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Abstract
Exercise is effective treatment for symptoms of mental disorders such as anxiety and substance abuse. However, the neural mechanisms that support these benefits are only beginning to be identified and dissected. Our laboratory has repeatedly shown that exercise increases levels of the peptide galanin in the locus coeruleus (LC). The effects of galanin share many qualities with those of exercise. Both manipulations are protective against the behavioral impact of stress and cocaine in rodent models of mental disease. We hypothesized that the behavioral protection provided by exercise is mediated by galanin, and similarly that galanin receptor agonists would protect against stress- and drug-induced perturbation of behavior. We also predicted that exercise or administration of a galanin agonist would block neural markers of stress or cocaine in the frontal cortex, a region particularly vulnerable to these challenges. Male Sprague Dawley rats were used in all experiments, and a subset underwent stereotaxic brain cannulation for drug delivery (ICV) and/or in vivo microdialysis (intra-frontal cortex). Rats were assigned to sedentary or exercise conditions and then exposed to stress or cocaine as detailed in the experiments. We measured behavior in tests of anxiety, including the elevated plus maze, open field, and shock probe defensive burying test. We measured galanin levels after exercise using in situ hybridization and ELISA. We also performed in vivo microdialysis and Golgi-impregnation in the frontal cortex. The results showed that exercise increased galanin levels in the locus coeruleus. Exercise and administration of a galanin receptor agonist (galnon or galanin) protected against the behavioral impacts of stress and cocaine. These manipulations also blunted the stress- and cocaine- induced increase in dopamine in the frontal cortex. Further, exercise protected against the loss of dendritic spines after stress. The behavioral protection induced by exercise was mimicked by repeated intracranial galanin administration, and blocked by repeated administration of the galanin receptor antagonist M40. Collectively, our data implicate an important role for galanin in behavioral resilience. Exercise, like galanin therapy, may protect against the aberrant neural plasticity seen in comorbid disorders like anxiety and drug addiction.