Jennifer W. Tidey

Acquisition of cocaine self-administration after social stress : role of accumbens dopamine

Abstract Exposure to either aversive or rewarding environmental stimuli increases extracellular dopamine (DA) concentrations in terminal areas of the mesocorticolimbic dopamine system. Furthermore, behavioral reactivity to an environmental stressor has been shown to correlate with latency to initiate self-administration of psychomotor stimulant drugs. The present study examined the behavioral and dopaminergic responses of rats to social defeat stress and compared latencies to initiate cocaine self-administration in defeated and non-defeated rats. In vivo microdialysis was used to examine the effects of social defeat stress on DA concentrations in nucleus accumbens of freely-moving rats. During the experimental session, dialysate and video recording samples were collected from previously-defeated and non-defeated “intruder” rats in consecutive phases, while (1) in the home cage, (2) when placed in the empty, soiled cage of a resident rat which had previously defeated them, and (3) when exposed to threat of defeat by the resident. Immediately following threat of defeat, previously-defeated and non-defeated intruders were given the opportunity to self-administer cocaine IV. When exposed to the olfactory cues of an aggressive resident, extracellular DA levels in nucleus accumbens increased to approximately 135% of baseline in previously defeated rats versus 125% of baseline in non-defeated rats. When exposed to social threat by the resident, DA levels further increased to 145% of baseline in previously defeated rats versus 120% in non-defeated rats. Previously defeated rats acquired cocaine self-administration in approximately half the time of non-defeated rats, consistent with the hypothesis that prior stress exposure may induce a cross-sensitization to the rewarding effects of cocaine. These results are consistent with the idea that exposure to stress may induce changes in central dopaminergic activity, which may render an individual more vulnerable to acquiring psychomotor stimulant self-administration.

Alcohol demand, delayed reward discounting, and craving in relation to drinking and alcohol use disorders

A behavioral economic approach to alcohol use disorders (AUDs) emphasizes both individual and environmental determinants of alcohol use. The current study examined individual differences in alcohol demand (i.e., motivation for alcohol under escalating conditions of price) and delayed reward discounting (i.e., preference for immediate small rewards compared to delayed larger rewards) in 61 heavy drinkers (62% with an AUD). In addition, based on theoretical accounts that emphasize the role of craving in reward valuation and preferences for immediate rewards, craving for alcohol was also examined in relation to these behavioral economic variables and the alcohol-related variables. Intensity of alcohol demand and delayed reward discounting were significantly associated with AUD symptoms, but not with quantitative measures of alcohol use, and were also moderately correlated with each other. Likewise, craving was significantly associated with AUD symptoms, but not with alcohol use, and was also significantly correlated with both intensity of demand and delayed reward discounting. These findings further emphasize the relevance of behavioral economic indices of motivation to AUDs and the potential importance of craving for alcohol in this relationship.

Randomized Trial of Reduced-Nicotine Standards for Cigarettes

BACKGROUND The Food and Drug Administration can set standards that reduce the nicotine content of cigarettes. METHODS We conducted a double-blind, parallel, randomized clinical trial between June 2013 and July 2014 at 10 sites. Eligibility criteria included an age of 18 years or older, smoking of five or more cigarettes per day, and no current interest in quitting smoking. Participants were randomly assigned to smoke for 6 weeks either their usual brand of cigarettes or one of six types of investigational cigarettes, provided free. The investigational cigarettes had nicotine content ranging from 15.8 mg per gram of tobacco (typical of commercial brands) to 0.4 mg per gram. The primary outcome was the number of cigarettes smoked per day during week 6. RESULTS A total of 840 participants underwent randomization, and 780 completed the 6-week study. During week 6, the average number of cigarettes smoked per day was lower for participants randomly assigned to cigarettes containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5, 16.3, and 14.9 cigarettes, respectively) than for participants randomly assigned to their usual brand or to cigarettes containing 15.8 mg per gram (22.2 and 21.3 cigarettes, respectively; P<0.001). Participants assigned to cigarettes with 5.2 mg per gram smoked an average of 20.8 cigarettes per day, which did not differ significantly from the average number among those who smoked control cigarettes. Cigarettes with lower nicotine content, as compared with control cigarettes, reduced exposure to and dependence on nicotine, as well as craving during abstinence from smoking, without significantly increasing the expired carbon monoxide level or total puff volume, suggesting minimal compensation. Adverse events were generally mild and similar among groups. CONCLUSIONS In this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked. (Funded by the National Institute on Drug Abuse and the Food and Drug Administration Center for Tobacco Products; ClinicalTrials.gov number, NCT01681875.).

Polymorphisms of the mu-opioid receptor and dopamine D4 receptor genes and subjective responses to alcohol in the natural environment.

Polymorphisms of the mu-opioid receptor (OPRM1) and dopamine D4 receptor (DRD4) genes are associated with subjective responses to alcohol and urge to drink under laboratory conditions. This study examined these associations in the natural environment using ecological momentary assessment. Participants were non-treatment-seeking heavy drinkers (n = 112, 52% female, 61% alcohol dependent) who enrolled in a study of naltrexone effects on craving and drinking in the natural environment. Data were culled from 5 consecutive days of drinking reports prior to medication randomization. Analyses revealed that, after drinking, carriers of the Asp40 allele of the OPRM1 gene reported higher overall levels of vigor and lower levels negative mood, as compared to homozygotes for the Asn40 variant. Carriers of the long allele (i.e., >or=7 tandem repeats) of the DRD4 endorsed greater urge to drink than homozygotes for the short allele. Effects of OPRM1 and DRD4 variable-number-of-tandem-repeats genotypes appear to be alcohol dose-dependent. Specifically, carriers of the DRD4-L allele reported slight decreases in urge to drink at higher levels of estimated blood alcohol concentration (eBAC), and Asp40 carriers reported decreases in vigor and increases in negative mood as eBAC rose, as compared to carriers of the major allele for each gene. Self-reported vigor and urge to drink were positively associated with alcohol consumption within the same drinking episode. This study extends findings on subjective intoxication, urge to drink, and their genetic bases from controlled laboratory to naturalistic settings.

Contingent monetary reinforcement of smoking reductions, with and without transdermal nicotine, in outpatients with schizophrenia.

This study was conducted to examine the effects of contingent monetary reinforcement (CM) for smoking reduction, with and without transdermal nicotine, on cigarette smoking in individuals with schizophrenia. Fourteen outpatients participated in each of 3 conditions: (a) CM combined with 21 mg transdermal nicotine, (b) CM combined with placebo patch, and (c) noncontingent reinforcement combined with placebo patch. Each condition lasted 5 days. Carbon monoxide levels were measured 3 times daily, and nicotine withdrawal symptoms were measured once daily in each condition. Results indicated that CM reduced smoking but that 21 mg transdermal nicotine did not enhance that effect. These results offer further evidence supporting the efficacy of CM for reducing smoking among people with schizophrenia, but higher doses of nicotine replacement therapy, or another pharmacotherapy, may be needed to enhance that effect.

Behavioral economic analysis of cue-elicited craving for alcohol

AIMS Craving as a motivational determinant of drug use remains controversial because of ambiguous empirical findings. A behavioral economic approach may clarify the nature of craving, theorizing that subjective craving functionally reflects an acute increase in a drugs value. The current study tested this hypothesis via a multidimensional assessment of alcohol demand over the course of an alcohol cue reactivity procedure. DESIGN One-way within-subjects design. SETTING Human laboratory environment. PARTICIPANTS Heavy drinkers (n = 92) underwent exposures to neutral (water) cues followed by personalized alcohol cues. ASSESSMENTS Participants were assessed for craving, alcohol demand, affect, and salivation following each exposure. FINDINGS Alcohol versus neutral cues significantly increased craving and multiple behavioral economic measures of the relative value of alcohol, including alcohol consumption under conditions of zero cost (intensity), maximum expenditure on alcohol (O(max)), persistence in drinking to higher prices (breakpoint) and proportionate price insensitivity (normalized P(max)). Craving was significantly correlated with demand measures at levels ranging from 0.21-0.43. CONCLUSIONS These findings support the potential utility of a behavioral economic approach to understanding the role of environmental stimuli in alcohol-related decision making. Specifically, they suggest that the behavioral economic indices of demand may provide complementary motivational information that is related to though not entirely redundant with measures of subjective craving.

Effects of topiramate on urge to drink and the subjective effects of alcohol: a preliminary laboratory study.

BACKGROUND Topiramate was recently reported to be efficacious in reducing drinking rates and craving among individuals with alcohol dependence in a randomized controlled trial, but dose effects could not be determined. This laboratory study systematically examined the dose-dependent effects of topiramate on cue-elicited craving and other putative mechanisms of its pharmacotherapeutic effects on drinking. METHODS Male and female heavy drinkers (n = 61) were randomized to 1 of 3 medication conditions (200 mg/d; 300 mg/d; placebo) in a double-blind study. Participants reached the target dose after a 32-day titration period, then were stabilized for approximately 1 week. All then participated in a laboratory assessment of alcohol cue reactivity and of the subjective effects of a moderate dose of alcohol. RESULTS Both doses of topiramate reduced the frequency of heavy drinking during the titration period as compared to placebo. However, topiramate did not affect self-reported craving for alcohol during the titration period, during the cue reactivity protocol, or in response to the alcohol challenge procedure. Topiramate reduced the stimulating effects of alcohol ingestion compared to placebo, but only in the 200 mg group. CONCLUSIONS The results of this study support previous findings that topiramate reduces drinking, but the behavioral mechanism underlying this effect does not appear to be attenuation of craving for alcohol as measured using the approaches employed in this study. Rather, the results tentatively suggest that topiramate may exert its beneficial effects by altering the subjective experiences of alcohol consumption. Limitations of the current study are discussed and complementary methods are recommended for future studies, such as the use of behavioral economic paradigms and ecological momentary assessment.

Validity of a demand curve measure of nicotine reinforcement with adolescent smokers

High or inelastic demand for drugs is central to many laboratory and theoretical models of drug abuse, but it has not been widely measured with human substance abusers. The authors used a simulated cigarette purchase task to generate a demand curve measure of nicotine reinforcement in a sample of 138 adolescent smokers. Participants reported the number of cigarettes they would purchase and smoke in a hypothetical day across a range of prices, and their responses were well-described by a regression equation that has been used to construct demand curves in drug self-administration studies. Several demand curve measures were generated, including breakpoint, intensity, elasticity, P(max), and O(max). Although simulated cigarette smoking was price sensitive, smoking levels were high (8+ cigarettes/day) at prices up to 50¢ per cigarette, and the majority of the sample reported that they would purchase at least 1 cigarette at prices as high as

Contingency management for alcohol use reduction: A pilot study using a transdermal alcohol sensor

2.50 per cigarette. Higher scores on the demand indices O(max) (maximum cigarette purchase expenditure), intensity (reported smoking level when cigarettes were free), and breakpoint (the first price to completely suppress consumption), and lower elasticity (sensitivity of cigarette consumption to increases in cost), were associated with greater levels of naturalistic smoking and nicotine dependence. Greater demand intensity was associated with lower motivation to change smoking. These results provide initial support for the validity of a self-report cigarette purchase task as a measure of economic demand for nicotine with adolescent smokers.

Latent structure of facets of alcohol reinforcement from a behavioral economic demand curve

BACKGROUND Contingency management (CM) has not been thoroughly evaluated as a treatment for alcohol abuse or dependence, in part because verification of alcohol use reduction requires frequent in-person breath tests. Transdermal alcohol sensors detect alcohol regularly throughout the day, providing remote monitoring and allowing for rapid reinforcement of reductions in use. METHODS The purpose of this study was to evaluate the efficacy of CM for reduction in alcohol use, using a transdermal alcohol sensor to provide a continuous measure of alcohol use. Participants were 13 heavy drinking adults who wore the Secure Continuous Remote Alcohol Monitoring (SCRAM) bracelet for three weeks and provided reports of alcohol and drug use using daily web-based surveys. In Week 1, participants were asked to drink as usual; in Weeks 2 and 3, they were reinforced on an escalating schedule with values ranging from