Jean M. Abel

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.

Sex Differences in the Cerebellum and Frontal Cortex: Roles of Estrogen Receptor Alpha and Sex Chromosome Genes

Most neurobehavioral diseases are sexually dimorphic in their incidence, and sex differences in the brain may be key for understanding and treating these diseases. Calbindin (Calb) D28K is used as a biomarker for the well-studied sexually dimorphic nucleus, a hypothalamic structure that is larger in males than in females. In the current study weanling C56BL/6J mice were used to examine sex differences in the Calb protein and message focusing on regions outside of the hypothalamus. A robust sex difference was found in Calb in the frontal cortex (FC) and cerebellum (CB; specifically in Purkinje cells); mRNA and protein were higher in females than in males. Using 2 mouse lines, i.e. one with a complete deletion of estrogen receptor alpha (ERα) and the other with uncoupled gonads and sex chromosomes, we probed the mechanisms that underlie sexual dimorphisms. In the FC, deletion of ERα reduced Calb1 mRNA in females compared to males. In addition, females with XY sex chromosomes had levels of Calb1 equal to those of males. Thus, both ERα and the sex chromosome complement regulate Calb1 in the FC. In the CB, ERα knockout mice of both sexes had reduced Calb1 mRNA, yet sex differences were retained. However, the sex chromosome complement, regardless of gonadal sex, dictated Calb1 mRNA levels. Mice with XX chromosomes had significantly greater Calb1 than did XY mice. This is the first study demonstrating that sex chromosome genes are a driving force producing sex differences in the CB and FC, which are neuoranatomical regions involved in many normal functions and in neurobehavioral diseases.

Calbindin Knockout Alters Sex-Specific Regulation of Behavior and Gene Expression in Amygdala and Prefrontal Cortex

Calbindin-D(28K) (Calb1), a high-affinity calcium buffer/sensor, shows abundant expression in neurons and has been associated with a number of neurobehavioral diseases, many of which are sexually dimorphic in incidence. Behavioral and physiological end points are affected by experimental manipulations of calbindin levels, including disruption of spatial learning, hippocampal long-term potentiation, and circadian rhythms. In this study, we investigated novel aspects of calbindin function on social behavior, anxiety-like behavior, and fear conditioning in adult mice of both sexes by comparing wild-type to littermate Calb1 KO mice. Because Calb1 mRNA and protein are sexually dimorphic in some areas of the brain, we hypothesized that sex differences in behavioral responses of these behaviors would be eliminated or revealed in Calb1 KO mice. We also examined gene expression in the amygdala and prefrontal cortex, two areas of the brain intimately connected with limbic system control of the behaviors tested, in response to sex and genotype. Our results demonstrate that fear memory and social behavior are altered in male knockout mice, and Calb1 KO mice of both sexes show less anxiety. Moreover, gene expression studies of the amygdala and prefrontal cortex revealed several significant genotype and sex effects in genes related to brain-derived neurotrophic factor signaling, hormone receptors, histone deacetylases, and γ-aminobutyric acid signaling. Our findings are the first to directly link calbindin with affective and social behaviors in rodents; moreover, the results suggest that sex differences in calbindin protein influence behavior.

Exercise as a Prevention for Substance Use Disorder: a Review of Sex Differences and Neurobiological Mechanisms

Purpose of ReviewThis report provides an update on clinical and preclinical findings for the efficacy of exercise to prevent substance use disorder with a focus on recent evidence for sex differences and neurobiological mechanisms.Recent FindingsExercise/physical activity is associated with decreased drug use in humans. Preclinical results further indicate that exercise decreases vulnerability to drug use and the development of features of substance use disorder, and suggest that females have an enhanced sensitivity to its reward-substitution effects. However, certain exercise conditions may sensitize the reward pathway and enhance vulnerability suggesting that parallel observations in humans (e.g., increased prescription opioid misuse and heroin use in high-school athletes) may be biologically based.SummaryExercise is a promising prevention strategy for substance use disorder. Further work is needed to establish its efficacy as a sex-specific strategy using larger samples and to understand the exercise conditions that induce beneficial versus risk-enhancing effects.

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.

Exercise as a Sex-Specific Treatment for Substance Use Disorder

Purpose of ReviewExercise is a promising treatment for substance use disorder that may reduce withdrawal symptoms and prevent relapse. In this review, we discuss recent evidence from clinical and preclinical studies for its efficacy, from a behavioral to a molecular level, in order to understand the exercise conditions that lead to beneficial effects. We also highlight the few recent findings of sex-specific differences.Recent FindingsClinical and preclinical findings show that exercise decreases withdrawal symptoms, including craving, in both males and females. Evidence from clinical studies support the efficacy of exercise to prevent relapse to smoking, although further research is needed to examine sex differences, establish long-term efficacy, and to determine if effects extend to other substance use disorders. Preclinical findings also support the potential utility of exercise to prevent relapse with evidence suggesting that its efficacy is enhanced in males and mediated by blocking drug-induced adaptations that occur during early abstinence.SummarySex differences and timing of exercise availability during abstinence should be considered in future studies examining exercise as an intervention for relapse. A better understanding of the neurobiological mechanisms underlying the efficacy of exercise to reduce withdrawal symptoms and prevent relapse is needed to guide its development as a sex-specific treatment.

Contents Vol. 93, 2011

D.H. Abbott, Madison, Wisc. H. Ahlman, Gothenburg E. Arzt, Buenos Aires T. Bartness, Atlanta, Ga. C.L. Bethea, Beaverton, Oreg. D.W. Brann, Augusta, Ga. B. Canny, Monash M. Caplin, London K. Catt, Bethesda, Md. A. Chodobski, Providence, R.I. W. de Herder, Rotterdam S.L. Dickson, Gothenburg J. Drouin, Montreal, Que. P.J. Enriori, Victoria, B.C. W. Farrell, Keele M. Freeman, Tallahassee, Fla. R.C. Gaillard, Lausanne A.C. Gore, Austin, Tex. K. Grove, Beaverton, Oreg. T. Harmar, Edinburgh A. Herbison, Dunedin J. Herman, Cincinnati, Ohio J.J. Hirst, Callaghan, N.S.W. T. Hökfelt, Stockholm U. Kaiser, Boston, Mass. A. Kauff man, La Jolla, Calif. K. Kim, Seoul J.Z. Kiss, Geneva A.C. Latronico, São Paulo G. Leng, Edinburgh J. Levine, Evanston, Ill. C. Libertun, Buenos Aires C. Llorens-Cortes, Paris A. Loudon, Manchester Z.-L. Lu, Edinburgh G. Martinez de la Escalera, Querétaro R. Melcangi, Milano I. Modlin, New Haven, Conn. Z. Naor, Tel Aviv M. Palkovits, Budapest I. Parhar, Kuala Lumpur D.W. Pfaff , New York, N.Y. J. Reul, Bristol R. Reynolds, Edinburgh E. Rissman, Charlottesville, Va. J.L. Roberts, San Antonio, Tex. I. Robinson, London P. Ruszniewski, Clichy W. Schlegel, Geneva D. Skinner, Laramie, Wyo. E. Spinedi, La Plata R. Steiner, Seattle, Wash. E. Terasawa, Madison, Wisc. A. Tilbrook, Clayton, Vic. W. Vale, La Jolla, Calif. B. Walker, Edinburgh H. Watanobe, Chiba M. Wierman, Denver, Colo. J. Wingfi eld, Seattle, Wash. S. Wray, Bethesda, Md. International Journal for Basic and Clinical Studies on Neuroendocrine Relationships