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 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.

Few treatments for obesity exist and, whereas efficacious therapeutics for hyperlipidemia are available, further improvements are desirable. Thyroid hormone receptors (TRs) regulate both body weight and cholesterol levels. However, thyroid hormones also have deleterious effects, particularly on the heart. The TR␤ subtype is involved in cholesterol lowering and possibly elevating metabolic rate, whereas TR␣ appears to be more important for control of heart rate (HR). In the current studies, we examined the effect of TR␤ activation on metabolic rate and HR with either TR␣1 ؊͞؊ mice or the selective TR␤ agonist KB-141 in mice, rats, and monkeys. 3,5,3 -triiodi-L-thyronine (T3) had a greater effect on increasing HR in WT than in TR␣ ؊͞؊ mice (ED15 values of 34 and 469 nmol͞kg͞day, respectively). T 3 increased metabolic rate [whole body oxygen consumption (MV O 2 )] in both WT and TR␣ ؊͞؊ mice, but the effect in the TR␣ 1 ؊͞؊ mice at the highest dose was half that of the WT mice. Thus, stimulation of MV O 2 is likely due to both TR␣ and -␤. T3 had equivalent potency for cholesterol reduction in WT and TR␣ ؊͞؊ mice. KB-141 increased MVO 2 with selectivities of 16.5-and 11.2-fold vs. HR in WT and TR␣ 1 ؊͞؊ mice, respectively. KB-141 also increased MV O 2 with a 10-fold selectivity and lowered cholesterol with a 27-fold selectivity vs. HR in rats. In primates, KB-141 caused significant cholesterol, lipoprotein (a), and body-weight reduction (up to 7% after 1 wk) with no effect on HR. TR␤-selective agonists may constitute a previously uncharacterized class of drugs to treat obesity, hypercholesterolemia, and elevated lipoprotein (a).O besity and atherosclerosis are important medical problems with major impact on morbidity and mortality. Current treatments for obesity have shown limited efficacy and safety; therefore, there is a need for improved therapies (1). A major risk factor for atherosclerosis is low-density lipoprotein (LDL) cholesterol. Although there are excellent treatments for elevated LDL cholesterol, therapeutic goals are commonly not met. As targets for lowering of cholesterol become more aggressive, there is a need for more modalities to meet these goals. Lipoprotein (a) [Lp(a)] is an important risk factor, elevated in many patients with premature atherosclerosis, and few therapies lower Lp(a) (2).Thyroid hormones reduce body weight, LDL cholesterol, and Lp(a); thus, exploitation of these properties may be useful for therapy (3-6). Unfortunately, endogenous thyroid hormones are nonselective and produce undesirable side effects, particularly cardiac stimulation (7,8). Development of thyromimetics devoid of cardiac effects could have therapeutic potential as antiobesity and lipid-lowering agents.Thyroid hormone receptors (TRs) are divided into two primary subtypes (TR␣ and -␤), which are the products of two genes of the superfamily of nuclear hormone receptors (4, 7). TRs mediate distinct physiologic effects due to differences in tissue abundance or receptor-specific activity (9). Studies in patients with th...

Aerobic exercise can serve as an alternative, non-drug reinforcer in laboratory animals and has been recommended as a potential intervention for substance abusing populations. Unfortunately, relatively little empirical data have been collected that specifically address the possible protective effects of voluntary, long-term exercise on measures of drug self-administration. The purpose of the present study was to examine the effects of chronic exercise on sensitivity to the positive-reinforcing effects of cocaine in the drug self-administration procedure. Female rats were obtained at weaning and immediately divided into two groups. Sedentary rats were housed individually in standard laboratory cages that permitted no exercise beyond normal cage ambulation; exercising rats were housed individually in modified cages equipped with a running wheel. After 6 weeks under these conditions, rats were surgically implanted with venous catheters and trained to self-administer cocaine on a fixedratio schedule of reinforcement. Once self-administration was acquired, cocaine was made available on a progressive ratio schedule and breakpoints were obtained for various doses of cocaine. Sedentary and exercising rats did not differ in the time to acquire cocaine self-administration or responding on the fixed-ratio schedule of reinforcement. However, on the progressive ratio schedule, breakpoints were significantly lower in exercising rats than sedentary rats when responding was maintained by both low (0.3 mg/kg/infusion) and high (1.0 mg/kg/infusion) doses of cocaine. In exercising rats, greater exercise output prior to catheter implantation was associated with lower breakpoints at the high dose of cocaine. These data indicate that chronic exercise decreases the positive-reinforcing effects of cocaine and support the possibility that exercise may be an effective intervention in drug abuse prevention and treatment programs.