Cannabinoid receptor 1 (CNR1) gene variant moderates neural index of cognitive disruption during nicotine withdrawal.

Nicotine withdrawal-related disruption of cognitive control may contribute to the reinforcement of tobacco use. Identification of gene variants that predict this withdrawal phenotype may lead to tailored pharmacotherapy for smoking cessation. Variation on the cannabinoid receptor 1 gene (CNR1) has been related to nicotine dependence, and CNR1 antagonists may increase attention and memory functioning. We targeted CNR1 variants as moderators of a validated neural marker of nicotine withdrawal-related cognitive disruption. CNR1 polymorphisms comprising the 'TAG' haplotype (rs806379, rs1535255 and rs2023239) were tested independently, as no participants in this sample possessed this haplotype. Nicotine withdrawal-related cognitive disruption was indexed as increased resting electroencephalogram (EEG) alpha-1 power density across 17 electrodes. Seventy-three Caucasian Non-Hispanic smokers (≥15 cigarettes per day) visited the laboratory on two occasions following overnight smoking/nicotine deprivation. Either two nicotine or two placebo cigarettes were smoked prior to collecting EEG data at each session. Analyses showed that rs806379 moderated the effects of nicotine deprivation increasing slow wave EEG (P = 0.004). Smokers homozygous for the major allele exhibited greater nicotine withdrawal-related cognitive disruption. The current findings suggest potential efficacy of cannabinoid receptor antagonism as a pharmacotherapy approach for smoking cessation among individuals who exhibit greater nicotine withdrawal-related cognitive disruption.

CHRNA5 variants moderate the effect of nicotine deprivation on a neural index of cognitive control.

Individuals with reduced attention and memory cognitive control-related processes may be motivated to smoke as a result of the cognitive enhancing effects of nicotine. Further, nicotine deprivation-induced reductions in cognitive control may negatively reinforce smoking. Minor allele carriers at rs16969968 in the nicotinic acetylcholine receptor α5 subunit gene (CHRNA5) have been shown to exhibit both reduced cognitive control and greater nicotine dependence. It is therefore of interest to see if variants in this gene moderate the influence of nicotine deprivation on cognitive control. P3b and P3a components of the event-related brain potential waveform evoked by a three-stimulus visual oddball task are widely viewed as positive indices of cognitive control-related processes. We tested the hypothesis that individuals possessing at least one minor allele at rs16969968 in CHRNA5 would show greater nicotine deprivation-induced reductions in P3b and P3a amplitude. The sample included 72 non-Hispanic, Caucasian heavy smokers (54 men and 18 women) with a mean age of 36.11 years (SD = 11.57). Participants completed the visual oddball task during counterbalanced nicotine and placebo smoking sessions. Findings indicated that rs16969968 status did not moderate nicotine effects on P3b or P3a, whereas variation in other CHRNA5 polymorphisms, which are not as well characterized and are not in linkage disequilibrium with rs16969968, predicted nicotine deprivation-induced reduction of P3a amplitude: rs588765 (F1,68 = 7.74, P = 0.007) and rs17408276 (F1,67 = 7.34, P = 0.009). Findings are interpreted in the context of vulnerability alleles that may predict nicotine effects on cognitive control.

Variation in the α 5 nicotinic acetylcholine receptor subunit gene predicts cigarette smoking intensity as a function of nicotine content.

A single-nucleotide polymorphism (SNP) in the α5 nicotinic acetylcholine receptor subunit gene, rs16969968, has been repeatedly associated with both smoking and respiratory health phenotypes. However, there remains considerable debate as to whether associations with lung cancer are mediated through effects on smoking behavior. Preclinical studies suggest that α5 receptor subunit expression and function may have a direct role in nicotine titration during self administration. The present study investigated the association of CHRNA5 polymorphisms and smoking topography in 66 smokers asked to smoke four nicotine-containing (nicotine yield=0.60 mg) and four placebo (nicotine yield <0.05 mg) cigarettes, during separate experimental sessions. Genotype at rs16969968 predicted nicotine titration, with homozygotes for the major allele (G:G) displaying significantly reduced puff volume in response to nicotine, whereas minor allele carriers (A:G or A:A) produced equivalent puff volumes for placebo and nicotine cigarettes. The present results suggest that puff volume may be a more powerful objective phenotype of smoking behavior than self-reported cigarettes per day and nicotine dependence. Further, these results suggest that the association between rs16969968 and lung cancer may be mediated by the quantity of smoke inhaled.

Neurocognitive variation in smoking behavior and withdrawal: genetic and affective moderators.

A burgeoning literature suggests that attentional factors are associated with smoking behavior (e.g. direct nicotine effects and smoking withdrawal). This study examined differences in attentional processing between nonsmokers, satiated smokers and overnight nicotine-deprived smokers by comparing the amplitude of the P300 (P3) component of the event-related brain potential (ERP) elicited during a go-nogo task. We also examined the moderating effects of a common dopamine receptor genotype and state negative affect (SNA) on this ERP index of attention. Nonsmokers relative to smokers had greater nogo P3 amplitude. Carrying the A1 allele at the dopamine receptor D2 (DRD2) Taq1A polymorphism site moderated the effects of withdrawal on nogo P3 amplitude, suggesting the A1 allele is a vulnerability marker for withdrawal-related attentional deficits. Increased SNA also predicted attenuated P3 amplitude among deprived smokers. These findings suggest that DRD2 status and SNA moderate the effects of smoking status and withdrawal on neurocognitive variation during attentional processing. This research contributes to a better understanding of the role of individual differences and attentional processing in smoking behavior.

Food deprivation and emotional reactions to food cues: implications for eating disorders.

Two studies examined emotional responding to food cues. In experiment 1, normal college students were assigned to 0-, 6- or 24-h of food deprivation prior to presentations of standard emotional and food-related pictures. Food deprivation had no impact on responses elicited by standard emotional pictures. However, subjective and psychophysiological reactions to food pictures were affected significantly by deprivation. Importantly, food-deprived subjects viewing food pictures showed an enhanced startle reflex and increased heart rate. Experiment 2 replicated the food deprivation effects from experiment 1, and examined participants reporting either a habitual pattern of restrained (anorexia-like) or binge (bulimia-like) eating. Food-deprived and binge eater groups showed startle potentiation to food cues, and rated these stimuli as more pleasant, relative to restrained eaters and control subjects. The results are interpreted from the perspective that startle modulation reflects activation of defensive or appetitive motivation. Implications of the data for understanding eating disorders are considered.

Neuroimaging in alcoholism: ethanol and brain damage.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The co-chairs were Karl Mann and Ingrid Agartz. The presentations were (1) Neuropathological changes in alcohol-related brain damage, by Clive Harper; (2) Regional brain volumes including the hippocampus and monoamine metabolites in alcohol dependence, by Ingrid Agartz, Susan Shoaf, Robert R, Rawlings, Reza Momenan, and Daniel W Hommer; (3) Diffusion tensor abnormalities in imaging of white matter alcoholism, by Adolf Pfefferbaum and Edith V. Sullivan; (4) Use of functional MRI to evaluate brain activity during alcohol cue exposure in alcoholics: Relationship to craving, by Raymond F. Anton, David J. Drobes, and Mark S. George; and (5) mu-Opiate receptor availability in alcoholism: First results from a positron emission tomography study, by Karl Mann, Roland Bares, Hans-Juergen Machulla, Goetz Mundle, Matthias Reimold, and Andreas Heinz.

Activation of prefrontal cortex and anterior thalamus in alcoholic subjects on exposure to alcohol-specific cues.

BACKGROUND: Functional imaging studies have recently demonstrated that specific brain regions become active in cocaine addicts when they are exposed to cocaine stimuli. To test whether there are regional brain activity differences during alcohol cue exposure between alcoholic subjects and social drinkers, we designed a functional magnetic resonance imaging (fMRI) protocol involving alcohol-specific cues. METHODS: Ten non-treatment-seeking adult alcoholic subjects (2 women) (mean [SD] age, 29.9 [9.9] years) as well as 10 healthy social drinking controls of similar age (2 women) (mean [SD] age, 29.4 [8.9] years) were recruited, screened, and scanned. In the 1.5-T magnetic resonance imaging scanner, subjects were serially rated for alcohol craving before and after a sip of alcohol, and after a 9-minute randomized presentation of pictures of alcoholic beverages, control nonalcoholic beverages, and 2 different visual control tasks. During picture presentation, changes in regional brain activity were measured with the blood oxygen level-dependent technique. RESULTS: Alcoholic subjects, compared with the social drinking subjects, reported higher overall craving ratings for alcohol. After a sip of alcohol, while viewing alcohol cues compared with viewing other beverage cues, only the alcoholic subjects had increased activity in the left dorsolateral prefrontal cortex and the anterior thalamus. The social drinkers exhibited specific activation only while viewing the control beverage pictures. CONCLUSIONS: When exposed to alcohol cues, alcoholic subjects have increased brain activity in the prefrontal cortex and anterior thalamus-brain regions associated with emotion regulation, attention, and appetitive behavior.

Drinking in alcoholics following an alcohol challenge research protocol.

OBJECTIVE: The present study examined the impact of participating in an alcohol administration study on the subsequent drinking behavior of 25 non-treatment-seeking alcoholics. METHOD: Subjects attended two assessment sessions, followed by a week-long regimen on one of three pharmacological agents (naltrexone, nalmefene, or placebo), a day-long laboratory assessment including a standardized alcohol administration procedure, and a debriefing session consisting of individualized feedback and alcohol counseling. Follow-up consisted of a telephone interview 6 weeks after the alcohol challenge session. RESULTS: At the follow-up interview, subjects reported significant reductions in drinking quantity and frequency from the prestudy period, and no subjects reported increased drinking following study participation. CONCLUSIONS: These findings suggest that alcohol administration research procedures may not be detrimental to the poststudy drinking behavior of alcoholics. The use of such procedures could be cautiously expanded to improve the generalizability of findings for alcoholic populations of interest.

Differential urge and salivary responsivity to alcohol cues in alcohol-dependent patients: a comparison of traditional and stringent classification approaches.

Seventy alcohol-dependent individuals were presented with alcohol and water cues on separate trials while salivary responding and self-reported urge for alcohol were measured. Researchers used 2 distinct classification approaches to classify participants as either responders or nonresponders on urge and salivation. Through a traditional classification approach, both urge and salivary responder groups reported higher pleasantness ratings in response to the alcohol cues than nonresponders, yet did not differ on measures of alcohol dependence or withdrawal. Through a more stringent classification approach, salivation responders reported fewer days since their last drink of alcohol and higher pleasantness ratings in response to the alcohol cues than the salivation nonresponder group. The stringently classified urge responders reported higher pleasantness ratings in response to the alcohol cues and more psychiatric distress than the urge nonresponder group. The stringently classified responder groups did not report more alcohol dependence or withdrawal symptoms. There was modest agreement between self-reported urge for alcohol and the physiological measure of salivation. Theoretical and treatment implications are discussed.

Assessing craving for alcohol.

Craving for alcohol is common among alcohol-dependent people. Accordingly, measures to assess craving can play important roles in alcohol research as well as in alcoholism treatment. When developing or employing craving-assessment instruments, researchers and clinicians must consider numerous factors, such as the specific characteristics of craving to be evaluated, the instrument's psychometric properties, and the timeframe over which craving is assessed. The measures most commonly used for assessing craving in clinical settings are single-item questionnaires, although several multi-item questionnaires also have been developed. Behavioral measures (e.g., amount of alcohol consumption or performance on cognitive tests) and psychophysiological measures (e.g., changes in salivation, respiration, or heart rate) are being used primarily in research settings. The assessment of craving can have numerous clinical benefits, such as helping the clinician to evaluate the severity of a patient's alcohol dependence, to select appropriate treatment approaches, and to monitor changes throughout a patient's treatment. The role of craving assessment in predicting treatment outcome, however, remains controversial.

Induction of smoking urge through imaginal and in vivo procedures: physiological and self-report manifestations.

This experiment assessed reactivity to imaginal and in vivo smoking and control cues. One hundred current smokers were assessed during 2 sessions separated by a 6-hr interval, and half of the participants were abstinent from smoking over this interval. Verbal and physiological reactivity measures were selected based on their relevance for several models of urge. Results indicated that imaginal and in vivo smoking cues were equally effective at eliciting high levels of self-reported urges. Smoking deprivation led to a general enhancement in urge report, rather than a specific increase to smoking cues. Physiological responding differed somewhat as a function of urge induction method, although autonomic responses to smoking cues were uniformly consistent with the direct effects of nicotine. There was no relationship between verbal and physiological urge indices. Implications of the findings for several contemporary models of drug urges are discussed.

Assessment of the effects of urges and negative affect on smokers' coping skills.

A taped-situation test designed to elicit descriptions of how subjects would cope with circumstances that placed them at high risk for relapse to smoking was administered to 60 cigarette smokers following their participation in one of three treatment groups. Two of these groups had coping-response training incorporated into the treatment format. The negative affect and urge contents of eight scenarios were manipulated to examine the effect of these variables on coping responses. The predictive validity of this assessment was evaluated by conducting follow-up interviews for up to 1 yr following the assessment. The manipulation of negative affect and urges had an impact on cognitive and behavioral coping. The type of treatment the subjects received had no effect on any of the coping-response measures. Among the 49 subjects abstinent at the time of the coping assessment, measures of coping (especially those obtained when urges and negative affect were increased) and self-efficacy ratings were predictive of days to first relapse. The implications of the results for the assessment of coping-responses and conceptualizations of the role of coping in the relapse process are discussed.

Contribution of associative and nonassociative processes to the development of morphine tolerance.

The contribution of associative and nonassociative processes to the development of tolerance to the analgesic effects of morphine in rats was investigated in two experiments. Associative contingencies were manipulated by administering a series of moderately high morphine doses (20 mg/kg) either explicitly paired or explicitly unpaired with a distinctive context. During distinctive context exposures, animals were placed for 60 min in plastic boxes located in a room adjacent to the colony room. The distinctiveness of this environment was enhanced by the presence of white noise and a pine scent. Nonassociative processes were manipulated by administering the morphine at either a very short (6 h) or relatively long (96 h) interdose-interval (IDI). Analgesia was measured on a tail-flick test. At the 96 h IDI, tolerance, as indexed by shifts in dose-response curves, was controlled primarily by associative processes. Associative control over tolerance at the long IDI was evident at an immediate test (experiment 1) and was retained for a 30 day interval (experiment 2). In contrast, tolerance that developed at the 6 h IDI was not influenced by associative contingencies at the immediate test (experiment 1) and showed no retention over a 30 day interval (experiment 2). These data suggest that tolerance that developed at the short IDI was nonassociative. Overall, the results indicate that conditions conductive to the development of non-associative tolerance disrupt the acquisition of associative tolerance. Hypotheses regarding the absence of associative effects at the short IDI are reviewed. Methodological implications of these results for evaluations of associative and nonassociative morphine tolerance are also discussed.

The development and initial validation of a questionnaire on smoking urges.

A 32-item questionnaire on smoking urges was administered to 230 daily cigarette smokers assigned to one of three levels of cigarette deprivation (0, 1 or 6 hours). Factor analyses showed that a two-factor solution best described the item structure for each of the three deprivation levels and for the entire sample. Factor scales of 15 and 11 items derived from rotation to simple structure were highly reliable, 0.95 and 0.93, respectively, and moderately correlated (r = 0.71). Average scores on both scales increased significantly with level of deprivation, and the Factor 1 scale was significantly higher than the Factor 2 scale at all levels. Factor 1 scale items reflected primarily intention and desire to smoke, and anticipation of pleasure from smoking. Factor 2 scale items were comprised primarily of anticipation of relief from negative affect and nicotine withdrawal, and urgent and overwhelming desire to smoke.

Effect of interdose interval on the development of associative tolerance to morphine in the rat: a dose-response analysis.

Three experiments examined the effect of interdose interval (IDI) on the development and retention of associative tolerance to the analgesic effects of morphine. Tolerance was indexed as the magnitude of the shift to the right of the dose-response curve (DRC). Experiment 1 showed that associative tolerance was characterized by a parallel shift in the DRC to the right in rats that had received morphine explicitly paired with the distinctive test context at 12-, 24-, and 96-hr IDIs. Associative tolerance was attenuated at the shortest IDI. Experiment 2 revealed that associative tolerance that developed in the 12- and 96-hr IDI conditions showed comparable levels of retention at 30 days. Experiment 3 showed that associative tolerance was not disrupted by the administration of unsignaled doses of morphine 12 hr before each drug-context pairing. Theoretical and methodological implications of the data are discussed.

Imagery and smoking urges: the manipulation of affective content.

This study investigated the impact of the affective content of imagery scripts used in an imagery paradigm designed to elicit smoking urges in a laboratory setting. Sixty cigarette smokers were instructed to vividly imagine 10 imagery scripts that described negative affect and explicit smoking urges, positive affect and explicit smoking urges, negative affect alone, positive affect alone, and neutral affect alone. Subjects' ratings of the vividness of their images across the five script types did not differ but ratings of urges and cravings indicated that scripts containing descriptions of smoking urges elicited strong reports of smoking urges/cravings comparable in magnitude across positive and negative affective content. Among scripts that did not explicitly describe smoking urges, negative affect scripts were more effective in generating smoking urges/craving than positive affect scripts, although positive affect scripts did produce significantly stronger urges/cravings than neutral affect scripts. An analysis of subjects' reports of the distribution of their strongest urges over imagery trials and regression analyses of the variables predictive of urge/craving report provided converging evidence that the content of the imagery scripts exerted considerable control over the generation of smoking urges in the imagery paradigm. The results indicated that the magnitude of urges and cravings produced by the imagery manipulation were clearly influenced by urge and affective content of the imagery scripts.