BRAIN-DERIVED NEUROTROPHIC FACTOR, NEUROTROPHIN-3 AND NEUROTROPHIN-4/5 MAINTAIN FUNCTIONAL TOLERANCE TO ETHANOL

Neurotrophins and growth factors not only affect neuronal development, but also maintain neuronal survival and influence neuronal function in the adult brain, and affect various cognitive processes related to learning and memory. Functional tolerance to ethanol represents an adaptive change in the central nervous system that has been hypothesized to have mechanisms in common with those underlying learning or memory. In the present work, the effects of neurotrophins on ethanol tolerance were compared to the effect of the neuropeptide, arginine vasopressin, which maintains (reduces the rate of dissipation of) both ethanol tolerance and memory. Functional tolerance to ethanol was induced in C57BL/6J mice by feeding them an ethanol-containing liquid diet, and the effect of neurotrophins on the rate of dissipation of tolerance to the hypnotic effect of ethanol was assessed. Human recombinant brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5, injected intracerebroventricularly once daily following ethanol withdrawal, maintained ethanol tolerance, while tolerance dissipated in ethanol-fed mice injected with vehicle (artificial cerebrospinal fluid) or with basic fibroblast growth factor. The results demonstrate that some neurotrophins can modulate neuroadaptation to ethanol, supporting the hypothesis that these factors can influence the function of postmitotic neurons in the adult brain.