Smoking Status, Nicotine Medication, Vaccination, and COVID-19 Hospital Outcomes: Findings from the COVID EHR Cohort at the University of Wisconsin (CEC-UW) Study.

INTRODUCTION: Available evidence is mixed concerning associations between smoking status and COVID-19 clinical outcomes. Effects of nicotine replacement therapy (NRT) and vaccination status on COVID-19 outcomes in smokers are unknown. METHODS: Electronic health record data from 104 590 COVID-19 patients hospitalized February 1, 2020 to September 30, 2021 in 21 U.S. health systems were analyzed to assess associations of smoking status, in-hospital NRT prescription, and vaccination status with in-hospital death and ICU admission. RESULTS: Current (n = 7764) and never smokers (n = 57 454) did not differ on outcomes after adjustment for age, sex, race, ethnicity, insurance, body mass index, and comorbidities. Former (vs never) smokers (n = 33 101) had higher adjusted odds of death (aOR, 1.11; 95% CI, 1.06-1.17) and ICU admission (aOR, 1.07; 95% CI, 1.04-1.11). Among current smokers, NRT prescription was associated with reduced mortality (aOR, 0.64; 95% CI, 0.50-0.82). Vaccination effects were significantly moderated by smoking status; vaccination was more strongly associated with reduced mortality among current (aOR, 0.29; 95% CI, 0.16-0.66) and former smokers (aOR, 0.47; 95% CI, 0.39-0.57) than for never smokers (aOR, 0.67; 95% CI, 0.57, 0.79). Vaccination was associated with reduced ICU admission more strongly among former (aOR, 0.74; 95% CI, 0.66-0.83) than never smokers (aOR, 0.87; 95% CI, 0.79-0.97). CONCLUSIONS: Former but not current smokers hospitalized with COVID-19 are at higher risk for severe outcomes. SARS-CoV-2 vaccination is associated with better hospital outcomes in COVID-19 patients, especially current and former smokers. NRT during COVID-19 hospitalization may reduce mortality for current smokers. IMPLICATIONS: Prior findings regarding associations between smoking and severe COVID-19 disease outcomes have been inconsistent. This large cohort study suggests potential beneficial effects of nicotine replacement therapy on COVID-19 outcomes in current smokers and outsized benefits of SARS-CoV-2 vaccination in current and former smokers. Such findings may influence clinical practice and prevention efforts and motivate additional research that explores mechanisms for these effects.

Exercise during abstinence normalizes ultrastructural synaptic plasticity associated with nicotine-seeking following extended access self-administration.

Nicotine-craving progressively increases, or incubates, over abstinence following extended access self-administration. While not yet examined for nicotine, the incubation of cocaine-seeking is accompanied by changes in synaptic plasticity in the nucleus accumbens. Here, we determined whether such changes also accompany enhanced nicotine-seeking following extended access self-administration and abstinence, and whether exercise, a potential intervention for nicotine addiction, may exert its efficacy by normalizing these changes. Given that in humans, tobacco/nicotine use begins during adolescence, we used an adolescent-onset model. Nicotine-seeking was assessed in male rats following extended access nicotine or saline self-administration (23-hr/day, 10 days) and 10 days of abstinence, conditions known to induce the incubation of nicotine-seeking, using a within-session extinction/cue-induced reinstatement procedure. A subset of rats had 2-hr/day access to a running wheel during abstinence. Ultrastructural alterations of synapses in the nucleus accumbens core and shell were examined using electron microscopy. Nicotine-seeking was elevated following extended access self-administration and abstinence (in sedentary group), and levels of seeking were associated with an increase in the density of asymmetric (excitatory) and symmetric (inhibitory) synapses onto dendrites in the core, as well as longer asymmetric synapses onto spines, a marker of synaptic potentiation, in both the core and shell. Exercise normalized each of these changes; however, in the shell, exercise and nicotine similarly increased the synapse length. Together, these findings indicate an association between nicotine-seeking and synaptic plasticity in the nucleus accumbens, particularly the core, and indicate that the efficacy of exercise to reduce nicotine-seeking may be mediated by reversing these adaptations.

Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function α6* nAChRs.

α6ß2* nicotinic acetylcholine receptors (nAChRs)s in the ventral tegmental area to nucleus accumbens (NAc) pathway are implicated in the response to nicotine, and recent work suggests these receptors play a role in the rewarding action of ethanol. Here, we studied mice expressing gain-of-function α6ß2* nAChRs (α6L9'S mice) that are hypersensitive to nicotine and endogenous acetylcholine. Evoked extracellular dopamine (DA) levels were enhanced in α6L9'S NAc slices compared to control, non-transgenic (non-Tg) slices. Extracellular DA levels in both non-Tg and α6L9'S slices were further enhanced in the presence of GBR12909, suggesting intact DA transporter function in both mouse strains. Ongoing α6ß2* nAChR activation by acetylcholine plays a role in enhancing DA levels, as α-conotoxin MII completely abolished evoked DA release in α6L9'S slices and decreased spontaneous DA release from striatal synaptosomes. In HPLC experiments, α6L9'S NAc tissue contained significantly more DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid compared to non-Tg NAc tissue. Serotonin (5-HT), 5-hydroxyindoleacetic acid, and norepinephrine (NE) were unchanged in α6L9'S compared to non-Tg tissue. Western blot analysis revealed increased tyrosine hydroxylase expression in α6L9'S NAc. Overall, these results show that enhanced α6ß2* nAChR activity in NAc can stimulate DA production and lead to increased extracellular DA levels.

Relations of Current and Past Cancer with Severe Outcomes among 104,590 Hospitalized COVID-19 Patients: The COVID EHR Cohort at the University of Wisconsin.

BACKGROUND: There is mixed evidence about the relations of current versus past cancer with severe COVID-19 outcomes and how they vary by patient and cancer characteristics. METHODS: Electronic health record data of 104,590 adult hospitalized patients with COVID-19 were obtained from 21 United States health systems from February 2020 through September 2021. In-hospital mortality and ICU admission were predicted from current and past cancer diagnoses. Moderation by patient characteristics, vaccination status, cancer type, and year of the pandemic was examined. RESULTS: 6.8% of the patients had current (n = 7,141) and 6.5% had past (n = 6,749) cancer diagnoses. Current cancer predicted both severe outcomes but past cancer did not; adjusted odds ratios (aOR) for mortality were 1.58 [95% confidence interval (CI), 1.46-1.70] and 1.04 (95% CI, 0.96-1.13), respectively. Mortality rates decreased over the pandemic but the incremental risk of current cancer persisted, with the increment being larger among younger vs. older patients. Prior COVID-19 vaccination reduced mortality generally and among those with current cancer (aOR, 0.69; 95% CI, 0.53-0.90). CONCLUSIONS: Current cancer, especially among younger patients, posed a substantially increased risk for death and ICU admission among patients with COVID-19; prior COVID-19 vaccination mitigated the risk associated with current cancer. Past history of cancer was not associated with higher risks for severe COVID-19 outcomes for most cancer types. IMPACT: This study clarifies the characteristics that modify the risk associated with cancer on severe COVID-19 outcomes across the first 20 months of the COVID-19 pandemic. See related commentary by Egan et al., p. 3.

Preclinical evidence that activation of mesolimbic alpha 6 subunit containing nicotinic acetylcholine receptors supports nicotine addiction phenotype.

INTRODUCTION: Nicotine is a major psychoactive ingredient in tobacco yet very few individuals quit smoking with the aid of nicotine replacement therapy. Targeted therapies with more selective action at nicotinic acetylcholine receptors (nAChRs) that contain a ß2 subunit (ß2*nAChRs; *denotes assembly with other subunits) have enjoyed significantly greater success, but exhibit potential for unwanted cardiac, gastrointestinal, and emotive side effects. DISCUSSION: This literature review focuses on the preclinical evidence that suggests that subclasses of ß2*nAChRs that assemble with the α6 subunit may provide an effective target for tobacco cessation. α6ß2*nAChRs have a highly selective pattern of neuroanatomical expression in catecholaminergic nuclei including the ventral tegmental area and its projection regions. α6ß2*nAChRs promote dopamine (DA) neuron activity and DA release in the mesolimbic dopamine system, a brain circuitry that is well-studied for its contributions to addiction behavior. A combination of genetic and pharmacological studies indicates that activation of α6ß2*nAChRs is necessary and sufficient for nicotine psychostimulant effects and nicotine self-administration. α6ß2*nAChRs support maintenance of nicotine use, support the conditioned reinforcing effects of drug-associated cues, and regulate nicotine withdrawal. CONCLUSIONS: These data suggest that α6ß2*nAChRs represent a critical pool of high affinity ß2*nAChRs that regulates nicotine dependence phenotype and suggest that inhibition of these receptors may provide an effective strategy for tobacco cessation therapy.

The first 20 months of the COVID-19 pandemic: Mortality, intubation and ICU rates among 104,590 patients hospitalized at 21 United States health systems.

MAIN OBJECTIVE: There is limited information on how patient outcomes have changed during the COVID-19 pandemic. This study characterizes changes in mortality, intubation, and ICU admission rates during the first 20 months of the pandemic. STUDY DESIGN AND METHODS: University of Wisconsin researchers collected and harmonized electronic health record data from 1.1 million COVID-19 patients across 21 United States health systems from February 2020 through September 2021. The analysis comprised data from 104,590 adult hospitalized COVID-19 patients. Inclusion criteria for the analysis were: (1) age 18 years or older; (2) COVID-19 ICD-10 diagnosis during hospitalization and/or a positive COVID-19 PCR test in a 14-day window (+/- 7 days of hospital admission); and (3) health system contact prior to COVID-19 hospitalization. Outcomes assessed were: (1) mortality (primary), (2) endotracheal intubation, and (3) ICU admission. RESULTS AND SIGNIFICANCE: The 104,590 hospitalized participants had a mean age of 61.7 years and were 50.4% female, 24% Black, and 56.8% White. Overall risk-standardized mortality (adjusted for age, sex, race, ethnicity, body mass index, insurance status and medical comorbidities) declined from 16% of hospitalized COVID-19 patients (95% CI: 16% to 17%) early in the pandemic (February-April 2020) to 9% (CI: 9% to 10%) later (July-September 2021). Among subpopulations, males (vs. females), those on Medicare (vs. those on commercial insurance), the severely obese (vs. normal weight), and those aged 60 and older (vs. younger individuals) had especially high mortality rates both early and late in the pandemic. ICU admission and intubation rates also declined across these 20 months. CONCLUSIONS: Mortality, intubation, and ICU admission rates improved markedly over the first 20 months of the pandemic among adult hospitalized COVID-19 patients although gains varied by subpopulation. These data provide important information on the course of COVID-19 and identify hospitalized patient groups at heightened risk for negative outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04506528 (https://clinicaltrials.gov/ct2/show/NCT04506528).

It is not "either/or": activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood.

Nicotine can both activate and desensitize/inactivate nicotinic acetylcholine receptors (nAChRs). An ongoing controversy in the field is to what extent the behavioral effects of nicotine result from activation of nAChRs, and to what extent receptor desensitization is involved in these behavioral processes. Recent electrophysiological studies have shown that both nAChR activation and desensitization contribute to the effects of nicotine in the brain, and these experiments have provided cellular mechanisms that could underlie the contribution of both these processes to nicotine-mediated behaviors. For instance, desensitization of nAChRs may contribute to the salience of environmental cues associated with smoking behavior and activation and desensitization of nAChRs may contribute to both primary and conditioned drug reward. Similarly, studies of the antidepressant-like effects of nicotinic agents have revealed a balance between activation and desensitization of nAChRs. This review will examine the evidence for the contribution of these two very different consequences of nicotine administration to behaviors related to nicotine addiction, including processes related to drug reinforcement and affective modulation. We conclude that there are effects of nAChR activation and desensitization on drug reinforcement and affective behavior, and that both processes are important in the behavioral consequences of nicotine in tobacco smoking.

Cholinergic Receptors and Addiction.

Human behavior can be controlled by physical or psychological dependencies associated with addiction. One of the most insidious addictions in our society is the use of tobacco products which contain nicotine. This addiction can be associated with specific receptors in the brain that respond to the natural neurotransmitter acetylcholine. These nicotinic acetylcholine receptors (nAChR) are ligand-gated ion channels formed by the assembly of one or multiple types of nAChR receptor subunits. In this paper, we review the structure and diversity of nAChR subunits and our understanding for how different nAChR subtypes play specific roles in the phenomenon of nicotine addiction. We focus on receptors containing ß2 and/or α6 subunits and the special significance of α5-containing receptors. These subtypes all have roles in regulating dopamine-mediated neurotransmission in the mesolimbic reward pathways of the brain. We also discuss the unique roles of homomeric α7 nAChR in behavioral responses to nicotine and how our knowledge of nAChR functional diversity may help guide pharmacotherapeutic approaches for treating nicotine addiction. While nicotine addiction is a truly global problem, the use of areca nut (betel) products is also a serious addiction associated with public health issues across most of South Asia, impacting as many as 600 million people. We discuss how cholinergic receptors of the brain are also involved with areca addiction and the unique challenges for dealing with addiction to this substance.

Exercise or saccharin during abstinence block estrus-induced increases in nicotine-seeking.

Recent evidence suggests that adolescent and young adult females may be particularly responsive to nicotine use interventions that include exercise or environmental enrichment. This possibility was addressed in the current study by comparing the efficacy of exercise versus non-exercise environmental enrichment (saccharin) during abstinence at reducing subsequent nicotine-seeking/relapse vulnerability in an adolescent-onset rat model. The efficacy of each intervention was examined as a function of estrous cycle phase given findings indicating that hormonal status influences relapse vulnerability and treatment outcome in females. Once adolescent female rats acquired nicotine self-administration, they were given 23-h/day access to nicotine (0.01mg/kg/infusion) for 10days. Following the last self-administration session, rats began a 10-day forced abstinence period with 2-h/day access to an unlocked wheel (exercise, n=15), a bottle containing a saccharin-sweetened solution (0.25%; saccharin, n=19), or without access to a wheel or saccharin (control, n=20). Nicotine-seeking, as assessed under an extinction/cued-induced reinstatement procedure, was examined on day 11 of abstinence. Levels of nicotine-seeking were highest in females tested during estrus as compared to females tested during non-estrus phases. Exercise or saccharin during abstinence reduced nicotine-seeking in females tested during estrus, but neither affected the low levels of nicotine-seeking observed in females tested during non-estrus phases, presumably due to a floor effect. These results demonstrate that exercise or saccharin during abstinence decrease nicotine-seeking, and suggest that either would be effective as an early intervention for nicotine use and addiction in females.

Galanin protects against behavioral and neurochemical correlates of opiate reward.

The mechanisms underlying responses to drugs of abuse have been widely investigated; however, less is known about pathways normally protective against the development of drug reinforcement. These pathways are also important since they may regulate individual differences in vulnerability to addiction. The neuropeptide galanin and its binding sites are expressed in brain areas important for drug reward. Previous studies have shown that centrally infused galanin attenuates morphine place preference and peripheral injection of galnon, a galanin agonist, decreases opiate withdrawal signs. The current studies in galanin knockout (GKO) mice examined the hypothesis that galanin is an endogenous negative regulator of opiate reward and identified downstream signaling pathways regulated by galanin. We show that GKO mice demonstrate increased locomotor activation following morphine administration, which is inhibited by acute administration of galnon. GKO mice also show enhanced morphine place preference, supporting the idea that galanin normally antagonizes opiate reward. In addition, morphine-induced ERK1/2 phosphorylation was increased in the VTA of both wild-type and GKO mice, but only the GKO mice showed increases in ERK1/2 and CREB phosphorylation in the amygdala or nucleus accumbens. Furthermore, a single systemic injection of galnon in GKO mice was sufficient to reverse some of the biochemical changes brought about by morphine administration. These data suggest that galanin normally attenuates behavioral and neurochemical effects of opiates; thus, galanin agonists may represent a new class of therapeutic targets for opiate addiction.

Initial Cross-Over Test of A Positive Allosteric Modulator of Alpha-7 Nicotinic Receptors to Aid Cessation in Smokers With Or Without Schizophrenia.

Preclinical research shows that compounds acting at α7 nicotinic receptors (nAChRs) can reduce nicotine self-administration, suggesting that a positive allosteric modulator (PAM) of α7 receptors, JNJ-39393406, may aid smoking cessation. Moreover, individuals with schizophrenia, who have very high rates of smoking, have reduced expression of α7 nAChRs and may particularly benefit from this compound. In two parallel studies using a within-subject cross-over design, 36 healthy smokers (Study 1) and 62 smokers with schizophrenia (Study 2), both groups high in quit interest, attempted to initiate quitting temporarily during each of two 3-week phases. Treatments were the α7 nicotinic receptor PAM JNJ-39393406 (100 mg b.i.d.) or placebo (double-blind, counter-balanced). In each phase, all smoked ad lib with no drug on week 1 or during dose run-up on week 2, and then tried to quit every day during week 3. Abstinence (confirmed by CO <5 p.p.m.) and smoking reduction (CO <8), as well as cigarettes/day (in Study 1), were assessed daily (Monday-Friday) each quit week and compared between conditions. Secondary outcomes included abstinence symptoms (withdrawal and craving) and cognitive test responding (N-back; continuous performance task). In both studies, compared with placebo, active JNJ-39393406 did not increase the number of abstinent days nor reduce total smoking exposure. We also found no significant improvements in craving, withdrawal, or cognitive function. With this dose and study duration, our findings do not support further testing of this α7 nAChR PAM compound for possible efficacy in smoking cessation, in smokers with or without schizophrenia.

beta2-Subunit-containing nicotinic acetylcholine receptors are involved in nicotine-induced increases in conditioned reinforcement but not progressive ratio responding for food in C57BL/6 mice.

RATIONALE: Nicotine administration potentiates conditioned reinforcement in rats, an effect that persists for weeks after chronic exposure. Little is known regarding the nicotinic receptor subtypes that may mediate this effect. OBJECTIVE: The purpose of this study was to determine whether beta2-subunit-containing nicotinic acetylcholine receptors (beta2*nAChRs) are necessary for lasting effects of nicotine on conditioned and primary reinforcement in mice. METHODS: Beta2 knockout (beta2KO) and wild-type (WT) mice received 14 days of nicotine exposure (NIC, 200 microg/ml in 2% saccharin) or saccharin alone (SAC) in their drinking water. Five days later, mice received paired presentations of a conditioned stimulus (CS) with water unconditioned stimulus (US) or explicitly unpaired presentations of the CS and US during Pavlovian discriminative approach training. Training was followed by two conditioned reinforcement tests. Mice were subsequently tested for food-reinforced responding in the absence of explicit cues followed by a progressive ratio test. RESULTS: During conditioned reinforcement testing, only mice in the paired condition showed increased responding in the CS-reinforced aperture over inactive apertures. WT-NIC mice showed enhanced conditioned reinforcement compared to WT-SAC animals. beta2KO-SAC mice showed elevated conditioned reinforcement compared to WT-SAC subjects, but beta2KO-NIC and beta2KO-SAC mice did not differ in responding with conditioned reinforcement. Prior nicotine exposure did not alter food-reinforced responding but resulted in elevated break points for food in both genotypes. CONCLUSION: These data show that nicotine exposure enhances conditioned reinforcement in mice and indicate that beta2*nAChRs are necessary for nicotine-dependent enhancement of incentive aspects of motivation but not motivation for primary reinforcement measured by progressive ratio responding.

Galanin can attenuate opiate reinforcement and withdrawal.

Galanin and its receptors are expressed in brain areas associated with opiate reinforcement and withdrawal. An emerging body of data suggests that galanin can attenuate the neurochemical, physiological and behavioral signs of opiate reinforcement and withdrawal. Experiments in transgenic mice overexpressing galanin and knockout mice lacking the peptide support a role for endogenous galanin in modulating the actions of opiates on brain regions associated with reinforcement and withdrawal. These studies suggest that galanin receptor agonists could be useful therapeutic agents to combat opiate addiction. Further, genetic variation in the genes encoding galanin and its receptors could be associated with altered susceptibility to opiate dependence.

Nicotinic receptor contributions to smoking: insights from human studies and animal models.

It is becoming increasingly evident that a variety of factors contribute to smoking behavior. Nicotine is a constituent of tobacco smoke that exerts its psychoactive effects via binding to nicotinic acetylcholine receptors (nAChRs) in brain. Human genetic studies have identified polymorphisms in nAChR genes, which predict vulnerability to risk for tobacco dependence. In vitro studies and animal models have identified the functional relevance of specific polymorphisms. Together with animal behavioral models, which parse behaviors believed to contribute to tobacco use in humans, these studies demonstrate that nicotine action at a diversity of nAChRs is important for expression of independent behavioral phenotypes, which support smoking behavior.

Wheel running exercise attenuates vulnerability to self-administer nicotine in rats.

BACKGROUND: Preventing or postponing tobacco use initiation could greatly reduce the number of tobacco-related deaths. While evidence suggests that exercise is a promising treatment for tobacco addiction, it is not clear whether exercise could prevent initial vulnerability to tobacco use. Thus, using an animal model, we examined whether exercise attenuates vulnerability to the use and reinforcing effects of nicotine, the primary addictive chemical in tobacco. METHODS: Initial vulnerability was assessed using an acquisition procedure wherein exercising (unlocked running wheel, n=10) and sedentary (locked or no wheel, n=12) male adolescent rats had access to nicotine infusions (0.01-mg/kg) during daily 21.5-h sessions beginning on postnatal day 30. Exercise/sedentary sessions (2-h/day) were conducted prior to each of the acquisition sessions. The effects of exercise on nicotine's reinforcing effects were further assessed in separate groups of exercising (unlocked wheel, n=7) and sedentary (no wheel, n=5) rats responding for nicotine under a progressive-ratio schedule with exercise/sedentary sessions (2-h/day) conducted before the daily progressive-ratio sessions. RESULTS: While high rates of acquisition of nicotine self-administration were observed among both groups of sedentary controls, acquisition was robustly attenuated in the exercise group with only 20% of exercising rats meeting the acquisition criterion within the 16-day testing period as compared to 67% of the sedentary controls. Exercise also decreased progressive-ratio responding for nicotine as compared to baseline and to sedentary controls. CONCLUSIONS: Exercise may effectively prevent the initiation of nicotine use in adolescents by reducing the reinforcing effects of nicotine.

Oral operant ethanol self-administration in the absence of explicit cues, food restriction, water restriction and ethanol fading in C57BL/6J mice.

RATIONALE: Mouse models of ethanol (EtOH) self-administration are useful to identify genetic and biological underpinnings of alcohol use disorder. OBJECTIVES: These experiments developed a novel method of oral operant EtOH self-administration in mice without explicitly paired cues, food/water restriction, or EtOH fading. METHODS: Following magazine and lever training for 0.2 % saccharin (SAC), mice underwent nine weekly overnight sessions with lever pressing maintained by dipper presentation of 0, 3, 10, or 15 % EtOH in SAC or water vehicle. Ad libitum water was available from a bottle. RESULTS: Water vehicle mice ingested most fluid from the water bottle in contrast to SAC vehicle mice, which despite lever pressing demands, drank most of their fluid from the liquid dipper. Although EtOH in SAC vehicle mice showed concentration-dependent increases of g/kg EtOH intake, lever pressing decreased with increasing EtOH concentration and did not exceed that of SAC vehicle alone at any EtOH concentration. Mice reinforced with EtOH in water ingested less EtOH than mice reinforced with EtOH in SAC. EtOH in water mice, however, showed concentration-dependent increases in g/kg EtOH intake and lever presses. Fifteen percent EtOH in water mice showed significantly greater levels of lever pressing than water vehicle mice and a significant escalation of responding across weeks of exposure. Naltrexone pretreatment reduced EtOH self-administration and intake in these mice without altering responding in the vehicle control condition during the first hour of the session. CONCLUSIONS: SAC facilitated EtOH intake but prevented observation of EtOH reinforcement. Water vehicle unmasked EtOH's reinforcing effects.

Differential roles of α6ß2* and α4ß2* neuronal nicotinic receptors in nicotine- and cocaine-conditioned reward in mice.

Mesolimbic α6* nicotinic acetylcholine receptors (nAChRs) are thought to have an important role in nicotine behavioral effects. However, little is known about the role of the various α6*-nAChRs subtypes in the rewarding effects of nicotine. In this report, we investigated and compared the role of α6*-nAChRs subtypes and their neuro-anatomical locus in nicotine and cocaine reward-like effects in the conditioned place preference (CPP) paradigm, using pharmacological antagonism of α6ß2* nAChRs and genetic deletion of the α6 or α4 subunits in mice. We found that α6 KO mice exhibited a rightward shift in the nicotine dose-response curve compared with WT littermates but that α4 KO failed to show nicotine preference, suggesting that α6α4ß2*-nAChRs are involved. Furthermore, α6ß2* nAChRs in nucleus accumbens were found to have an important role in nicotine-conditioned reward as the intra-accumbal injection of the selective α6ß2* α-conotoxin MII [H9A; L15A], blocked nicotine CPP. In contrast to nicotine, α6 KO failed to condition to cocaine, but cocaine CPP in the α4 KO was preserved. Intriguingly, α-conotoxin MII [H9A; L15A], blocked cocaine conditioning in α4 KO mice, implicating α6ß2* nAChRs in cocaine reward. Importantly, these effects did not generalize as α6 KO showed both a conditioned place aversion to lithium chloride as well as CPP to palatable food. Finally, dopamine uptake was not different between the α6 KO or WT mice. These data illustrate that the subjective rewarding effects of both nicotine and cocaine may be mediated by mesolimbic α6ß2* nAChRs and that antagonists of these receptor subtypes may exhibit therapeutic potential.

Effect of nicotine and nicotinic receptors on anxiety and depression.

Nicotine has been shown to have effects on anxiety and depression in both human and animal studies. These studies suggest that nicotinic acetylcholine receptors (nAChRs) can modulate the function of pathways involved in stress response, anxiety and depression in the normal brain, and that smoking can result in alterations of anxiety level and mood. The effects of nicotine are complex however, and nicotine treatment can be either anxiolytic or anxiogenic depending on the anxiety model tested, the route of nicotine administration and the time course of administration. The paradoxical effects of nicotine on emotionality are likely due to the broad expression of nAChRs throughout the brain, the large number of nAChR subtypes that have been identified and the ability of nicotine treatment to both activate and desensitize nAChRs. Activation of nAChRs has been shown to modulate many systems associated with stress response including stress hormone pathways, monoaminergic transmission and release of classical neurotransmitters throughout the brain. Local administration studies in animals have identified brain areas that may be involved in the anxiogenic and anxiolytic actions of nicotine including the lateral septum, the dorsal raphe nuclei, the mesolimbic dopamine system and the hippocampus. The ensemble of studies to date suggest that under certain conditions nicotine can act as an anxiolytic and an antidepressant, but that following chronic use, adaptations to nicotine can occur resulting in increased anxiety and depression following withdrawal.

Effects of prenatal cocaine exposure on latent inhibition in 1-year-old female rats.

Prenatal cocaine exposure has been shown to produce attentional changes in human infants and children, as well as in preweanling and young adult animals. The aim of the current study was to determine whether attentional effects of in utero cocaine exposure persist into middle adulthood. Sprague-Dawley dams received twice-daily subcutaneous (sc) administration of either 20 mg/kg cocaine HCl or 0.9% saline vehicle from Gestational Day 8 to 20. Saline-injected dams were pair-fed to cocaine-injected subjects during prenatal treatment. A second control group received no treatment and had ad lib access to food. One-year-old female offspring were tested for latent inhibition (LI) of a context conditioning task, using freezing and vertical nose crossing (VNC) as behavioral measures of fear. Although freezing did not reveal any differences between prenatal treatment groups, a cocaine-dependent reduction in baseline VNC indicated that cocaine-exposed adult offspring were less explorative than controls. In addition, cocaine-exposed animals showed enhanced LI as measured by greater levels of VNC than controls in the context preexposed condition of the task. These results provide insight into the nature of attentional contributions to prenatal cocaine effects on learning and indicate that such effects persist well into adulthood.

Prenatal cocaine effects on fear conditioning: exaggeration of sex-dependent context extinction.

Prenatal cocaine exposure results in deficits in sensory preconditioning, discrimination reversal, and spatial navigation, tasks that require input from the hippocampus. However, there are no previous studies concerning prenatal cocaine effects on contextual fear conditioning, another hippocampal-dependent task. The present experiments tested whether chronic subcutaneous administration of 40 mg/kg of cocaine HCl to pregnant rats, from gestational day (GD) 8 through 20 would lead to disruption of contextual fear conditioning in adult male and female offspring. Offspring of saline-injected/pair-fed and untreated dams served as controls. Experiment 1 used a one-trial context conditioning preparation. Rats received a 2-s, 1-mA footshock in either the test context or a novel context, or received no shock on the day prior to the no-shock test. Defecation and freezing were measures of fear. Experiment 2 used a multiple measures protocol to optimize detection of prenatal treatment effects and was preceded by an open-field test. Rats received a 2-s, 0.8-mA footshock or no shock once daily over 4 days of conditioning. During 3 days of extinction, access to an adjacent chamber enabled the observation of four additional measures of fear: side crossing, latency, nose crossing, and side-differential. There were gender-dependent effects of conditioning on freezing and the four added measures of fear. Males showed higher levels of context conditioning and extinguished more slowly than females. The measures of nose crossing and side-differential revealed that prenatal cocaine exposure exaggerated gender-specific effects of context conditioning. The effects of prenatal cocaine exposure on context extinction are sexually dimorphic.