Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the central nervous system. However, the role of endogenous BDNF in the development and function of these neurons has not been established in vivo because of the early postnatal lethality of BDNF null mice. In the present study, we use heterozygous BDNF ؉͞؊ mice that have a normal life span and show that these animals develop enhanced intermale aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood; these behavioral abnormalities are known to correlate with 5-HT dysfunction. Forebrain 5-HT levels and fiber density in BDNF ؉͞؊ mice are normal at an early age but undergo premature age-associated decrements. However, young adult BDNF ؉͞؊ mice show a blunted c-fos induction by the specific serotonin releaser-uptake inhibitor dexfenfluramine and alterations in the expression of several 5-HT receptors in the cortex, hippocampus, and hypothalamus. The heightened aggressiveness can be ameliorated by the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that endogenous BDNF is critical for the normal development and function of central 5-HT neurons and for the elaboration of behaviors that depend on these nerve cells. Therefore, BDNF ؉͞؊ mice may provide a useful model to study human psychiatric disorders attributed to dysfunction of serotonergic neurons.T he neurotrophin brain-derived neurotrophic factor (BDNF) influences the phenotype, structural plasticity, and perhaps survival of central serotonergic (5-HT) neurons (1-3). Disturbances in brain 5-HT systems have been implicated in psychiatric syndromes characterized by behavioral dyscontrol, such as obsessive-compulsive disorder, bulimia, chronic impulsivity͞ aggression, and violent suicide (4-7). Many of these psychiatric syndromes are being treated with compounds that augment 5-HT neurotransmission in the brain, including selective serotonin reuptake inhibitors and 5-HT receptor agonists (8, 9). Pharmacological studies indicate that exogenously administered BDNF has trophic effects on 5-HT neurons. For example, BDNF administration increases 5-HT metabolism in the brain (3) and stimulates the local sprouting of 5-HT fibers in the cerebral cortex and spinal cord (2, 10, 11). The enhancement of 5-HT neurotransmission by exogenous BDNF potentiates several behaviors regulated by serotonin (12, 13) and has antidepressantlike effects in animal models of depression (14). However, the role of endogenous BDNF in the normal development and function of 5-HT neurons has not been determined.A major obstacle in elucidating the role of endogenous BDNF has been the early postnatal lethality of BDNF Ϫ͞Ϫ mice. However, recent studies confirmed the presence of several nonlethal, functional defects within the peripheral and central nervous systems of heterozygous animals with one functional BDNF allele, suggesting that BDNF is haploinsufficient. For example, targeted mutation of the BDNF locus causes deficits in hippocampal synaptic funct...

Methamphetamine and methcathinone are psychostimulant drugs with high potential for abuse. In animals, methamphetamine and related drugs are known to damage brain dopamine (DA) neurons, and this damage has recently been shown to be detectable in living nonhuman primates by means of positron emission tomography (PET) with [11 C]WIN-35,428, a DA transporter (DAT) ligand. The present studies determined whether living humans with a history of methamphetamine or methcathinone abuse showed evidence of lasting decrements in brain DAT density. PET studies were performed in 10 control subjects, six abstinent methamphetamine users, four abstinent methcathinone users, and three patients with Parkinson's disease (PD). On average, subjects had abstained from amphetamine use for ϳ3 years. Before PET studies, all subjects underwent urine and blood toxicology screens to rule out recent drug use. Compared with controls, abstinent methamphetamine and methcathinone users had significant decreases in DAT density in the caudate nucleus (Ϫ23 and Ϫ24%, respectively) and putamen (Ϫ25 and Ϫ16%, respectively). Larger decreases in DAT density were evident in patients with PD (47 and 68% in caudate and putamen, respectively). Neither methamphetamine nor methcathinone users showed clinical signs of parkinsonism. Persistent reductions of DAT density in methamphetamine and methcathinone users are suggestive of loss of DAT or loss of DA terminals and raise the possibility that as these individuals age, they may be at increased risk for the development of parkinsonism or neuropsychiatric conditions in which brain DA neurons have been implicated.

Abstinent MDMA users have impairment in verbal and visual memory. The extent of memory impairment correlates with the degree of MDMA exposure and the reduction in brain 5-HT, as indexed by CSF 5-HIAA.