Changes in the pattern of brain-derived neurotrophic factor immunoreactivity in the rat brain after acute and subchronic haloperidol treatment

Our earlier work has shown that repeated administration of classical neurol eptic drugs gives rise to structural alterations in target regions of the m esolimbic pathway, most notably, nucleus accumbens. Such changes could be r esponsible for the efficacious or motor side effects associated with these drugs. Growth factors such as brain-derived neurotrophic factor (BDNF) prov ide trophic support for dopaminergic neurons during development and mediate synaptic and morphological plasticity in numerous regions of the adult CNS . The present study examines whether BDNF is altered in the mesolimbic path way by classical neuroleptic treatment. Animals were administered haloperid ol, 0.5 mg/kg, or vehicle, i.p., for either 3 or 21 days, followed by trans cardiac perfusion with fixative. Three days of haloperidol administration d ramatically decreased BDNF immunostaining in the neurons and fibers of the prefrontal cortex, hippocampus (dentate gyrus, CA2, and CA3), extended amyg dala, and ventral tegmental area. BDNF-immunoreactive fibers virtually disa ppeared from the neostriatum and nucleus accumbens. Subchronic (21 days) tr eatment led to a rebound in BDNF immunoreactivity in most cell bodies but n ot in fibers. These results show that blockade of dopaminergic receptors wi th haloperidol rapidly downregulates BDNF in reward and emotional centers o f the brain. Such rapid inactivation and subsequent reappearance of BDNF im munoreactivity could affect synaptic strength and plasticity and therefore be important preliminary steps in the cascade of neuronal events that lead to the efficacious or detrimental side effects of classical neuroleptic dru gs. (C) 2001 Wiley-Liss, Inc.