Wendy J. Lynch

Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis.

Physical activity, and specifically exercise, has been suggested as a potential treatment for drug addiction. In this review, we discuss clinical and preclinical evidence for the efficacy of exercise at different phases of the addiction process. Potential neurobiological mechanisms are also discussed focusing on interactions with dopaminergic and glutamatergic signaling and chromatin remodeling in the reward pathway. While exercise generally produces an efficacious response, certain exercise conditions may be either ineffective or lead to detrimental effects depending on the level/type/timing of exercise exposure, the stage of addiction, the drug involved, and the subject population. During drug use initiation and withdrawal, its efficacy may be related to its ability to facilitate dopaminergic transmission, and once addiction develops, its efficacy may be related to its ability to normalize glutamatergic and dopaminergic signaling and reverse drug-induced changes in chromatin via epigenetic interactions with brain-derived neurotrophic factor (BDNF) in the reward pathway. We conclude with future directions, including the development of exercise-based interventions alone or as an adjunct to other strategies for treating drug addiction.

Exercise as a potential treatment for drug abuse: evidence from preclinical studies.

Epidemiological studies reveal that individuals who engage in regular aerobic exercise are less likely to use and abuse illicit drugs. Until recently, very few studies had examined the causal influences that mediate this relationship, and it was not clear whether exercise was effective at reducing substance use and abuse. In the past few years, several preclinical studies have revealed that exercise reduces drug self-administration in laboratory animals. These studies have revealed that exercise produces protective effects in procedures designed to model different transitional phases that occur during the development of, and recover from, a substance use disorder (e.g., acquisition, maintenance, escalation, and relapse/reinstatement of drug use). Moreover, recent studies have revealed several behavioral and neurobiological consequences of exercise that may be responsible for its protective effects in these assays. Collectively, these studies have provided convincing evidence to support the development of exercise-based interventions to reduce compulsive patterns of drug intake in clinical and at-risk populations.

How to study sex differences in addiction using animal models.

The importance of studying sex as a biological variable in biomedical research is becoming increasingly apparent. There is a particular need in preclinical studies of addiction to include both sexes, as female animals are often excluded from studies, leaving large gaps in our knowledge of not only sex differences and potential prevention and treatment strategies but also with regard to the basic neurobiology of addiction. This review focuses on methodology that has been developed in preclinical studies to examine sex differences in the behavioral aspects and neurobiological mechanisms related to addiction across the full range of the addiction process, including initiation (acquisition), maintenance, escalation, withdrawal, relapse to drug seeking and treatment. This review also discusses strategic and technical issues that need to be considered when comparing females and males, including the role of ovarian hormones and how sex differences interact with other major vulnerability factors in addiction, such as impulsivity, compulsivity and age (adolescent versus adult). Novel treatments for addiction are also discussed, such as competing non‐drug rewards, repurposed medications such as progesterone and treatment combinations. Practical aspects of conducting research comparing female and male animals are also considered. Making sex differences a point of examination requires additional effort and consideration; however, such studies are necessary given mounting evidence demonstrating that the addiction process occurs differently in males and females. These studies should lead to a better understanding of individual differences in the development of addiction and effective treatments for males and females.

Alcohol preferring (P) rats as a model for examining sex differences in alcohol use disorder and its treatment.

RATIONALE Despite epidemiological and clinical data indicating marked gender differences in alcohol use disorders (AUDs), few preclinical studies have examined sex differences in animal models of AUDs. OBJECTIVE The purpose of this study was to first characterize sex differences in ethanol consumption and reinforcement in an alcohol preferring (P) rat model of alcoholism, then use this model to screen pharmacological treatments for sex-specific effects. METHODS Ethanol consumption was first assessed in male and female P rats under a three-bottle free-choice procedure. Next, ethanols reinforcing effects were assessed under a fixed-ratio 1 (FR1) schedule followed by a progressive-ratio (PR) schedule. Finally, the effects of two pharmacological treatments for AUDs, naltrexone (1mg/kg) and topiramate (10 or 20mg/kg), alone and in combination, were tested for sex-specific differences in their efficacy at reducing ethanols reinforcing effects. RESULTS Although females initially had higher consumption of and preference for ethanol, male rats increased their consumption and preference over time and rapidly became equal to females. Following prolonged 24-hour/day access, males and females self-administered similar levels of ethanol under FR1 and PR schedules. In response to pharmacological treatment, we observed some sex differences and similarities, most notably, a more robust effect of the combination of naltrexone and topiramate in males as compared to females. CONCLUSIONS This model of selectively bred P rats may be useful for understanding sex differences in AUDs and related behavior and their underlying neurobiological mechanisms and treatment.

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

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

A Shift in the Role of Glutamatergic Signaling in the Nucleus Accumbens Core With the Development of an Addicted Phenotype

BACKGROUND While dopamine signaling in the nucleus accumbens (NAc) plays a well-established role in motivating cocaine use in early nonaddicted stages, recent evidence suggests that other signaling pathways may be critical once addiction has developed. Given the importance of glutamatergic signaling in the NAc for drug seeking and relapse, here we examined its role in motivating cocaine self-administration under conditions known to produce either a nonaddicted or an addicted phenotype. METHODS Following acquisition, male and female Sprague Dawley rats were given either short access (three fixed-ratio 1 sessions, 20 infusions/day) or extended 24-hour access (10 days; 4 trials/hour; up to 96 infusions/day) to cocaine. Following a 14-day abstinence period, motivation for cocaine was assessed under a progressive-ratio schedule, and once stable, the effects of intra-NAc infusions of the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate receptor antagonist CNQX (0, .01, .03, .1 μg/side) were determined. As an additional measure for the development of an addicted phenotype, separate groups of rats were screened under an extinction/cue-induced reinstatement procedure following abstinence from short-access versus extended-access self-administration. RESULTS Motivation for cocaine and levels of extinction and reinstatement responding were markedly higher following extended-access versus short-access self-administration, confirming the development of an addicted phenotype in the extended-access group. CNQX dose-dependently reduced motivation for cocaine in the extended-access group but was without effect in the short-access group. CONCLUSIONS These results suggest that the role of glutamatergic signaling in the NAc, though not essential for motivating cocaine use in nonaddicted stages, becomes critical once addiction has developed.

Time and sex-dependent effects of an adenosine A2A/A1 receptor antagonist on motivation to self-administer cocaine in rats.

Adenosine is an important neuromodulator, known to interact with both dopaminergic and glutamatergic systems to influence psychostimulant action. In the present study, we examined the effects of ATL444, a novel adenosine receptor antagonist, on motivation for cocaine in male and female rats. Adult male and female Sprague-Dawley rats were trained to self-administer cocaine (1.5mg/kg/infusion) on a fixed-ratio 1 schedule with a daily maximum of 20 infusions. Following 5 consecutive sessions during which all 20 available infusions were obtained, motivation for cocaine (0.5 mg/kg/infusion) was assessed under a progressive ratio (PR) schedule, and once responding stabilized, the effect of treatment with ATL444 (0, 15, and 30 mg/kg, i.p.) was examined. As a control, we also assessed its effects on PR responding for sucrose. Binding studies revealed that ATL 444 was 3-fold, 25-fold, and 400-fold more selective for the A2A receptor as compared to A1, A2B, and A3 receptors, respectively. ATL444 produced a significant increase in motivation for cocaine on the day of treatment in females with a trend for an increase in males. In addition, over the two PR sessions following ATL444 treatment a significant decrease in responding was observed in males but not females. Responding for sucrose was unaffected by ATL444 treatment. Our results reveal that adenosine receptor blockade may mediate both acute increases in the reinforcing effects of cocaine, and longer term inhibitory effects on cocaine reinforcement that differ according to sex.

Modeling the development of drug addiction in male and female animals

&NA; An increasing emphasis has been placed on the development and use of animal models of addiction that capture defining features of human drug addiction, including escalation/binge drug use, enhanced motivation for the drug, preference for the drug over other reward options, use despite negative consequences, and enhanced drug‐seeking/relapse vulnerability. The need to examine behavior in both males and females has also become apparent given evidence demonstrating that the addiction process occurs differently in males and females. This review discusses the procedures that are used to model features of addiction in animals, as well as factors that influence their development. Individual differences are also discussed, with a particular focus on sex differences. While no one procedure consistently produces all characteristics, different models have been developed to focus on certain characteristics. A history of escalating/binge patterns of use appears to be critical for producing other features characteristic of addiction, including an enhanced motivation for the drug, enhanced drug seeking, and use despite negative consequences. These characteristics tend to emerge over abstinence, and appear to increase rather than decrease in magnitude over time. In females, these characteristics develop sooner during abstinence and/or following less drug exposure as compared to males, and for psychostimulant addiction, may require estradiol. Although preference for the drug over other reward options has been demonstrated in non‐human primates, it has been more difficult to establish in rats. Future research is needed to define the parameters that optimally induce each of these features of addiction in the majority of animals. Such models are essential for advancing our understanding of human drug addiction and its treatment in men and women. HighlightsProcedures used to induce features of addiction in animals are reviewed.Extended access drug self‐administration is critical for modeling addiction.Features emerge over abstinence and increase in magnitude over time.In females, features develop sooner/after less drug, and may require estradiol.Future research is needed to optimize conditions that induce addiction features.

The efficacy of a low dose combination of topiramate and naltrexone on ethanol reinforcement and consumption in rat models

RATIONALE Combined medication approaches, by targeting multiple neurotransmitter systems involved in alcohol use disorders (AUDs), may be more efficacious than single-medication approaches. OBJECTIVES We examined, in animal models of consumption and reinforcement, the combined effects of naltrexone (an opioid antagonist) and topiramate (a GABA/glutamate modulator), two medications that have shown promise for treating AUDs, hypothesizing that their combination would be more efficacious than either alone. METHODS The effects of naltrexone and topiramate on ethanol consumption were examined in alcohol preferring (P) rats (N=10) and in rats from their background strain (Wistar, N=9) using conditions that induce high levels of consumption (24-h, 3-bottle, free-choice procedure). Low doses of each medication (1mg/kg, naltrexone; 10mg/kg, topiramate) were selected in an attempt to maximize their combined efficacy while minimizing potential side-effects. Their effects on ethanol reinforcement were assessed under a progressive-ratio schedule in additional groups of (N=22) P rats. A moderate dose of topiramate (20mg/kg) was also included to verify topiramates efficacy on its own. RESULTS In P rats, but not in Wistar rats, the combination effectively and persistently reduced consumption; whereas, neither dose alone was effective. The combination and naltrexone alone were equally effective at reducing ethanol reinforcement; however, with the combination, but not naltrexone alone, this effect was selective for ethanol. All treatments produced a similar decrease in home-cage food consumption. The 20mg/kg dose of topiramate also effectively reduced ethanol consumption and reinforcement. CONCLUSIONS With greater efficacy and fewer side-effects, the combination shows promise as a treatment for AUDs.

Resistance exercise decreases heroin self-administration and alters gene expression in the nucleus accumbens of heroin-exposed rats

RationalePreclinical studies consistently report that aerobic exercise decreases drug self-administration and other forms of drug-seeking behavior; however, relatively few studies have examined other types of physical activity.ObjectivesThe purpose of the present study was to examine the effects of resistance exercise (i.e., strength training) on heroin self-administration and mRNA expression of genes known to mediate opioid reinforcement and addictive behavior in the nucleus accumbens (NAc) of heroin-exposed rats.MethodsFemale rats were obtained during late adolescence and divided into two groups. Resistance exercise rats were trained to climb a vertical ladder wearing a weighted vest; sedentary control rats were placed repeatedly on the ladder oriented horizontally on its side. All rats were implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement. mRNA expression in the NAc core and shell was examined following behavioral testing.ResultsResistance exercise significantly decreased heroin self-administration, resulting in a downward shift in the dose-effect curve. Resistance exercise also reduced mRNA expression for mu opioid receptors and dopamine D1, D2, and D3 receptors in the NAc core. Resistance exercise increased mRNA expression of dopamine D5 receptors in the NAc shell and increased mRNA expression of brain-derived neurotrophic factor (exons I, IIB, IIC, IV, VI, IX) in the NAc core.ConclusionsThese data indicate that resistance exercise decreases the positive reinforcing effects of heroin and produces changes in opioid and dopamine systems in the NAc of heroin-exposed rats.