, understanding how dopamine controls associative learning in response to aversive stimuli is critical to understanding the role of dopamine in behavior in health and disease.MethodsUsing an optical dopamine sensor combined with in-vivo fiber photometry in the NAc core of male and female C57BL/6J mice (N=38), we recorded dopamine responses to expected and omitted aversive outcomes during learning. We derived predictions from a theory-driven model of associative learning (Kutlu-Calipari-Schmajuk, KCS model) and tested the causality of these predictions using optogenetics.ResultsDopamine release was evoked by the predicted omission of aversive stimuli in a fashion that cannot be explained by dopamine as a reward-based prediction signal. The magnitude of the dopamine response during omissions scaled with predictions about the probability of their occurrence; however, dopamine did not track the associative value of predictive cues. Finally, we showed that the observed effects are causal to learned behavior and can only be explained by dopamine signaling the perceived saliency of predicted aversive events.ConclusionsWe elucidate the role of NAc core dopamine signaling in aversive learning in a theory-based and stimulus-specific fashion and offer potential avenues for understanding the neural mechanisms involved in anxiety and stress disorders.

Cognitive flexibility is the ability to switch strategic responses adaptively in changing environments. Cognitive rigidity imposed by neural circuit adaptations during nicotine abstinence may foster maladaptive nicotine taking in addicts. We systematically examined the effects of spontaneous withdrawal in mice exposed to either nicotine (6.3 or 18 mg/kg/day) or saline for 14 days on cognitive flexibility using an operant strategy set-shifting task. Because frontostriatal circuits are critical for cognitive flexibility and brain-derived neurotrophic factor (BDNF) modulates glutamate plasticity in these circuits, we also explored the effects of nicotine withdrawal on these neurochemical substrates. Mice undergoing nicotine withdrawal required more trials to attain strategy-switching criterion. Error analysis show that animals withdrawn from both nicotine doses committed higher perseverative errors, which correlated with measures of anxiety. However, animals treated with the higher nicotine dose also displayed more strategy maintenance errors that remained independent of negative affect. BDNF mRNA expression increased in the medial prefrontal cortex (mPFC) following nicotine withdrawal. Surprisingly, BDNF protein declined in mPFC but was elevated in dorsal striatum (DS). DS BDNF protein positively correlated with perseverative and maintenance errors, suggesting mPFC-DS overflow of BDNF during withdrawal. BDNF-evoked glutamate release and synapsin phosphorylation was attenuated within DS synapses, but enhanced in the nucleus accumbens, suggesting a dichotomous role of BDNF signaling in striatal regions. Taken together, these data suggest that spontaneous nicotine withdrawal impairs distinct components of cognitive set-shifting and these deficits may be linked to BDNF-mediated alterations in glutamate signaling dynamics in discrete frontostriatal circuits.

Studies investigating the neural mechanisms by which associations between cues and predicted outcomes control behavior often use associative learning frameworks to understand the neural control of behavior. These frameworks do not always account for the full range of effects that novelty can have on behavior and future associative learning. Here, in mice, we show that dopamine in the nucleus accumbens core is evoked by novel, neutral stimuli, and the trajectory of this response over time tracked habituation to these stimuli. Habituation to novel cues before associative learning reduced future associative learning, a phenomenon known as latent inhibition. Crucially, trial-by-trial dopamine response patterns tracked this phenomenon. Optogenetic manipulation of dopamine responses to the cue during the habituation period bidirectionally influenced future associative learning. Thus, dopamine signaling in the nucleus accumbens core has a causal role in novelty-based learning in a way that cannot be predicted based on purely associative factors.

Cognitive deficits, such as disrupted learning, are a major symptom of nicotine withdrawal. These deficits are heritable, yet their genetic basis is largely unknown. Our lab has developed a mouse model of nicotine withdrawal deficits in learning, using chronic nicotine exposure via osmotic minipumps and fear conditioning. Here, we utilized the BXD genetic reference panel to identify genetic variants underlying nicotine withdrawal deficits in learning. Male and female mice (n = 6-11 per sex per strain, 31 strains) received either chronic saline or nicotine (6.3 mg/kg per day for 12 days), and were then tested for hippocampus-dependent learning deficits using contextual fear conditioning. Quantitative trait locus (QTL) mapping analyses using GeneNetwork identified a significant QTL on Chromosome 4 (82.13 Mb, LRS = 20.03, p < 0.05). Publicly available hippocampal gene expression data were used to identify eight positional candidates (Snacpc3, Mysm1, Rps6, Plaa, Lurap1l, Slc24a2, Hacd4, Ptprd) that overlapped with our behavioral QTL and correlated with our behavioral data. Overall, this study demonstrates that genetic factors impact cognitive deficits during nicotine withdrawal in the BXD recombinant inbred panel and identifies candidate genes for future research.

Microglia, the brain’s resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival1. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A1R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease. Microglia, the brain’s immune cells, suppress neuronal activity in response to synaptic ATP release and alter behavioural responses in mice.

Numerous studies have attributed the psychopathology of anxiety and stress disorders to maladaptive behavioral responses such as an inability to extinguish fear. Therefore, understanding neural substrates of fear extinction is imperative for developing more effective therapies for anxiety and stress disorders. Although several studies indicated a role for cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) in anxiety and stress disorder symptomatology, very little is known about the specific contribution of nAChRs in the fear extinction process. In the present study, we first examined the involvement of several brain regions essential for fear extinction (i.e., dorsal and ventral hippocampus, dHPC and vHPC; infralimbic, IL, and prelimbic, PL of the medial prefrontal cortex, mPFC; basolateral nucleus of the amygdala, BLA) in the impairing effects of a nAChR agonist, nicotine, on contextual fear extinction in mice. Our results showed that systemic administration of nicotine during contextual fear extinction increased c-fos expression in the vHPC and BLA while not affecting dHPC, IL or PL. In line with these results, local nicotine infusions into the vHPC, but not dHPC, resulted in impaired contextual fear extinction. Interestingly, we found that local nicotine infusions into the PL also resulted in impairment of contextual fear extinction. Second, we measured the protein levels of the GABA synthesizing enzymes GAD65 and GAD67 in the dHPC and vHPC during contextual fear extinction. Our results showed that in the group that received acute nicotine, both GAD65 and GAD67 protein levels were downregulated in the vHPC, but not in dHPC. This effect was negatively correlated with the level of freezing response during fear extinction suggesting that the downregulated GAD65/67 levels were associated with disrupted fear extinction. Finally, using c-fos/GAD65/67 double immunofluorescence, we showed that nicotine mainly increased c-fos expression in non-GABAergic ventral hippocampal cells, indicating that acute nicotine increases vHPC excitability. Overall, our results suggest that acute nicotine's impairing effects on fear extinction are associated with ventral hippocampal disinhibition. Therefore, these results further our understanding of the interaction between nicotine addiction and anxiety and stress disorders by describing novel neural mechanisms mediating fear extinction.

Deficits in motivation and cognition are hallmark symptoms of multiple psychiatric diseases. These symptoms are disruptive to quality of life and often do not improve with available medications. In recent years there has been increased interest in the role of the immune system in neuropsychiatric illness, but to date no immune-related treatment strategies have come to fruition. The cytokine granulocyte-colony stimulating factor (G-CSF) is known to have trophic and neuroprotective properties in the brain, and we recently identified it as a modulator of neuronal and behavioral plasticity. By combining operant tasks that assess discrete aspects of motivated behavior and decision-making in male mice and rats with subsecond dopamine monitoring via fast-scan cyclic voltammetry, we defined the role of G-CSF in these processes as well as the neural mechanism by which it modulates dopamine function to exert these effects. G-CSF enhanced motivation for sucrose as well as cognitive flexibility as measured by reversal learning. These behavioral outcomes were driven by mesolimbic dopamine system plasticity, as systemically administered G-CSF increased evoked dopamine release in the nucleus accumbens independent of clearance mechanisms. Importantly, sustained increases in G-CSF were required for these effects as acute exposure did not enhance behavioral outcomes and decreased dopamine release. These effects seem to be a result of the ability of G-CSF to alter local inflammatory signaling cascades, particularly tumor necrosis factor α. Together, these data show G-CSF as a potent modulator of the mesolimbic dopamine circuit and its ability to appropriately attend to salient stimuli.SIGNIFICANCE STATEMENTEmerging evidence has highlighted the importance of the immune system in psychiatric diseases states. However, the effects of peripheral cytokines on motivation and cognitive function are largely unknown. Here, we report that granulocyte-colony stimulating factor (G-CSF), a pleiotropic cytokine with known trophic and neuroprotective properties in the brain, acts directly on dopaminergic circuits to enhance their function. These changes in dopaminergic dynamics enhance reward learning and motivation for natural stimuli. Together, these results suggest that targeting immune factors may provide a new avenue for therapeutic intervention in the multiple psychiatric disorders that are characterized by motivational and cognitive deficits.

Background Nicotine exposure affects the hippocampus through activation of hippocampal nicotinic acetylcholine receptors (nAChRs), which are present throughout excitatory and inhibitory hippocampal circuitry. The role of cholinergic functioning in the hippocampus varies across developmental stages so that nicotine exposure differentially affects this region depending upon timing of exposure, producing developmentally distinct changes in structure, function, and behavior. Methods We synthesize findings across literature in this area to comprehensively review current understanding of the unique effects of nicotine exposure on the hippocampus throughout the lifespan with a focus on hippocampal morphology, cholinergic functioning, and hippocampus-dependent learning and memory. Conclusions Chronic and acute nicotine exposure differentially affect hippocampus structure, functioning, and related learning and memory in the perinatal period, adolescence, and aging. Age-related differences in sensitivity to nicotine exposure should be considered in the research of nicotine addiction and the development of nicotine addiction treatments.

Post-traumatic stress disorder (PTSD) is a devastating disorder with symptoms such as flashbacks, hyperarousal, and avoidance of reminders of the traumatic event. Exposure therapy, which attempts to extinguish fear responses, is a commonly used treatment for PTSD but relapse following successful exposure therapy is a frequent problem. In rodents, spontaneous recovery (SR), where extinguished fear responses resurface following extinction treatment, is used as a model of fear relapse. Previous studies from our lab showed that chronic nicotine impaired fear extinction and acute nicotine enhanced SR of contextual fear in adult male mice. In addition, we showed that acute nicotine's effects were specific to SR as acute nicotine did not affect recall of contextual fear conditioning in the absence of extinction. However, effects of chronic nicotine administration on SR are not known. Therefore, in the present study, we investigated if chronic nicotine administration altered SR or recall of contextual fear in adult male and female C57BL/6J mice. Our results showed that chronic nicotine significantly enhanced SR in female mice and significantly decreased SR in males. Chronic nicotine had no effect on recall of contextual fear in males or females. Female sham mice also had significantly less baseline SR than male sham mice. Overall, these results demonstrate sex differences in SR of fear memories and that chronic nicotine modulates these effects on SR but nicotine does not alter recall of contextual fear.

Stress and anxiety disorders such as posttraumatic stress disorder (PTSD) are characterized by disrupted safety learning. Tobacco smoking has been strongly implicated in stress and anxiety disorder symptomatology, both as a contributing factor and as a vulnerability factor. Rodent studies from our lab have recently shown that acute and chronic nicotine exposure disrupts safety learning. However, it is unknown if these effects of nicotine translate to humans. The present studies addressed this gap by administering a translational differential cued fear conditioning paradigm to both mice and humans. In mice, we found that chronic nicotine exposure reduced discrimination between a conditioned stimulus (CS) that signals for danger (CS+) and another CS that signals for safety (CS−) during both acquisition and testing. We then employed a similar differential cued fear conditioning paradigm in human smokers and non-smokers undergoing functional magnetic resonance imaging (fMRI). Smokers showed reduced CS+/CS− discrimination during fear conditioning compared to non-smokers. Furthermore, using fMRI, we found that subgenual and dorsal anterior cingulate cortex activations were lower in smokers than in non-smokers during differential cued fear conditioning. These results suggest a potential biological mechanism underlying a dysregulated ability to discriminate between danger and safety cues. Our results indicate a clear parallel between the effects of nicotine exposure on safety learning in mice and humans and therefore suggest that smoking might represent a risk factor for inability to process information related to danger and safety related cues.

Anxiety and stress disorders have been linked to deficits in fear extinction. Our laboratory and others have demonstrated that acute nicotine impairs contextual fear extinction, suggesting that nicotine exposure may have negative effects on anxiety and stress disorder symptomatology. However, the neurobiological mechanisms underlying the acute nicotine-induced impairment of contextual fear extinction are unknown. Therefore, based on the previous studies showing that brain-derived neurotrophic factor is central for fear extinction learning and acute nicotine dysregulates brain-derived neurotrophic factor signaling, we hypothesized that the nicotine-induced impairment of contextual fear extinction may involve changes in tyrosine receptor kinase B signaling. To test this hypothesis, we systemically, intraperitoneally, injected C57BL/6J mice sub-threshold doses (2.5 and 4.0 mg/kg) of 7,8-dihydroxyflavone, a small-molecule tyrosine receptor kinase B agonist that fully mimics the effects of brain-derived neurotrophic factor, or vehicle an hour before each contextual fear extinction session. Mice also received injections, intraperitoneally, of acute nicotine (0.18 mg/kg) or saline 2-4 min before extinction sessions. While the animals that received only 7,8-dihydroxyflavone did not show any changes in contextual fear extinction, 4.0 mg/kg of 7,8-dihydroxyflavone ameliorated the extinction deficits in mice administered acute nicotine. Overall, these results suggest that acute nicotine-induced impairment of context extinction may be related to a disrupted brain-derived neurotrophic factor signaling.

RATIONALE: Numerous studies have attributed the psychopathology of post-traumatic stress disorder (PTSD) to maladaptive behavioral responses such as an inability to extinguish fear. While exposure therapies are mostly effective in treating these disorders by enhancing extinction learning, relapse of PTSD symptoms is common. Although several studies indicated a role for cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) in anxiety and stress disorder symptomatology, very little is known about the specific contribution of nAChRs to fear extinction OBJECTIVES: In the present study, we examined the effects of inhibition and desensitization of α4β2 nAChRs via a full antagonist (Dihydro-beta-erythroidine, DhβE) and two α4β2 nAChR partial-agonists (varenicline and sazetidine-A) on contextual fear extinction, locomotor activity, and spontaneous recovery of contextual fear in mice. METHODS: We trained and tested the subjects in a contextual fear extinction as well as an open field paradigm and spontaneous recovery following injections of DhβE, varenicline and sazetidine-A. RESULTS: Our results demonstrated that lower doses of DhβE (1 mg/kg) and sazetidine-A (0.01 mg/kg) enhanced contextual fear extinction whereas higher doses of varenicline (0.1 mg/kg) and sazetidine-A (0.1 mg/kg) resulted in impaired contextual fear extinction. However, the higher dose of sazetidine-A (0.1 mg/kg) decreased locomotor activity, which may contribute to increased freezing response observed during fear extinction. Finally, we found that the low dose of DhβE, but not sazetidine-A, also decreased spontaneous recovery of contextual fear following fear extinction. CONCLUSIONS: Overall, these results suggest that inhibition and desensitization of α4β2 nAChRs enhance extinction of contextual fear memories. This suggests that modulation of α4β2 nAChRs may be employed as an alternative pharmacological strategy to aid exposure therapies associated with PTSD by augmenting contextual fear extinction processes.

A large body of work has aimed to define the precise information encoded by dopaminergic projections innervating the nucleus accumbens (NAc). Prevailing models are based on reward prediction error (RPE) theory, in which dopamine updates associations between rewards and predictive cues by encoding perceived errors between predictions and outcomes. However, RPE cannot describe multiple phenomena to which dopamine is inextricably linked, such as behavior driven by aversive and neutral stimuli. We combined a series of behavioral tasks with direct, subsecond dopamine monitoring in the NAc of mice, machine learning, computational modeling, and optogenetic manipulations to describe behavior and related dopamine release patterns across multiple contingencies reinforced by differentially valenced outcomes. We show that dopamine release only conforms to RPE predictions in a subset of learning scenarios but fits valence-independent perceived saliency encoding across conditions. Here, we provide an extended, comprehensive framework for accumbal dopamine release in behavioral control.

Previous research has shown that acute nicotine, an agonist of nAChRs, impaired fear extinction. However, the effects of acute nicotine on consolidation of contextual fear extinction memories and associated cell signaling cascades are unknown. Therefore, we examined the effects of acute nicotine injections before (pre-extinction) and after (post-extinction) contextual fear extinction on behavior and the phosphorylation of dorsal and ventral hippocampal ERK1/2 and JNK1 and protein levels on the 1st and 3rd day of extinction. Our results showed that acute nicotine administered prior to extinction sessions downregulated the phosphorylated forms of ERK1/2 in the ventral hippocampus, but not dorsal hippocampus, and JNK1 in both dorsal and ventral hippocampus on the 3rd extinction day. These effects were absent on the 1st day of extinction. We also showed that acute nicotine administered immediately and 30 min, but not 6 h, following extinction impaired contextual fear extinction suggesting that acute nicotine disrupts consolidation of contextual fear extinction memories. Finally, acute nicotine injections immediately after extinction sessions upregulated the phosphorylated forms of ERK1/2 in the ventral hippocampus, but did not affect JNK1. These results show that acute nicotine impairs contextual fear extinction potentially by altering molecular processes responsible for the consolidation of extinction memories.

Nicotine use remains highly prevalent with tobacco and e-cigarette products consumed worldwide. However, increasing evidence of transgenerational epigenetic inheritance suggests that nicotine use may alter behavior and neurobiology in subsequent generations. We tested the effects of chronic paternal nicotine exposure in C57BL6/J mice on fear conditioning in F1 and F2 offspring, as well as conditioned fear extinction and spontaneous recovery, nicotine self-administration, hippocampal cholinergic functioning, RNA expression, and DNA methylation in F1 offspring. Paternal nicotine exposure was associated with enhanced contextual and cued fear conditioning and spontaneous recovery of extinguished fear memories. Further, nicotine reinforcement was reduced in nicotine-sired mice, as assessed in a self-administration paradigm. These behavioral phenotypes were coupled with altered response to nicotine, upregulated hippocampal nicotinic acetylcholine receptor binding, reduced evoked hippocampal cholinergic currents, and altered methylation and expression of hippocampal genes related to neural development and plasticity. Gene expression analysis suggests multigenerational effects on broader gene networks potentially involved in neuroplasticity and mental disorders. The changes in fear conditioning similarly suggest phenotypes analogous to anxiety disorders similar to post-traumatic stress.

Substance use disorder is a behavioral disorder characterized by volitional drug consumption, compulsive behavior, drug seeking, and relapse. Mouse models of substance use disorder allow for the use of molecular, genetic, and circuit level tools, which provide enormous potential for defining the underlying mechanisms of this disorder. However, the relevance of results depends entirely on the validity of the mouse models used. Self-administration models have long been considered the gold standard of preclinical addiction models, as they allow for volitional drug use, this providing strong face validity. In a series of experiments, we show that traditional mouse models of self-administration, where behavior is maintained on a fixed-ratio one schedule of reinforcement, show similar levels of responding in the presence and absence of drug delivery - demonstrating that it is impossible to determine when intake is and is not volitional. Further, when assessing inclusion criteria, we find a sex-bias in exclusion criteria where females that acquired food self-administration were eliminated when traditional criteria were applied. To address these issues, we have developed a novel mouse self-administration procedure where animals do not need to be pre-trained on food and behavior is maintained on a variable ratio schedule of reinforcement. This procedure increases rates of reinforcement behavior, increases levels of drug intake, and eliminates sex bias in inclusion criteria. Together, these data highlight a major issue with fixed-ratio models in mice that complicates subsequent analysis and provide a simple and novel approach to minimize these confounds with escalating variable-ratio schedules of reinforcement.

BackgroundSex is a critical biological variable in the neuropathology of psychiatric disease, and in many cases, women represent a vulnerable population. It has been hypothesized that sex differences in neuropsychiatric disorders are manifestations of differences in basic reward processing. However, preclinical models often present rewards in isolation, ignoring that ethologically, reward seeking requires the consideration of potential aversive outcomes.MethodsWe developed a Multidimensional Cue Outcome Action Task (MCOAT) to dissociate motivated action from cue learning and valence. Mice are trained in a series of operant tasks. In phase 1, mice acquire positive and negative reinforcement in the presence of discrete discriminative stimuli. In phase 2, both discriminative stimuli are presented concurrently allowing us to parse innate behavioral strategies based on reward seeking and shock avoidance. Phase 3 is punished responding where a discriminative stimulus predicts that nose-poking for sucrose occurs concurrently with footshock, allowing for the assessment of how positive and negative outcomes are relatively valued.ResultsFemales prioritize avoidance of negative outcomes over seeking positive, while males have the opposite strategy. In cases where rules are uncertain, males and females employ different strategies, with females demonstrating bias for shock avoidance.ConclusionsThe MCOAT has broad utility for neuroscience research where pairing this task with recording and manipulation techniques will allow for the definition of the discrete information encoded within cellular populations. Ultimately, we show that making conclusions from unidimensional data leads to inaccurate generalizations about sex-specific behaviors that do not accurately represent ground truth.

Chronic nicotine and withdrawal from chronic nicotine have been shown to be major modulators of fear learning behavior. Moreover, recent studies from our laboratory have shown that acute nicotine impaired fear extinction and safety learning in mice. However, the effects of chronic nicotine and withdrawal on fear extinction are unknown. Therefore, the current experiments were conducted to investigate the effects of chronic nicotine as well as withdrawal from chronic nicotine on contextual fear extinction in mice. C57BL6/J mice were given contextual fear conditioning training and retention testing during chronic nicotine administration. Mice then received contextual fear extinction either during chronic nicotine or during withdrawal from chronic nicotine. Our results showed that contextual fear extinction was impaired both during chronic nicotine administration and subsequent withdrawal. However, it was also observed that the effects of prior chronic nicotine disappeared after 72 h in withdrawal, a timeline that closely matches with the timing of the chronic nicotine-induced upregulation of hippocampal nicotinic acetylcholine receptor (nAChR) density. Additional experiments found that 4 days, but not 1 day, of continuous nicotine administration upregulated hippocampal nAChRs and impaired contextual fear extinction. These effects disappeared following 72 h withdrawal. Overall, these experiments provide a potential link between nicotine-induced upregulation of hippocampal nAChRs and fear extinction deficits observed in patients with anxiety disorders, which may lead to advancements in the pharmacological treatment methods for this disorder.

It has long been hypothesized that conditioning mechanisms play major roles in addiction. Specifically, the associations between rewarding properties of drugs of abuse and the drug context can contribute to future use and facilitate the transition from initial drug use into drug dependency. On the other hand, the self-medication hypothesis of drug abuse suggests that negative consequences of drug withdrawal result in relapse to drug use as an attempt to alleviate the negative symptoms. In this review, we explored these hypotheses and the involvement of the hippocampus in the development and maintenance of addiction to widely abused drugs such as cocaine, amphetamine, nicotine, alcohol, opiates, and cannabis. Studies suggest that initial exposure to stimulants (i.e., cocaine, nicotine, and amphetamine) and alcohol may enhance hippocampal function and, therefore, the formation of augmented drug-context associations that contribute to the development of addiction. In line with the self-medication hypothesis, withdrawal from stimulants, ethanol, and cannabis results in hippocampus-dependent learning and memory deficits, which suggest that an attempt to alleviate these deficits may contribute to relapse to drug use and maintenance of addiction. Interestingly, opiate withdrawal leads to enhancement of hippocampus-dependent learning and memory. Given that a conditioned aversion to drug context develops during opiate withdrawal, the cognitive enhancement in this case may result in the formation of an augmented association between withdrawal-induced aversion and withdrawal context. Therefore, individuals with opiate addiction may return to opiate use to avoid aversive symptoms triggered by the withdrawal context. Overall, the systematic examination of the role of the hippocampus in drug addiction may help to formulate a better understanding of addiction and underlying neural substrates.

Adolescence is a critical developmental period associated with both increased vulnerability to substance abuse and maturation of certain brain regions important for learning and memory such as the hippocampus. In this study, we employed a hippocampus-dependent learning context pre-exposure facilitation effect (CPFE) paradigm in order to test the effects of acute nicotine on contextual processing during adolescence (post-natal day (PND) 38) and adulthood (PND 53). In Experiment 1, adolescent or adult C57BL6/J mice received either saline or one of three nicotine doses (0.09, 0.18, and 0.36 mg/kg) prior to contextual pre-exposure and testing. Our results demonstrated that both adolescent and adult mice showed CPFE in the saline groups. However, adolescent mice only showed acute nicotine enhancement of CPFE with the highest nicotine dose whereas adult mice showed the enhancing effects of acute nicotine with all three doses. In Experiment 2, to determine if the lack of nicotine’s effects on CPFE shown by adolescent mice is specific to the age when they are tested, mice were either given contextual pre-exposure during adolescence or adulthood and received immediate shock and testing during adulthood after a 15 day delay. We found that both adolescent and adult mice showed CPFE in the saline groups when tested during adulthood. However, like Experiment 1, mice that received contextual pre-exposure during adolescence did not show acute nicotine enhancement except at the highest dose (0.36 mg/kg) whereas both low (0.09 mg/kg) and high (0.36 mg/kg) doses enhanced CPFE in adult mice. Finally, we showed that the enhanced freezing response found with 0.36 mg/kg nicotine in the 15-day experiment may be a result of decreased locomotor activity as mice that received this dose of nicotine traveled shorter distances in an open field paradigm. Overall, our results indicate that while adolescent mice showed normal contextual processing when tested both during adolescence and adulthood, they are less sensitive to the enhancing effects of nicotine on contextual processing.

Introduction The prevalence of tobacco use in the population with schizophrenia is enormously high. Moreover, nicotine dependence is found to be associated with symptom severity and poor outcome in patients with schizophrenia. The neurobiological mechanisms that explain schizophrenia-nicotine dependence comorbidity are not known. This study systematically reviews the evidence highlighting the contribution of nicotinic acetylcholine receptors (nAChRs) to nicotine abuse in schizophrenia. Methods Electronic data bases (Medline, Google Scholar, and Web of Science) were searched using the selected key words that match the aims set forth for this review. A total of 276 articles were used for the qualitative synthesis of this review. Results Substantial evidence from preclinical and clinical studies indicated that dysregulation of α7 and β2-subunit containing nAChRs account for the cognitive and affective symptoms of schizophrenia and nicotine use may represent a strategy to remediate these symptoms. Additionally, recent meta-analyses proposed that early tobacco use may itself increase the risk of developing schizophrenia. Genetic studies demonstrating that nAChR dysfunction that may act as a shared vulnerability factor for comorbid tobacco dependence and schizophrenia were found to support this view. The development of nAChR modulators was considered an effective therapeutic strategy to ameliorate psychiatric symptoms and to promote smoking cessation in schizophrenia patients. Conclusions The relationship between schizophrenia and smoking is complex. While the debate for the self-medication versus addiction vulnerability hypothesis continues, it is widely accepted that a dysfunction in the central nAChRs represent a common substrate for various symptoms of schizophrenia and comorbid nicotine dependence.

While preclinical work has aimed to outline the neural mechanisms of drug addiction, it has overwhelmingly focused on male subjects. There has been a push in recent years to incorporate females into existing addiction models; however, males and females often have different behavioral strategies, making it important to not only include females, but to develop models that assess the factors that comprise female drug addiction. Traditional self-administration models often include light or tone cues that serve as discriminative stimuli and/or consequent stimuli, making it nearly impossible to disentangle the effects of cue learning, the cues themselves, and acute effects of psychostimulant drugs. To disentangle the interaction between drug-associated cues and the consummatory and appetitive responding driven by cocaine, we have developed a new behavioral procedure that combines Pavlovian-instrumental transfer with behavioral economic analysis. This task can be completed within a single session, allowing for studies looking at estrous cycle stage-dependent effects in intact cycling females, something that has been difficult in the past. In this study, we found no differences in self-administration across the estrous cycle in the absence of cues; however, when cues were introduced, the cues that acquired value during estrus—but not during diestrus or in males—increased motivation. Cues paired during estrus also increased c-fos expression to a greater extent in striatal regions, an effect that may underlie the observed increases in seeking induced by these cues, even weeks later. Together, these data suggest that fundamental differences in the motivational properties of psychostimulant drugs between males and females are complex and are driven primarily by the interaction between drug-associated stimuli and drug effects.

Drug addiction is a major public health concern across the world for which there are limited treatment options. In order to develop new therapies to correct the behavioral deficits that result from repeated drug use, we need to understand the neural circuit dysfunction that underlies the pathophysiology of the disorder. Because the initial reinforcing effects of drugs are dependent on increases in dopamine in reward-related brain regions such as the mesolimbic dopamine pathway, a large focus of addiction research has centered on the dysregulation of this system and its control of positive reinforcement and motivation. However, in addition to the processing of positive, rewarding stimuli, there are clear deficits in the encoding and valuation of information about potential negative outcomes and how they control decision making and motivation. Further, aversive stimuli can motivate or suppress behavior depending on the context in which they are encountered. We propose a model where rewarding and aversive information guides the execution of specific motivated actions through mesocortical and mesolimbic dopamine acting on D1- and D2- receptor containing neuronal populations. Volitional drug exposure alters the processing of rewarding and aversive stimuli through remodeling of these dopaminergic circuits, causing maladaptive drug seeking, self-administration in the face of negative consequences, and drug craving. Together, this review discusses the dysfunction of the circuits controlling different types of aversive learning as well as how these guide specific discrete behaviors, and provides a conceptual framework for how they should be considered in preclinical addiction models.

Previously, studies from our lab have shown that while acute nicotine administered prior to training and testing enhances contextual fear conditioning, acute nicotine injections prior to extinction sessions impair extinction of contextual fear. Although there is also strong evidence showing that the acute nicotine’s enhancing effects on contextual fear conditioning require high-affinity α4β2 nicotinic acetylcholine receptors (nAChRs), it is unknown which nAChR subtypes are involved in the acute nicotine-induced impairment of contextual fear extinction. In this study, we investigated the effects of acute nicotine administration on contextual fear extinction in knock-out (KO) mice lacking α4, β2 or α7 subtypes of nAChRs and their wild-type (WT) littermates. Both KO and WT mice were first trained and tested for contextual fear conditioning and received a daily contextual extinction session for 4 days. Subjects received intraperitoneal injections of nicotine (0.18 mg/kg) or saline 2–4 mins prior to each extinction session. Our results showed that the that mice lack α4 and β2 subtypes of nAChRs showed normal contextual fear extinction but not the acute nicotine-induced impairment while the mice that lack the α7 subtype showed both normal contextual extinction and nicotine-induced impairment of contextual extinction. In addition, control experiments showed that acute nicotine-induced impairment of contextual fear extinction persisted when nicotine administration was ceased and repeated acute nicotine administrations alone did not induce freezing behavior in the absence of context-shock learning. These results clearly demonstrate that high-affinity α4β2 nAChRs are necessary for the effects of acute nicotine on contextual fear extinction.

Dopaminergic signaling has long been known to be a critical factor in nicotine addiction, as well as other drugs of abuse. Dopaminergic projections from the VTA to the nucleus accumbens and prefrontal cortex have been well established to be critical to the reinforcing effects of these drugs. However, other projections of dopamine neurons are likely to have significant roles in this process. Also, the relative contributions of D1 and D2 dopamine receptors in drug addiction and its treatment remain to be fully understood. In this study, we examined the effects of blocking D1 and D2 receptors in the nucleus accumbens shell (AcS), anterior cingulate cortex (ACC), and parietal association cortex (PtA) on nicotine self-administration in rats. Female Sprague–Dawley rats were fitted with jugular catheters and allowed to self-administer nicotine (0.03 mg/kg/infusion) on an FR1 schedule. Rats were fitted with bilateral infusion cannulae to allow infusion of D1 or D2 antagonists (SCH-23390 or haloperidol) into each targeted brain area. Acute local infusions of SCH-23390 (1–4 μg/side) into the AcS and PtA significantly reduced nicotine self-administration by up to 75%. SCH-23390 infusion into the ACC was less effective with only suggestive non-significant reductions of nicotine self-administration. Acute, local infusions of haloperidol (0.5–2 μg/side) in any of the brain regions targeted did not have significant effects on nicotine self-administration. These results demonstrate a more significant role for D1 receptor mechanisms in the process of nicotine reinforcement and help provide a more detailed neuroanatomic map of nicotine dependence in the brain.

Nicotine addiction is most likely a result of a combination of factors including the rewarding effects of the drug; these effects, however, might be influenced by genetic background. Using a conditioned place preference (CPP) paradigm and 8 inbred mouse strains, we conducted an initial examination of the role of genetic background in the rewarding effects of nicotine. Following habituation and initial place preference test, inbred strains (A/J, BALB/cByJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/1J, DBA/2J, and 129/SvEv) were trained and tested in CPP for nicotine (0.35 mg/kg). Although several strains (C57BL/6J, CBA/J, and 129/SvEv) showed nicotine-induced CPP, 1 strain (DBA/1J) showed conditioned place aversion (CPA), and other strains (A/J, BALB/cByJ, C3H/HeJ, and DBA/2J) did not show CPP. Overall, these results indicate that nicotine's rewarding effects tested in CPP are differentially affected by the genetic background, and this trait has a relatively high heritability (42%-57%). This initial investigation lays the foundation for future studies examining the genetic substrates of nicotine reward.

Anxiety and stress disorders occur at a higher rate in women compared to men as well as in smokers in comparison to non-smoker population. Nicotine is known to impair fear extinction, which is altered in anxiety disorders. However, nicotine differentially affects fear learning in men and women, which may mean that sex and nicotine-product use can interact to also alter fear extinction. For this study, we examined sex differences in the effects of acute and chronic nicotine administration on fear memory extinction in male and female C57BL/6J mice. To study the acute effects of nicotine, animals trained in a background contextual fear conditioning paradigm were administered nicotine (0.09, 0.18 or 0.36 mg/kg) prior to extinction sessions. For chronic nicotine, animals continuously receiving nicotine (12.6, 18, or 24 mg/kg/day) were trained in a background contextual fear conditioning paradigm followed by fear extinction sessions. Males exhibited contextual fear extinction deficits following acute and chronic nicotine exposure. Females also exhibited extinction deficits, but only at the highest doses of acute nicotine (0.36 mg/kg) while chronic nicotine did not result in extinction deficits in female mice. These results suggest that sex mediates sensitivity to nicotine’s effects on contextual fear memory extinction.

Adolescence is a period of high risk for the initiation of nicotine product usage and exposure to traumatic events. In parallel, nicotine exposure has been found to age-dependently modulate acquisition of contextual fear memories; however, it is unknown if adolescent nicotine exposure alters extinction of fear related memories. Age-related differences in sensitivity to the effects of nicotine on fear extinction could increase or decrease susceptibility to anxiety disorders. In this study, we examined the effects of acute nicotine administration on extinction and spontaneous recovery of contextual fear memories in pre-adolescent (PND 23), late adolescent (PND 38), and adult (PND 53) C57B6/J mice. Mice were first trained in a background contextual fear conditioning paradigm and given an intraperitoneal injection of one of four doses of nicotine (0.045, 0.09, 0.18, or 0.36 mg/kg, freebase) prior to subsequent extinction or spontaneous recovery sessions. Results indicated that all acute nicotine doses impaired extinction of contextual fear in adult mice. Late adolescent mice exhibited impaired extinction of contextual fear only following higher doses of acute nicotine, and extinction of contextual fear was unaffected by acute nicotine exposure in pre-adolescent mice. Finally, acute nicotine exposure enhanced spontaneous recovery of fear memory, but only in adult mice. Overall, our results suggest that younger mice were less sensitive to nicotine’s impairing effects on extinction of contextual fear and to nicotine’s enhancing effects on spontaneous recovery of contextual fear memory.

Anxiety disorders, such as post-traumatic stress disorder (PTSD), may be related to an inability to distinguish safe versus threatening environments and to extinguish fear memories. Given the high rate of cigarette smoking in patients with PTSD, as well as the recent finding that an acute dose of nicotine impairs extinction of contextual fear memory, we conducted a series of experiments to investigate the effect of acute nicotine in an animal model of contextual safety discrimination. Following saline or nicotine (at 0.0275, 0.045, 0.09 and 0.18 mg/kg) administration, C57BL/6J mice were trained in a contextual discrimination paradigm, in which the subjects received presentations of conditioned stimuli (CS) that co-terminated with a foot-shock in one context (context A (CXA)) and only CS presentations without foot-shock in a different context (context B (CXB)). Therefore, CXA was designated as the ‘dangerous context’, whereas CXB was designated as the ‘safe context’. Our results suggested that saline-treated animals showed a strong discrimination between dangerous and safe contexts, while acute nicotine dose-dependently impaired contextual safety discrimination (Experiment 1). Furthermore, our results demonstrate that nicotine-induced impairment of contextual safety discrimination learning was not a result of increased generalized freezing (Experiment 2) or contingent on the common CS presentations in both contexts (Experiment 3). Finally, our results show that increasing the temporal gap between CXA and CXB during training abolished the impairing effects of nicotine (Experiment 4). The findings of this study may help link nicotine exposure to the safety learning deficits seen in anxiety disorder and PTSD patients.

Smoking is linked to post-traumatic stress disorder (PTSD) which suggests smoking is either a risk factor or an attempt at self-medication. The ability to reduce or extinguish fear-related memories may be altered in patients with PTSD and it is possible that nicotine modulates this. Although there are numerous studies examining the effects of nicotine on acquisition of fear learning, the effects of nicotine on extinction of contextual fear are not well understood. In the present study, we examined the effects of acute nicotine (0.18 mg/kg) on extinction of contextual fear in C57BL/6 J mice. Animals were first trained in a background contextual fear conditioning paradigm using a white noise as a conditioned stimulus (CS), which co-terminated with a 2 s 0.57 mA unconditioned foot-shock stimulus (US). Animals were then administered either nicotine or saline and exposed to either the training context or a novel context in order to measure freezing to the context during extinction. Our results demonstrate that nicotine administration during extinction delays extinction of contextual freezing while nicotine did not affect cued freezing or freezing to the novel context.

Despite experimental findings and some treatment research supporting the use of cues as a means to induce and extinguish cravings, interventions using cue exposure have not been well integrated into contemporary substance abuse treatments. A primary problem with exposure-based interventions for addiction is that after learning not to use substances in the presence of addiction cues inside the clinic (i.e., extinction), stimuli in the naturalistic setting outside the clinic may continue to elicit craving, drug use, or other maladaptive conditioned responses. For exposure-based substance use interventions to be efficacious, new approaches are needed that can prevent relapse by directly generalizing learning from the therapeutic setting into naturalistic settings associated with a high risk for relapse. Basic research suggests that extinction reminders (ERs) can be paired with the context of learning new and more adaptive conditioned responses to substance abuse cues in exposure therapies for addiction. Using mobile phones and automated dialing and data collection software, ERs can be delivered in everyday high-risk settings to inhibit conditioned responses to substance-use-related stimuli. In this review, we describe how associative learning mechanisms (e.g., conditioned inhibition) can inform how ERs are conceptualized, learned, and implemented to prevent substance use when delivered via mobile phones. This approach, exposure with portable reminders of extinction, is introduced as an adjunctive intervention that uses brief automated ERs between clinic visits when individuals are in high-risk settings for drug use.

The insular cortex has been associated with the processing of rewarding stimuli and with the neural bases of drug addiction. Ischemic damage to the insula has been associated with decreased desire to smoke cigarettes. Which component of insular function is involved in the neural basis of cigarette smoking is not clear. Dopamine systems are crucial for the reinforcing value of addictive drugs. The DA projection from the ventral tegmental area to the nucleus accumbens (NAc) has been shown to be a vital pathway for the primary reinforcement caused by taking a variety of abused drugs. In the current set of studies, the roles of D₁ and D₂ receptors in the insular cortex in the self-administration of nicotine by rats were assessed. Adult female Sprague-Dawley rats were fitted with jugular catheters and given access to self-administer nicotine. Bilateral local infusion cannulae were implanted into the agranular insular cortex to locally administer D₁ and D₂ antagonists (SCH-23390 and haloperidol). Acute local infusions of the D₁ antagonist SCH-23390 into the insula (1-2 μg/side) significantly decreased nicotine self-administration by more than 50%. Repeated infusions of SCH-23390 into the agranular insula caused continuing decreases in nicotine self-administration without signs of tolerance. In contrast, local infusions of the D₂ antagonist haloperidol 0.5-2 μg/side did not have any discernable effect on nicotine self-administration. These studies show the importance of DA D₁ systems in the insula for nicotine reward.

While smoking prevalence rates have fallen dramatically over the last several decades, tobacco abuse remains one of the leading causes of preventable death. In smokers, changes in cognition during periods of abstinence are associated with relapse. Therefore, understanding the effects of nicotine on cognition underlying neural changes could advance the treatment of nicotine addiction. This chapter explores the relationship between nicotine withdrawal and changes in learning and memory as demonstrated in animal models. Of particular importance is how nicotine acts in the hippocampus and how withdrawal from chronic nicotine leads to deficits in hippocampal-dependent learning. In addition, this chapter will explore how genetic variation modulates the effects of nicotine withdrawal on learning. Specifically, we know that the heritability of nicotine withdrawal-associated deficits in learning is moderate to strong. Finally, the chapter will conclude with an examination of age-dependent effects of nicotine withdrawal and how early and late adolescents differ from adults in sensitivity to the effects of nicotine on learning.

Exposure therapy, which focuses on extinguishing fear-triggering cues and contexts, is widely used to treat post-traumatic stress disorder (PTSD). Yet, PTSD patients who received successful exposure therapy are vulnerable to relapse of fear response after a period of time, a phenomenon known as spontaneous recovery (SR). Increasing evidence suggests ventral hippocampus, basolateral amygdala, and infralimbic cortex may be involved in SR. PTSD patients also show high rates of comorbidity with nicotine dependence. While the comorbidity between smoking and PTSD might suggest nicotine may alter SR, the effects of nicotine on SR of contextual fear are unknown. In the present study, we tested the effects of acute nicotine administration on SR of extinguished contextual fear memories and c-fos immediate early gene immunohistochemistry in mice. Our results demonstrated that acute nicotine enhanced SR of extinguished fear whereas acute nicotine did not affect retrieval of unextinguished contextual memories. This suggests that the effect of acute nicotine on SR is specific for memories that have undergone extinction treatment. C-fos immunoreactive (IR) cells in the ventral hippocampus and basolateral amygdala were increased in the nicotine-treated mice following testing for SR, whereas the number of IR cells in the infralimbic cortex was decreased in the same group. Overall, this study suggests that nicotine may adversely affect context-specific relapse of fear memories and this effect is potentially mediated by the suppression of cortical regions and increased activity in the ventral hippocampus and amygdala.

We show that the attentional-associative SLG model of classical conditioning, based on the 1996 research of Schmajuk, Lam, and Gray, correctly describes experimental results regarded as evidence of causal learning in rats: (a) interventions attenuate responding following common-cause training but do not interfere on subsequent responding during observation, and (b) interventions do not affect responding after direct-cause training or (c) causal-chain training. According to the model, responding to the weakly attended test stimulus is strongly inhibited by the intervention in the common-cause case. Instead, in the direct-cause and causal-chain cases, the strongly attended test stimulus becomes inhibitory, thereby overshadowing the inhibitory effect of interventions. Most importantly, the model predicted that with relatively few test trials (a) the 2008 results of Experiment 3 by Leising, Wong, Waldmann, and Blaisdell should be similar to those of Dwyer, Starns, and Honey's 2009 Experiment 1, showing that interventions equally affect responding after common-cause and direct-cause training; and (b) the 2006 results of Experiment 2a by Blaisdell, Sawa, Leising, and Waldmann should be similar to those of Dwyer, Starns, and Honey's 2009 Experiment 2, showing that interventions equally affect responding after common-cause and causal-chain training. When those data were made available to us, we confirmed those predictions. In agreement with the SLG associative model, but not with causal model theory, this evidence supports the notion that the attenuation of responding by interventions only following common-cause training is the consequence of well-known learning processes-latent inhibition, sensory preconditioning, conditioned inhibition, protection from extinction, and overshadowing.

Schmajuk, Lam, and Gray (SLG, 1996) presented a neural network model of classical conditioning that addresses the multiple properties of latent inhibition (LI). According to the model, LI is the result of the decreased attention to the target stimulus during preexposure and testing. Recently, Holmes and Harris (2009) suggested that, although the model was able to describe their experimental results showing that LI to a preexposed stimulus disappears with extended compound conditioning, it could not describe the fact that LI is not affected by a delay following compound conditioning. However, computer simulations demonstrate that the SLG model describes and explains both results. Because the model also explains both the deleterious and the facilitating effects on LI of a delay following simple conditioning, the SLG model seems unique in explaining the complete range of reported effects of temporal delays on LI as well as most of the properties of LI.

Anxiety disorders are a group of crippling mental diseases affecting millions of Americans with a 30% lifetime prevalence and costs associated with healthcare of $42.3 billion. While anxiety disorders show high levels of co-morbidity with smoking (45.3% vs. 22.5% in healthy individuals), anxiety disorders are also more common among the smoking population (22% vs. 11.1% in the non-smoking population). Moreover, there is clear evidence that smoking modulates symptom severity in patients with anxiety disorders. In order to better understand this relationship, several animal paradigms are used to model several key symptoms of anxiety disorders; these include fear conditioning and measures of anxiety. Studies clearly demonstrate that nicotine mediates acquisition and extinction of fear as well as anxiety through the modulation of specific subtypes of nicotinic acetylcholine receptors (nAChRs) in brain regions involved in emotion processing such as the hippocampus. However, the direction of nicotine’s effects on these behaviors is determined by several factors that include the length of administration, hippocampus-dependency of the fear learning task, and source of anxiety (novelty-driven vs. social anxiety). Overall, the studies reviewed here suggest that nicotine alters behaviors related to fear and anxiety and that nicotine contributes to the development, maintenance, and reoccurrence of anxiety disorders.

Nicotinic acetylcholine receptors (nAChRs) modulate the neurobiological processes underlying hippocampal learning and memory. In addition, nicotine's ability to desensitize and upregulate certain nAChRs may alter hippocampus-dependent memory processes. Numerous studies have examined the effects of nicotine on hippocampus-dependent learning, as well as the roles of low- and high-affinity nAChRs in mediating nicotine's effects on hippocampus-dependent learning and memory. These studies suggested that while acute nicotine generally acts as a cognitive enhancer for hippocampus-dependent learning, withdrawal from chronic nicotine results in deficits in hippocampus-dependent memory. Furthermore, these studies demonstrated that low- and high-affinity nAChRs functionally differ in their involvement in nicotine's effects on hippocampus-dependent learning. In the present chapter, we reviewed studies using systemic or local injections of acute or chronic nicotine, nAChR subunit agonists or antagonists; genetically modified mice; and molecular biological techniques to characterize the effects of nicotine on hippocampus-dependent learning.

Nicotinic acetylcholine receptors (nAChRs) modulate the neurobiological processes underlying hippocampal learning and memory. In addition, nicotine’s ability to desensitize and upregulate certain nAChRs may alter hippocampus-dependent memory processes. Numerous studies have examined the effects of nicotine on hippocampus-dependent learning, as well as the roles of low- and high-affinity nAChRs in mediating nicotine’s effects on hippocampus-dependent learning and memory. These studies suggested that while acute nicotine generally acts as a cognitive enhancer for hippocampus-dependent learning, withdrawal from chronic nicotine results in deficits in hippocampus-dependent memory. Furthermore, these studies demonstrated that low- and high-affinity nAChRs functionally differ in their involvement in nicotine’s effects on hippocampus-dependent learning. In the present chapter, we reviewed studies using systemic or local injections of acute or chronic nicotine, nAChR subunit agonists or antagonists; genetically modified mice; and molecular biological techniques to characterize the effects of nicotine on hippocampus-dependent learning.

Even though smoking rates have long been on the decline, nicotine addiction still affects 20% of the US population today. Moreover, nicotine dependence shows high comorbidity with many mental illnesses including, but are not limited to, attention deficit hyperactivity disorder, anxiety disorders, and depression. The reason for the high rates of smoking in patients with mental illnesses may relate to attempts to self-medicate with nicotine. While nicotine may alleviate the symptoms of mental disorders, nicotine abstinence has been shown to worsen the symptoms of these disorders. In this chapter, we review the studies from animal and human research examining the bidirectional relationship between nicotine and attention deficit hyperactivity disorder, anxiety disorders, and depression as well as studies examining the roles of specific subunits of nicotinic acetylcholine receptors (nAChRs) in the interaction between nicotine and these mental illnesses. The results of these studies suggest that activation, desensitization, and upregulation of nAChRs modulate the effects of nicotine on mental illnesses.