Stephanie S. O'Malley

Psychological stress, drug-related cues and cocaine craving

Abstract. Rationale: While several environmental situations may produce cocaine craving, there is little research on whether patterns of drug cue reactivity are similar across different environmental situations. Objective: This study examined whether two different environmental situations, psychological stress and drug cues, produce similar or varying patterns of cue reactivity in 20 cocaine dependent individuals. Methods: All subjects participated in a single laboratory session and were exposed to stress, drug cues and neutral-relaxing imagery conditions. Cocaine and alcohol craving, emotion state ratings, subjective anxiety, heart rate and salivary cortisol measures were assessed. Results: Significant increases in cocaine and alcohol craving were observed with stress and drug cues imagery but not with neutral-relaxing imagery. In addition, stress and drug cues situations produced similar increases in subjective anxiety, heart rate and salivary cortisol levels. Significant increases in negative emotion ratings and decreases in positive emotion ratings were found for stress and drug cues conditions as compared to the neutral condition. Conclusions: The findings indicate that a similar and comparable pattern of cue reactivity is induced by stress and drug cue manipulations. Furthermore, the comparable increases in subjective anxiety and negative affect observed with stress-induced and drug cue-induced craving provides support for the negative reinforcement model of drug craving and relapse. The negative affectivity co-occurring with the craving state appears to be an important target in the development of new treatments for cocaine dependence.

Understanding the construct of impulsivity and its relationship to alcohol use disorders

There are well‐established links between impulsivity and alcohol use in humans and other model organisms; however, the etiological nature of these associations remains unclear. This is likely due, in part, to the heterogeneous nature of the construct of impulsivity. Many different measures of impulsivity have been employed in human studies, using both questionnaire and laboratory‐based tasks. Animal studies also use multiple tasks to assess the construct of impulsivity. In both human and animal studies, different measures of impulsivity often show little correlation and are differentially related to outcome, suggesting that the impulsivity construct may actually consist of a number of more homogeneous (and potentially more meaningful) subfacets. Here, we provide an overview of the different measures of impulsivity used across human and animal studies, evidence that the construct of impulsivity may be better studied in the context of more meaningful subfacets, and recommendations for how research in this direction may provide for better consilience between human and animal studies of the connection between impulsivity and alcohol use.

Stress-induced craving and stress response in cocaine dependent individuals

Abstract Two laboratory studies were conducted to examine the effects of acute psychological stress on craving and stress reactivity in cocaine abusers. In the first preliminary study, we examined the effects of a speech stressor task and a personalized stress imagery task on self-reported craving and emotional state in ten cocaine abusers. Both stressors led to significant decreases in neutral and joy states, and significant increases in fear ratings as compared to baseline ratings. In addition, the stress imagery condition led to significant increases in cocaine craving and sadness and anger ratings, as compared to baseline. Thus, the personalized stress imagery task appeared to be more effective than the speech stress task in inducing craving in the laboratory. The second study examined the effects of stress imagery as compared to neutral imagery on cocaine craving, subjective anxiety and physiological responses in a second group of ten cocaine abusers. The stress imagery task once again produced significant increases in cocaine craving along with increases in heart rate, salivary cortisol and subjective anxiety ratings. These data are the first to document that acute psychological stress consistently increases craving for cocaine in cocaine abusers. The studies also provide a promising method for examining the association between stress and drug craving in the laboratory.

Neuropsychological impairment in chronic cocaine abusers

Twenty chronic cocaine abusers were compared with age and education matched controls using standardized neuropsychological assessment procedures to determine whether the cocaine abusers were impaired. Fifty percent of the cocaine abusers in contrast to 15% of the controls scored in the impaired range on the summary index of the Neuropsychological Screening Exam. The cocaine abusers also performed more poorly on the Halstead Category Test, the Symbol Digit Modalities Test, the WAIS-R Arithmetic Test, and a test of verbal memory (forgetting). In the cocaine abuser sample, neuropsychological performance was related to the amount and recency of cocaine use, suggesting a direct role of cocaine on cognitive functioning.

Varenicline Reduces Alcohol Self-Administration in Heavy-Drinking Smokers

BACKGROUND Alcohol and tobacco dependence are highly comorbid disorders, with preclinical evidence suggesting a role for nicotinic acetylcholine receptors (nAChRs) in alcohol consumption. Varenicline, a partial nicotinic agonist with high affinity for the alpha4beta2 nAChR receptor, reduced ethanol intake in rodents. We aimed to test whether varenicline would reduce alcohol consumption and alcohol craving in humans. METHODS This double-blind, placebo-controlled investigation examined the effect of varenicline (2 mg/day vs. placebo) on alcohol self-administration using an established laboratory paradigm in non-alcohol-dependent heavy drinkers (n = 20) who were daily smokers. Following 7 days of medication pretreatment, participants were first administered a priming dose of alcohol (.3 g/kg) and subjective, and physiologic responses were assessed. A 2-hour alcohol self-administration period followed during which participants could choose to consume up to 8 additional drinks (each .15 g/kg). RESULTS Varenicline (.5 +/- SE = .40) significantly reduced the number of drinks consumed compared to placebo (2.60 +/- SE = .93) and increased the likelihood of abstaining from any drinking during the self-administration period. Following the priming drink, varenicline attenuated alcohol craving and reduced subjective reinforcing alcohol effects (high, like, rush, feel good, intoxicated). Adverse events associated with varenicline were minimal and, when combined with alcohol, produced no significant effects on physiologic reactivity, mood, or nausea. CONCLUSIONS This preliminary investigation demonstrated that varenicline significantly reduced alcohol self-administration and was well tolerated, alone and in combination with alcohol in heavy-drinking smokers. Varenicline should be investigated as a potential treatment for alcohol use disorders.

Cue-dose Training with Monetary Reinforcement: Pilot Study of an Antiretroviral Adherence Intervention

AbstractOBJECTIVE: To assess the feasibility and efficacy of two interventions for improving adherence to antiretroviral therapy regimens in HIV-infected subjects compared with a control intervention. DESIGN: Randomized, controlled, pilot study. SETTING: Department of Veterans Affairs HIV clinic and community-based HIV clinical trials site. PARTICIPANTS: Fifty-five HIV-infected subjects on stable antiretroviral therapy regimens. Subjects were predominantly male (89%) and African American (69%), and had histories of heroin or cocaine use (80%). INTERVENTIONS: Four weekly sessions of either nondirective inquiries about adherence (control group, C), cue-dose training, which consisted of the use of personalized cues for remembering particular dose times, and feedback about medication taking using Medication Event Monitoring System (MEMS) pill bottle caps, which record time of bottle opening (CD group), or cue-dose training combined with cash reinforcement for correctly timed bottle opening (CD+CR). MEASUREMENTS: Opening of the pill bottle within 2 hours before or after a predetermined time was measured by MEMS. RESULTS: Adherence to the medication as documented by MEMS was significantly enhanced during the 4-week training period in the CD+CR group, but not in the CD group, compared with the control group. Improvement was also seen in adherence to antiretroviral drugs that were not the object of training and reinforcement. Eight weeks after training and reinforcement were discontinued, adherence in the cash-reinforced group returned to near-baseline levels. CONCLUSIONS: Cue-dose training with cash reinforcement led to transient improvement in adherence to antiretroviral therapy in a population including mostly African Americans and subjects with histories of drug abuse. However, we were not able to detect any sustained improvement beyond the active training period, and questions concerning the timing and duration of such an intervention require further study. Randomized, controlled clinical studies with objective measures of adherence can be conducted in HIV-infected subjects and should be employed for further evaluation of this and other adherence interventions.

Human Tobacco Smokers in Early Abstinence Have Higher Levels of β2* Nicotinic Acetylcholine Receptors than Nonsmokers

Nicotine, the addictive chemical in tobacco smoke, initiates its actions in brain through nicotinic acetylcholine receptors (nAChRs). In particular, nAChRs containing β2-subunits (β2*-nAChRs) the most prevalent subtype, mediate the reinforcing properties of nicotine. We hypothesized that abnormal numbers of β2*-nAChRs during early abstinence contribute to the perpetuation of addiction to tobacco smoking. Using molecular imaging, specifically single-photon emission computed tomography with the nAChR agonist radiotracer [123I]5-IA-85380 ([123I]5-IA), we imaged β2*-nAChR availability in human smokers. First, using nonhuman primates treated chronically with nicotine, we estimated the time interval necessary for smokers to abstain from smoking so that residual nicotine would not interfere with [123I]5-IA binding to the β2*-nAChR as ∼7 d. Thus, we imaged human smokers at 6.8 ± 1.9 d (mean ± SD) of abstinence. Abstinence was confirmed by daily assessments of urinary cotinine and expired carbon monoxide levels. In smokers, [123I]5-IA uptake was significantly higher throughout the cerebral cortex (26–36%) and in the striatum (27%) than in nonsmokers, suggesting higher β2*-nAChR in recently abstinent smokers. β2*-nAChR availability in recently abstinent smokers correlated with the days since last cigarette and the urge to smoke to relieve withdrawal symptoms but not the severity of nicotine dependence, severity of nicotine withdrawal, or the desire to smoke. Higher brain β2*-nAChR during early abstinence indicates that, when smokers quit smoking, they do so in the face of a significant increase in the receptors normally activated by nicotine. Greater β2*-nAChR availability during early abstinence may impact the ability of smokers to maintain abstinence.

Translational research in medication development for nicotine dependence

A major obstacle to the development of medications for nicotine dependence is the lack of animal and human laboratory models with sufficient predictive clinical validity to support the translation of knowledge from laboratory studies to clinical research. This Review describes the animal and human laboratory paradigms commonly used to investigate the pathophysiology of nicotine dependence, and proposes how their predictive validity might be determined and improved, thereby enhancing the development of new medications.

Individuals Family History Positive for Alcoholism Show Functional Magnetic Resonance Imaging Differences in Reward Sensitivity That Are Related to Impulsivity Factors

BACKGROUND Substance-abusing individuals tend to display abnormal reward processing and a vulnerability to being impulsive. Detoxified alcoholics show differences in regional brain activation during a monetary incentive delay task. However, there is limited information on whether this uncharacteristic behavior represents a biological predisposition toward alcohol abuse, a consequence of chronic alcohol use, or both. METHODS We investigated proposed neural correlates of substance disorder risk by examining reward system activity during a monetary incentive delay task with separate reward prospect, reward anticipation, and reward outcome phases in 30 individuals with and 19 without family histories of alcoholism. All subjects were healthy, lacked DSM-IV past or current alcohol or substance abuse histories, and were free of illegal substances as verified by a urine toxicology screening at the time of scanning. Additionally, we explored specific correlations between task-related nucleus accumbens (NAcc) activation and distinct factor analysis-derived domains of behavioral impulsivity. RESULTS During reward anticipation, functional magnetic resonance imaging data confirmed blunted NAcc activation in family history positive subjects. In addition, we found atypical activation in additional reward-associated brain regions during additional task phases. We further found a significant negative correlation between NAcc activation during reward anticipation and an impulsivity construct. CONCLUSIONS Overall, results demonstrate that sensitivity of the reward circuit, including NAcc, is functionally different in alcoholism family history positive individuals in multiple regards.

Sex Differences in Striatal Dopamine Release in Young Adults After Oral Alcohol Challenge: A Positron Emission Tomography Imaging Study With [11C]Raclopride

BACKGROUND We used a positron emission tomography paradigm with the D2/3 radiotracer [¹¹C]raclopride and an alcohol challenge to examine the magnitude of alcohol-induced dopamine release and compare it between young men and women. METHODS Twenty-one nonalcohol-dependent young social drinkers completed two positron emission tomography scans on separate days following ingestion of a juice mix containing either ethanol (.75 mg/kg body water) or trace ethanol only. The extent of dopamine released after alcohol was estimated by the percentage difference in [¹¹C]raclopride binding potential (ΔBP(ND)) between days. RESULTS Alcohol administration significantly displaced [¹¹C]raclopride in all striatal subregions, indicating dopamine release, with the largest effect observed in the ventral striatum. Linear mixed model analysis across all striatal subregions of regional ΔBP(ND) with region of interest as repeated measure showed a highly significant effect of sex (p < .001). Ventrostriatal dopamine release in men, but not in women, showed a significant positive correlation to alcohol-induced measures of subjective activation. Furthermore, we found a significant negative correlation between the frequency of maximum alcohol consumption per 24 hours and ventrostriatal ΔBP(ND) (r = .739, p = .009) in men. CONCLUSIONS This study provides definitive evidence that oral alcohol induces dopamine release in nonalcoholic human subjects and shows sex differences in the magnitude of this effect. The ability of alcohol to stimulate dopamine release may contribute to its rewarding effects and, thereby, to its abuse liability in humans. Our report further suggests several biological mechanisms that may mediate the difference in vulnerability for alcoholism between men and women.