Our earlier work has shown that repeated administration of classical neuroleptic drugs gives rise to structural alterations in target regions of the mesolimbic pathway, most notably, nucleus accumbens. Such changes could be responsible for the efficacious or motor side effects associated with these drugs. Growth factors such as brain-derived neurotrophic factor (BDNF) provide 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 pathway by classical neuroleptic treatment. Animals were administered haloperidol, 0.5 mg/kg, or vehicle, i.p., for either 3 or 21 days, followed by transcardiac perfusion with fixative. Three days of haloperidol administration dramatically decreased BDNF immunostaining in the neurons and fibers of the prefrontal cortex, hippocampus (dentate gyrus, CA2, and CA3), extended amygdala, and ventral tegmental area. BDNF-immunoreactive fibers virtually disappeared from the neostriatum and nucleus accumbens. Subchronic (21 days) treatment led to a rebound in BDNF immunoreactivity in most cell bodies but not in fibers. These results show that blockade of dopaminergic receptors with haloperidol rapidly downregulates BDNF in reward and emotional centers of the brain. Such rapid inactivation and subsequent reappearance of BDNF immunoreactivity 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 drugs.
Copyright 2001 Wiley-Liss, Inc.