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Drug and alcohol dependence  2008;99(1-3):47-57.
Initial sensitivity to nicotine’s effects during early exposure to tobacco may relate to dependence vulnerability. We examined the association of initial nicotine sensitivity with individual difference factors of sex, other drug use history (i.e. cross-tolerance or cross-sensitization), and parental smoking status in young adult nonsmokers (N=131). Participants engaged in 4 sessions, the first 3 to assess the dose-response effects of nasal spray nicotine (0, 5, 10 μg/kg) on rewarding, mood, physiological, sensory processing, and performance effects, and the fourth to assess nicotine reinforcement using a choice procedure. Men had greater initial sensitivity than women to some self-reported effects of nicotine related to reward and incentive salience and to impairment in sensory processing, but men and women did not differ on most other effects. Prior marijuana use was associated with greater nicotine reward, nicotine reinforcement was greater in men versus women among those with prior marijuana use, and having parents who smoked was related to increased incentive salience. However, history of other drug use and parental smoking were not otherwise associated with initial nicotine sensitivity. These findings warrant replication with other methods of nicotine administration, especially cigarette smoking, and in more diverse samples of subjects naïve to nicotine. Yet, they suggest that sex differences in initial sensitivity to nicotine reward occur before the onset of dependence. They also suggest that parental smoking may not increase risk of nicotine dependence in offspring by altering initial nicotine sensitivity, and that cross-tolerance between other drugs and nicotine may not be robust in humans.
PMCID: PMC2648532  PMID: 18775605
nicotine; sensitivity; nonsmokers; reward; reinforcement; sex differences; cross-tolerance; parental smoking history
Behavioural pharmacology  2008;19(5-6):641-649.
Negative mood increases smoking reinforcement and risk of relapse. We explored associations of gene variants in the dopamine, opioid, and serotonin pathways with smoking reward (“liking”) and reinforcement (latency to first puff, total puffs) as a function of negative mood and expected vs. actual nicotine content of the cigarette. Smokers of European ancestry (n=72) were randomized to one of four groups in a 2 × 2 balanced-placebo design, corresponding to manipulation of actual (0.6 mg vs. 0.05 mg) and expected (told nicotine, told denicotinized) nicotine “dose” in cigarettes during each of two sessions (negative vs. positive mood induction). Following mood induction and expectancy instructions, they sampled and rated the assigned cigarette, and then smoked additional cigarettes ad lib during continued mood induction. The increase in smoking amount due to negative mood was associated with: DRD2 C957T (CC>TT or CT), SLC6A3 (presence of 9 repeat > absence of 9), and among those given a nicotine cigarette, DRD4 (presence of 7 repeat > absence of 7) and DRD2/ANKK1 TaqIA (TT or CT > CC). SLC6A3 and DRD2/ANKK1 TaqIA were also associated with smoking reward and smoking latency. OPRM1 (AA > AG or GG) was associated with smoking reward, but SLC6A4 VNTR was unrelated to any of these measures. These results warrant replication but provide the first evidence for genetic associations with the acute increase in smoking reward and reinforcement due to negative mood.
PMCID: PMC2717609  PMID: 18690118
smoking reward; reinforcement; mood; genetics; dopamine
3.  Pharmacogenetic Association of the Galanin Receptor (GALR1) SNP rs2717162 with Smoking Cessation 
Neuropsychopharmacology  2012;37(7):1683-1688.
Galanin modulates dopaminergic neurotransmission in the mesolimbic dopamine system, thereby influencing the rewarding effects of nicotine. Variants in the galanin receptor 1 (GALR1) gene have been associated with retrospective craving severity and heaviness of smoking in prior research. We investigated pharmacogenetic associations of the previously studied GALR1 polymorphism, rs2717162, in 1217 smokers of European ancestry who participated in one of three pharmacogenetic smoking cessation clinical trials and were treated with nicotine patch (n=623), nicotine nasal spray (n=189), bupropion (n=213), or placebo (n=192). The primary endpoint was abstinence (7-day point prevalence, biochemically confirmed) at the end of treatment. Cravings to smoke were assessed on the target quit day (TQD). The longitudinal regression model revealed a significant genotype by treatment interaction (P=0.03). There was a reduced odds of quitting success with the presence of at least one minor (C) allele in the bupropion-treated group (OR=0.43; 95% CI=0.22–0.77; P=0.005) but equivalent quit rates by genotype in the nicotine-replacement therapy groups. This genotype by treatment interaction was reproduced in a Cox regression model of time to relapse (P=0.04). In the bupropion trial, smokers carrying the C allele also reported more severe TQD cravings. Further research to identify functional variants in GALR1 and to replicate pharmacogenetic associations is warranted.
PMCID: PMC3358736  PMID: 22373943
nicotine; addiction; craving; pharmacogenetics; galanin receptor; behavioral science; neurogenetics; pharmacogenetics / pharmacogenomics; psychiatry & behavioral sciences; nicotine; addiction; craving; pharmacogenetics; galanin receptor 1
4.  Blockade of Dopamine D4 Receptors Attenuates Reinstatement of Extinguished Nicotine-Seeking Behavior in Rats 
Neuropsychopharmacology  2011;37(3):685-696.
Since cloning of the dopamine receptor D4 (DRD4), its role in the brain has remained unclear. It has been reported that polymorphism of the DRD4 gene in humans is associated with reactivity to cues related to tobacco smoking. However, the role of DRD4 in animal models of nicotine addiction has seldom been explored. In our study, male Long-Evans rats learned to intravenously self-administer nicotine under a fixed-ratio (FR) schedule of reinforcement. Effects of the selective DRD4 antagonist L-745,870 were evaluated on nicotine self-administration behavior and on reinstatement of extinguished nicotine-seeking behavior induced by nicotine-associated cues or by priming injections of nicotine. L-745,870 was also tested on reinstatement of extinguished food-seeking behavior as a control. In addition, the selective DRD4 agonist PD 168,077 was tested for its ability to reinstate extinguished nicotine-seeking behavior. Finally, L-745,870 was tested in Sprague Dawley rats trained to discriminate administration of 0.4 mg/kg nicotine from vehicle under an FR schedule of food delivery. L-745,870 significantly attenuated reinstatement of nicotine-seeking induced by both nicotine-associated cues and nicotine priming. In contrast, L-745,870 did not affect established nicotine self-administration behavior or reinstatement of food-seeking behavior induced by food cues or food priming. L-745,870 did not produce nicotine-like discriminative-stimulus effects and did not alter discriminative-stimulus effects of nicotine. PD 168,077 did not reinstate extinguished nicotine-seeking behavior. As DRD4 blockade by L-745,870 selectively attenuated both cue- and nicotine-induced reinstatement of nicotine-seeking behavior, without affecting cue- or food-induced reinstatement of food-seeking behavior, DRD4 antagonists are potential therapeutic agents against tobacco smoking relapse.
PMCID: PMC3260983  PMID: 22030716
dopamine receptor D4; receptor antagonist; nicotine self-administration; reinstatement of nicotine-seeking behavior; tobacco smoking; relapse; addiction & substance abuse; animal models; dopamine; psychopharmacology; dopamine receptor; D4 receptor antagonist; nicotine self-administration; reinstatement of nicotine-seeking behavior; tobacco smoking
5.  Genetic variation in the dopamine D4 receptor (DRD4) gene and smoking cessation: follow-up of a randomised clinical trial of transdermal nicotine patch 
The pharmacogenomics journal  2007;8(2):122-128.
Smokers of European ancestry (n = 720) who participated in a double-blind, randomised, placebo-controlled trial of transdermal nicotine replacement therapy, were genotyped for two functional polymorphisms (variable number of tandem repeats (VNTR) and a C to T transition at position −521 (C-521T)) in the dopamine D4 receptor gene (DRD4) gene. Logistic regression models of abstinence at 12- and 26-week follow-ups were carried out separately for each polymorphism. For the DRD4 VNTR models, the main effect of treatment was significant at both 12-week (P = 0.001) and 26-week (P = 0.006) follow-ups, indicating an increased likelihood of successful cessation on active nicotine replacement therapy transdermal patch relative to placebo. The main effect of DRD4 VNTR genotype was associated with abstinence at 12-week follow-up (P = 0.034), with possession of one or more copies of the long allele associated with reduced likelihood of cessation (17 vs 23%), but this effect was not observed at 26-week follow-up. For the DRD4 C-521T models, no main effect or interaction terms involving genotype were retained in the models at either 12- or 26-week follow-up. These data are consistent with observations from studies of the DRD2 gene that genetic variants related to relatively decreased dopaminergic tone in the mesocorticolimbic system are associated with increased risk for relapse to smoking following a cessation attempt.
PMCID: PMC2288552  PMID: 17387332
DRD4; VNTR; C-521T; smoking cessation; nicotine replacement therapy
6.  Pharmacology of Nicotine: Addiction, Smoking-Induced Disease, and Therapeutics 
Nicotine sustains tobacco addiction, a major cause of disability and premature death. Nicotine binds to nicotinic cholinergic receptors, facilitating neurotransmitter release and thereby mediating the complex actions of nicotine in tobacco users. Dopamine, glutamate, and gamma aminobutyric acid release are particularly important in the development of nicotine dependence, and corticotropin-releasing factor appears to contribute to nicotine withdrawal. Nicotine dependence is highly heritable. Genetic studies indicate roles for nicotinic receptor subtypes, as well as genes involved in neuroplasticity and learning, in development of dependence. Nicotine is primarily metabolized byCYP2A6, and variability in rate of metabolism contributes to vulnerability to tobacco dependence, response to smoking cessation treatment, and lung cancer risk. Tobacco addiction is much more common in persons with mental illness and substance abuse disorders, representing a high proportion of current smokers. Pharmacotherapeutic approaches to tobacco addiction include nicotine replacement, bupropion, and varenicline, the latter a selective nicotine receptor partial agonist.
PMCID: PMC2946180  PMID: 18834313
nicotine; addiction; smoking; pharmacogenetics; varenicline; bupropion
7.  Nicotine Differentially Inhibits the Acoustic Startle Reflex in African American and Caucasian American Smokers 
Addictive behaviors  2008;33(12):1521-1528.
Research suggests that there are racial disparities in smoking behaviors, cessation rates, mortality, and morbidity. However, little is known regarding racial differences in affect regulation by smoking. The purpose of this study was to examine racial differences in the effects of nicotine deprivation and administration on smokers’ startle responding to smoking and affective cues. 104 African American (AA) and Caucasian American (CA) smokers completed 4 laboratory sessions crossing nicotine deprivation (12-hour deprived vs. nondeprived) with nicotine nasal spray (active vs. placebo). Participants viewed affective (positive, neutral, and negative) and smoking slides while startle probes were administered. The results showed that relative to placebo, AA smokers given nicotine spray exhibited significantly lower startle responses when they were exposed to smoking cues and CA smokers given nicotine spray exhibited significantly lower startle responses when they were exposed to negative and neutral cues. Although nicotine suppresses startle responding in both AA and CA smokers, the effect is modulated by different cue conditions, suggesting that there may be racial differences in components of smoking motivation.
PMCID: PMC2612003  PMID: 18771859
African Americans; Caucasian Americans; nicotine; startle reflex
8.  Mood, nicotine, and dose expectancy effects on acute responses to nicotine spray 
Nicotine & Tobacco Research  2009;11(5):540-546.
We recently showed effects of nicotine dose and nicotine expectancy on some responses to cigarette smoking, with generally no influence of induced mood on these effects. The present study extended this line of research to Nicotrol nasal spray, to determine whether formulation (spray vs. smoking) alters responses.
Smokers abstained overnight before each of two virtually identical sessions, involving negative or positive mood induction. They were randomized to one of five groups, four comprising the 2 × 2 balanced placebo design, varying actual and expected dose of nicotine in the nasal spray, and the fifth group a no-spray control. Dependent measures included self-reported affect, craving, withdrawal, and spray ratings of “liking” and “how much nicotine.” Analyses were limited to those whose nicotine expectancies were manipulated successfully (N = 48).
The following results matched those from our smoking study: expecting nicotine increased liking; expected, but not actual, nicotine dose increased dose perception; neither actual nor expected nicotine dose had much influence on affect or withdrawal; and mood had no influence on these effects. However, both actual and expected nicotine dose decreased craving in response to spray, contrary to our prior study with smoking.
Formulation made little difference in some effects of nicotine and expectancies, but other effects differed by formulation. Some of these findings, particularly for craving reduction, may have implications for enhancing the acute therapeutic effects of nasal spray and, perhaps, other medications in smokers trying to maintain abstinence after quitting.
PMCID: PMC2671464  PMID: 19351782
9.  Noradrenergic α1 Receptors as a Novel Target for the Treatment of Nicotine Addiction 
Neuropsychopharmacology  2010;35(8):1751-1760.
Nicotine is the main psychoactive ingredient in tobacco and its rewarding effects are considered primarily responsible for persistent tobacco smoking and relapse. Although dopamine has been extensively implicated in the rewarding effects of nicotine, noradrenergic systems may have a larger role than previously suspected. This study evaluated the role of noradrenergic α1 receptors in nicotine and food self-administration and relapse, nicotine discrimination, and nicotine-induced dopamine release in the nucleus accumbens in rats. We found that the noradrenergic α1 receptor antagonist prazosin (0.25–1 mg/kg) dose dependently reduced the self-administration of nicotine (0.03 mg/kg), an effect that was maintained over consecutive daily sessions; but did not reduce food self-administration. Prazosin also decreased reinstatement of extinguished nicotine seeking induced by either a nicotine prime (0.15 mg/kg) or nicotine-associated cues, but not food-induced reinstatement of food-seeking, and decreased nicotine-induced (0.15 mg/kg) dopamine release in the nucleus accumbens shell. However, prazosin did not have nicotine-like discriminative effects and did not alter the dose-response curve for nicotine discrimination. These findings suggest that stimulation of noradrenergic α1 receptors is involved in nicotine self-administration and relapse, possibly via facilitation of nicotine-induced activation of the mesolimbic dopaminergic system. The findings point to α1 adrenoceptor blockade as a potential new approach to the treatment of tobacco dependence in humans.
PMCID: PMC3055474  PMID: 20357760
nicotine; noradrenergic α1 receptors; prazosin; dopamine; self-administration; relapse; Addiction & Substance Abuse; Dopamine; Animal models; Neuropharmacology; nicotine; dopamine; noradrenergic a1 receptors; self-administration; prazosin
10.  The μ-opioid receptor gene and smoking initiation and nicotine dependence 
The gene encoding the mu-opioid receptor (OPRM1) is reported to be associated with a range of substance dependence. Experiments in knockout mice indicate that the mu-opioid receptor may mediate reinforcing effects of nicotine. In humans, opioid antagonist naltrexone may reduce the reinforcing effects of tobacco smoking. Additionally, the OPRM1 gene is located in a region showing linkage to nicotine dependence. The OPRM1 is thus a plausible candidate gene for smoking behavior. To investigate whether OPRM1 contributes to the susceptibility of smoking initiation and nicotine dependence, we genotyped 11 SNPs in the gene for 688 Caucasian subjects of lifetime smokers and nonsmokers. Three SNPs showed nominal significance for smoking initiation and one reached significance for nicotine dependence. The global test for three-marker (rs9479757-rs2075572-rs10485057) haplotypes was significant for smoking initiation (p = 0.0022). The same three-marker haplotype test was marginal (p = 0.0514) for nicotine dependence. These results suggest that OPRM1 may be involved in smoking initiation and nicotine dependence.
PMCID: PMC1557520  PMID: 16887046
11.  Adolescent Exposure to Nicotine Results in Reinforcement Enhancement but does not Affect Adult Responding in Rats 
Drug and alcohol dependence  2012;125(3):307-312.
Adolescence is a period of development associated with a peak in an organism’s responsiveness to reward. Epidemiological data indicate that the initiation of smoking is high during adolescence and that earlier age of onset is associated with increased incidence of dependence as adults. In rats, nicotine is known to have primary reinforcing and reinforcement enhancing effects. Although the primary reinforcing effects of nicotine have been demonstrated in adolescent rats (self-administration), less is known about its reinforcement enhancing effects during this period. Moreover, the impact of adolescent nicotine exposure on its reinforcement enhancing effects during adulthood has not yet been examined. The objectives of this study were to assess whether 1) nicotine enhances operant responding for an unconditioned visual reinforcer (VS) in adolescent rats, and 2) exposure to nicotine during adolescence affects responsiveness to the VS in adulthood.
Rats were exposed to nicotine (0.32 mg/kg, subcutaneous injection) or saline during adolescence (Postnatal day 29–42) and adulthood. Nose-poking for the VS was assessed under fixed and progressive ratio schedules.
Nicotine increased responding for the VS during adolescence. Adolescent nicotine exposure failed to significantly affect adult responsiveness for the VS, regardless of adult nicotine exposure, but early exposure to the VS affected responsiveness to the VS in adulthood.
Nicotine exhibits reinforcement enhancing effects in adolescent rats. Long-term effects of adolescent nicotine on reinforcement enhancement are minimal, but the impact of early exposure to the VS and/or the primary reinforcing effects of nicotine requires further investigation.
PMCID: PMC3398206  PMID: 22483812
Nicotine; Adolescent; Reinforcement; Reinforcement Enhancement; Rat; Nose-poke; Operant Behavior
12.  Affective and somatic aspects of spontaneous and precipitated nicotine withdrawal in C57BL/6J and BALB/cByJ mice 
Neuropharmacology  2008;54(8):1223-1232.
The aversive aspects of nicotine withdrawal are powerful motivational forces contributing to the tobacco smoking habit. We evaluated measures of affective and somatic aspects of nicotine withdrawal in C57BL/6J and BALB/cByJ mice. Nicotine withdrawal was induced by termination of chronic nicotine delivery through osmotic minipumps or precipitated with the nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine or dihydro-β-erythroidine (DHβE). A rate-independent discrete-trial intracranial self-stimulation threshold procedure was used to assess brain reward function. Anxiety-like behavior and sensorimotor gating were assessed in the light-dark box and prepulse inhibition (PPI) tests, respectively. Acoustic startle response and somatic signs of withdrawal were also evaluated. Spontaneous nicotine withdrawal after 14-day exposure to 10–40 mg/kg/day nicotine induced no alterations in anxiety-like behavior, startle reactivity, PPI, or somatic signs in either strain, and no changes in thresholds in C57BL/6J mice. Extended 28-day exposure to 40 mg/kg/day nicotine induced threshold elevations, increased somatic signs, and anxiety-like behavior 24 h post-nicotine in C57BL/6J mice; thresholds returned to baseline levels by day 4 in nicotine-exposed mice. Mecamylamine or DHβE administration induced threshold elevations in nicotine-exposed C57BL/6J mice compared with saline-exposed mice. In conclusion, administration of relatively high nicotine doses over prolonged periods of time induces both the affective and somatic aspects of spontaneous nicotine withdrawal in the mouse, while exposure to nicotine for shorter periods of time is sufficient for nAChR antagonist-precipitated nicotine withdrawal. The current study is one of the first to demonstrate reward deficits associated with both spontaneous and nAChR antagonist-precipitated nicotine withdrawal in C57BL/6J mice.
PMCID: PMC2496875  PMID: 18452957
nicotine; withdrawal; brain stimulation reward; anxiety; light-dark box; startle; prepulse inhibition; somatic signs; mice; strains
13.  Effects of acute tobacco abstinence in adolescent smokers as compared with nonsmokers 
Abstinence effects such as nicotine withdrawal and mood changes contribute to the maintenance of cigarette smoking in adult smokers and emerging reports on adolescent smokers suggest they may experience similar subjective effects when deprived. This study aimed to prospectively document tobacco abstinence induced changes during the first 48 hours of abstinence in adolescent smokers compared with nonsmokers, to distinguish effects distinct from typical adolescent lability.
57 adolescent smokers and 44 adolescent nonsmokers were assessed during a 48 hour inpatient session. Characteristic nicotine withdrawal symptoms, cravings for cigarettes, and mood symptoms were measured at 13 time points following initiation of abstinence.
The only abstinence related effects observed were changes in craving for tobacco and feelings of anger. Tobacco craving increased and peaked quickly following initiation of abstinence and displayed a slight decrease towards the end of the 48 hour abstinence period, while anger symptoms peaked after more prolonged abstinence. Overall, smokers’ symptoms and cravings were positively associated with amount of daily smoking but not with reports of dependence or biological measures of extent of use.
We observed that among adolescent smokers, the primary effects associated with abstinence from cigarettes are relatively minimal and include a heightened and persistent craving to smoke and increases in anger. Although smokers had greater negative mood symptoms compared with nonsmokers, the presence and severity of most of these symptoms appear to be minimally altered by abstinence and not associated with dependency or biological indicators of amount of tobacco use.
PMCID: PMC2527725  PMID: 18565437
14.  A psychobiological framework of the substrates that mediate nicotine use during adolescence 
Neuropharmacology  2008;56(Suppl 1):263-278.
Adolescents are especially likely to initiate tobacco use and are more vulnerable to long-term nicotine dependence. A unifying hypothesis is proposed based largely on animals studies that adolescents, as compared to adults, experience enhanced short-term positive and reduced aversive effects of nicotine, as well as less negative effects during nicotine withdrawal. Thus, during adolescence the strong positive effects of nicotine are inadequately balanced by negative effects that contribute to nicotine dependence in adults. This review provides a neural framework to explain developmental differences within the mesolimbic pathway based on the established role of dopamine in addiction. This pathway originates in the ventral tegmental area (VTA) and terminates in the nucleus accumbens (NAcc) where dopamine is increased by nicotine but decreased during withdrawal. During adolescence, excitatory glutamatergic systems that facilitate dopamine are overdeveloped, whereas inhibitory GABAergic systems are underdeveloped. Thus, it is hypothesized that adolescents display enhanced nicotine reward and reduced withdrawal via enhanced excitation and reduced inhibition of VTA cell bodies that release dopamine in the NAcc. Although this framework focuses on adolescents and adults, it may also apply to the understanding of enhanced vulnerability to nicotine in adults that were previously exposed to nicotine during adolescence. The hypothesis presented in this review suggests that the clinical diagnostic criteria developed for nicotine dependence in adults, based primarily on withdrawal, may be inappropriate during adolescence when nicotine withdrawal does not appear to play a major role in nicotine use. Furthermore, treatment strategies involving nicotine replacement may be harmful for adolescents because it may cause enhanced vulnerability to nicotine dependence later in adulthood.
PMCID: PMC2634831  PMID: 18723034
development; adolescent; withdrawal; dependence; abstinence; reward
15.  Neurobiological mechanisms involved in nicotine dependence and reward: participation of the endogenous opioid system 
Nicotine is the primary component of tobacco that maintains the smoking habit and develops addiction. The adaptive changes of nicotinic acetylcholine receptors produced by repeated exposure to nicotine play a crucial role in the establishment of dependence. However, other neurochemical systems also participate in the addictive effects of nicotine including glutamate, cannabinoids, GABA and opioids. This review will cover the involvement of these neurotransmitters in nicotine addictive properties, with a special emphasis on the endogenous opioid system. Thus, endogenous enkephalins and beta-endorphins acting on mu-opioid receptors are involved in nicotine rewarding effects, whereas opioid peptides derived from prodynorphin participate in nicotine aversive responses. An upregulation of mu-opioid receptors has been reported after chronic nicotine treatment that could counteract the development of nicotine tolerance, whereas the downregulation induced on kappa-opioid receptors seems to facilitate nicotine tolerance. Endogenous enkephalins acting on mu-opioid receptors also play a role in the development of physical dependence to nicotine. In agreement with these actions of the endogenous opioid system, the opioid antagonist naltrexone has shown to be effective for smoking cessation in certain subpopulations of smokers.
PMCID: PMC2908214  PMID: 20170672
addiction; enkephalin; dynorphin; beta-endorphin; tolerance; withdrawal; naltrexone; opioid receptor
16.  The genetic components of alcohol and nicotine co-addiction: From genes to behavior 
Current drug abuse reviews  2008;1(2):124-134.
Co-occurrence of alcohol and nicotine addiction in humans is well documented and there is good evidence that common genes may contribute to both disorders. Although genetic factors contributing to tobacco and alcohol problem use have been well established through adoption, twin and family studies, specific genes remain to be identified and their mode of action elucidated. Recent work from human genetics studies has provided evidence that neuronal nicotinic acetylcholine receptors (nAChR) genes may have a role in mediating early behaviors that are risk factors for alcohol and nicotine dependence, such as age of initiation and early subjective responses to the drugs. Converging evidence suggests that the dopaminergic system is likely to be important in mediating the pleasurable feelings of reward when activated by nicotine and/or alcohol consumption. The nAChRs are important components of the dopaminergic reward system because some of the receptors have been shown to activate the release of dopamine, and mice lacking genes for specific nAChR gene subunits show altered behavioral responses to nicotine and alcohol. Furthermore, complex interactions between other neurotransmitter circuits including GABA, glutamate and serotonin may be modulated by nAChRs, leading researchers to study genes involved in neurobiology shared by different drugs. Future studies aimed at understanding the variation among these genes, and their corresponding functional implications, will help elucidate how natural variants in nicotinic receptor genes contribute to these common co-morbid disorders.
PMCID: PMC2600802  PMID: 19492010
nicotine; alcohol; co-morbidity; genetics; nicotinic receptors; linkage; association; behavior; neurotransmitters
17.  Biological basis of tobacco addiction: Implications for smoking-cessation treatment 
Indian Journal of Psychiatry  2010;52(4):301-307.
Tobacco use became common all over the world after discovery of Americas. Tobacco, a plant carries in its leaves an alkaloid called nicotine, which is responsible not only for several pathophysiological changes in the body but also develops tolerance to its own action with repeated use. Studies suggest that the alpha-4 beta-2 nicotine acetylcholine receptor subtype is the main receptor that mediates nicotine dependence. Nicotine acts on these receptors to facilitate neurotransmitter release (dopamine and others), producing pleasure and mood modulation. Repeated exposure to nicotine develops neuroadaptation of the receptors, resulting in tolerance to many of the effects of nicotine. Withdrawal symptoms appear on stoppage of tobacco use, which are characterized by irritability, anxiety, increased eating, dysphoria, and hedonic dysregulation, among others. Smoking is also reinforced by conditioning. Pharmacotherapies for smoking cessation should reduce withdrawal symptoms and block the reinforcing effects of nicotine obtained from smoking without causing excessive adverse effects.
PMCID: PMC3025154  PMID: 21267362
Acetylcholine receptors; addiction; dopamine; nicotine
18.  Pharmacologic Intervention in Habitual Smoking 
The Ochsner Journal  1999;1(3):145-148.
The health risks associated with smoking justify efforts at cessation. Of the 50 million smokers in the United States, about 20 million attempt to quit each year. Approximately 6% are successful. Nicotine, the addictive agent within tobacco smoke, acts to enhance the release of neurotransmitters in the pleasure reinforcing area of the brain. Nicotine replacement therapy has been successfully used to relieve patients' withdrawal symptoms when cessation has been attempted. Nicotine replacement is available as a gum, patch, inhaler, and nasal spray. Bupropion, an antidepressant, is the first non-nicotine drug approved for smoking cessation. It blocks the neuronal uptake of serotonin and norepinephrine. Bupropion, like nicotine replacement therapy, is twice as effective as a placebo in smoking cessation.
PMCID: PMC3145451  PMID: 21845133
19.  Nicotine-induced brain metabolism associated with anger provocation 
Cortico-limbic brain activity associated with anger may be susceptible to nicotine and, thus, may contribute to smoking initiation and nicotine addiction. The purpose of the study was to identify the brain regions that are most reactive to nicotine and show the greatest association with anger task performance. Twenty adult nonsmokers (9 women, 11 men) participated in two laboratory sessions to assess brain metabolism with fluoro deoxy-glucose Positron Emission Topography (FDG-PET) in response to nicotine and placebo patches during an anger provocation task. Outcome variables for the anger provocation task were reaction time, intensity and length of retaliation. Reaction time was associated with nicotine-induced changes in the left thalamus. Length of retaliation was associated with a functionally linked set of cortical and subcortical structures such as right frontal lobe, right anterior cingulate (BA 24), right uncus, left parietal lobe, left BA 11, left cingulate, left BA 25, left amygdala, left BA 30, left BA 38 and BA 9. These findings reveal the underlying brain circuitry targeted by nicotine during anger provocation.
PMCID: PMC2680866  PMID: 19393039
20.  The Serotonin Transporter Gene and Startle Response During Nicotine Deprivation 
Biological Psychology  2010;86(1):1-8.
Affective startle probe methodology was used to examine the effects of nicotine administration and deprivation on emotional processes among individuals carrying at least one s allele versus those with the l/l genotype of the 5-Hydroxytryptamine (Serotonin) Transporter Linked Polymorphic Region, 5-HTTLPR in the promoter region of the serotonin transporter gene [Solute Ligand Carrier family 6 member A4 (SLC6A4) or SERT]. Smokers (n = 84) completed four laboratory sessions crossing deprivation (12-hour deprived vs. non-deprived) with nicotine spray (nicotine vs. placebo). Participants viewed affective pictures (positive, negative, neutral) while acoustic startle probes were administered. We found that smokers with the l/l genotype showed significantly greater suppression of the startle response when provided with nicotine vs. placebo than those with the s/s or s/l genotypes. The results suggest that l/l smokers, who may have higher levels of the serotonin transporter and more rapid synaptic serotonin clearance, experience substantial reduction in activation of the defensive system when exposed to nicotine.
PMCID: PMC3378389  PMID: 20888887
affect; 5-HTTLPR; SERT; SLC6A4; smoking; startle probe
21.  Developmental Effects of Acute, Chronic, and Withdrawal from Chronic Nicotine on Fear Conditioning 
Pre-adolescence and adolescence are developmental periods associated with increased vulnerability for tobacco addiction, and exposure to tobacco during these periods may lead to long-lasting changes in behavioral and neuronal plasticity. The present study examined the short- and long-term effects of nicotine and nicotine withdrawal on fear conditioning in pre-adolescent, adolescent, and adult mice, and potential underlying substrates that may mediate the developmental effects of nicotine, such as changes in nicotinic acetylcholine receptor (nAChR) binding, CREB expression, and nicotine metabolism. Age-related differences existed in sensitivity to the effects of acute nicotine, chronic nicotine and nicotine withdrawal on contextual fear conditioning (no changes in cued fear conditioning were seen); younger mice were more sensitive to the acute effects and less sensitive to the effects of nicotine withdrawal 24 hours post treatment cessation. Developmental differences in nAChR binding were associated with the effects of nicotine withdrawal on contextual learning. Developmental differences in nicotine metabolism and CREB expression were also observed, but were not related to the effects of nicotine withdrawal on contextual learning 24 hours post treatment. Chronic nicotine exposure during pre-adolescence or adolescence, however, produced long-lasting impairments in contextual learning that were observed during adulthood, whereas adult chronic nicotine exposure did not. These developmental effects could be related to changes in CREB. Overall, there is a developmental shift in the effects of nicotine on hippocampus-dependent learning and developmental exposure to nicotine results in adult cognitive deficits; these changes in cognition may play an important role in the development and maintenance of nicotine addiction.
PMCID: PMC3358528  PMID: 22521799
Hippocampus; Adolescent; Addiction; Learning; Acetylcholine
22.  Negative reinforcement smoking outcome expectancies are associated with affective response to acute nicotine administration and abstinence 
Drug and alcohol dependence  2011;120(1-3):196-201.
Negative affect is an important predictor of smoking behavior, and many smokers believe that smoking reduces negative affect. However, it is unclear whether such beliefs, known as negative reinforcement smoking outcome expectancies (NRSOE), are associated with changes in negative affect in response to nicotine deprivation and administration.
Smokers (N = 114) participated in 4 sessions that balanced overnight smoking deprivation (12-hr deprived vs. ad lib) and nasal spray administration (nicotine vs. placebo). Corrugator supercilii (COR) EMG, skin conductance (SCR), and in-session ratings were collected while the participants viewed affective, cigarette-related, and neutral slides. Retrospective questionnaire data were collected prior to slide viewing. NRSOE were determined using the Smoking Consequences Questionnaire-Adult Nicotine Affect Reduction scale (SCQ-NAR).
High scores on the SCQ-NAR were associated with smaller COR EMG to unpleasant slides following nicotine nasal spray administration compared to placebo spray, regardless of overnight deprivation. Smokers who had high scores on the SCQ-NAR had smaller SCR, following nicotine nasal spray administration compared to placebo spray, but only after overnight deprivation. The in-session ratings and retrospective questionnaire measures indicated that smokers who had high scores on the SCQ-NAR experienced greater negative affect and craving, and less positive affect, than smokers with low scores on the SCQ-NAR, regardless of nicotine exposure.
Our questionnaire results suggest that while smokers who have high NRSOE self-report greater overall levels of negative affect and craving, while the psychophysiological data suggest that such smokers may experience negative affect reduction when blindly administered a dose of nicotine.
PMCID: PMC3242897  PMID: 21868175
smoking; expectancy; negative affect; reinforcement; corrugator EMG; skin conductance
23.  Effect of the selective kappa-opioid receptor antagonist JDTic on nicotine antinociception, reward, and withdrawal in the mouse 
Psychopharmacology  2010;210(2):285-294.
Several lines of evidence support a role for the endogenous opioid system in mediating behaviors associated with drug dependence. Specifically, recent findings suggest that the kappa-opioid receptor (KOR) may play a role in aspects of nicotine dependence, which contribute to relapse and continued tobacco smoking.
The objective of this study is to determine the involvement of the KOR in the initial behavioral responses of nicotine, nicotine reward, and nicotine withdrawal using the highly selective KOR antagonist JDTic. JDTic doses of 1, 4, 8, or 16 mg/kg were administered subcutaneously (s.c.) 18 h prior to nicotine treatment.
JDTic dose-dependently blocked acute nicotine-induced antinociception in the tail-flick but not the hot-plate test and did not significantly attenuate morphine’s antinociceptive effect in either the tail-flick or hot-plate test. Furthermore, JDTic (8 and 16 mg/kg, s.c.) failed to block the expression of nicotine reward as measured by the conditioned place preference model. In contrast, JDTic and the KOR antagonist norBNI attenuated the expression of both the physical (somatic signs and hyperalgesia) and affective (anxiety-related behavior and conditioned place aversion) nicotine withdrawal signs.
Our findings clearly show that the KOR is involved in mediating the withdrawal aspects of nicotine dependence. The results from this study suggest that blockade of the KOR by selective KOR antagonists may be useful smoking cessation pharmacotherapies.
PMCID: PMC2866121  PMID: 20232057
Nicotinic acetylcholine receptors; Nicotine dependence; Kappa-opioid receptors; JDTic; Nicotine withdrawal
24.  Offspring of Prenatal IV Nicotine Exposure Exhibit Increased Sensitivity to the Reinforcing Effects of Methamphetamine 
Maternal smoking during pregnancy is associated with increased substance abuse in offspring. Preclinical research shows that in utero exposure to nicotine, the primary psychoactive compound in tobacco smoke, influences the neurodevelopment of reward systems and alters motivated behavior in offspring. The present study determined if prenatal nicotine (PN) exposure altered the sensitivity to the reinforcing and aversive effects of methamphetamine (METH) in offspring using a low dose, intravenous (IV) exposure method. Pregnant dams were administered nicotine (0.05 mg/kg/injection) or prenatal saline (PS) 3×/day on gestational days 8–21, and adult offspring were tested using METH self-administration (experiment 1) or METH-induced conditioned taste aversion (CTA; experiment 2) procedures. For METH self-administration, animals were trained to respond for IV METH (0.05 mg/kg/infusion; fixed-ratio 3) and they were tested on varying doses of the reinforcer (0.0005–1.0 mg/kg/infusion). For METH CTA, rats received three saccharin and METH pairings (0, 0.3, or 0.5 mg/kg, sc) followed by 14 daily extinction trials. Experiment 1: PN and PS animals exhibited inverted U-shaped dose-response curves; however, the PN animal’s curve was shifted to the left, suggesting PN animals were more sensitive to the reinforcing effects of METH. Experiment 2: METH CTA was acquired in a dose-dependent manner and the factor of PN exposure was not related to the acquisition or extinction of METH-induced CTA. There were no sex differences in either experiment. These results indicate that IV PN-exposed adult offspring exhibited increased sensitivity to IV METH. This suggests that PN exposure, via maternal smoking, will alter the reinforcing effects of METH during later stages of development, and furthermore, will influence substance use vulnerability in adult human offspring.
PMCID: PMC3376423  PMID: 22719728
maternal smoking; prenatal nicotine; intravenous; methamphetamine; self-administration; conditioned taste aversion
25.  A C. elegans model of nicotine-dependent behavior: regulation by TRP family channels 
Cell  2006;127(3):621-633.
Nicotine, the primary addictive substance in tobacco, induces profound behavioral responses in mammals, but the underlying genetic mechanisms are not well understood. Here we develop a C. elegans model of nicotine-dependent behavior. We show that worms exhibit behavioral responses to nicotine that parallel those observed in mammals, including acute response, tolerance, withdrawal and sensitization. These nicotine responses require nicotinic acetylcholine receptor (nAChR) family genes that are known to mediate nicotine dependence in mammals, suggesting functional conservation of nAChRs in nicotine responses. Importantly, we find that mutant worms lacking TRPC (transient-receptor-potential canonical) channels are defective in response to nicotine and that such a defect can be rescued by a human TRPC channel, revealing an unexpected role for TRPC channels in regulating nicotine-dependent behavior. Thus, C. elegans can be used to characterize known genes as well as to identify new genes regulating nicotine responses.
PMCID: PMC2859215  PMID: 17081982

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