1-Methyl-4-(2Ј-aminophenyl)-1,2,3,6-tetrahydropyridine (2Ј-NH 2 -MPTP) causes long-term loss of forebrain serotonin (5-HT) and norepinephrine (NE) and consequently, is unlike 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its other 2Ј-analogs that primarily deplete striatal dopamine (DA). In the present investigation into the acute effects of 2Ј-NH 2 -MPTP in mice, profound decreases in cortical and hippocampal 5-HT and NE to 10 to 40% of control were observed as early as 30 min post-treatment and lasted throughout the ensuing 21 days. Striatal DA was decreased to 60 to 80% of control during the first 48 h but returned to normal by 72 h. Reactive gliosis, which occurs in response to neurodegeneration was not evident by immunocytochemistry but was detected by enzyme-linked immunosorbent assay, where glial fibrillary acidic protein (GFAP) was increased to 130% of control in cortex, hippocampus, and brain stem 48 to 72 h post-treatment.To explore the possibility that 5-HT modulates the astrocytic response to injury, 2Ј-NH 2 -MPTP was used to damage 5-HT axons 2 weeks before administration of the potent DA neurotoxin 1-methyl-4-(2Ј-methylphenyl)-1,2,3,6-tetrahydropyridine (2Ј-CH 3 -MPTP). Despite a 90% decrement in striatal DA in 2Ј-NH 2 -MPTP/ 2Ј-CH 3 -MPTP-treated mice, increases in GFAP were attenuated compared to mice treated with 2Ј-CH 3 -MPTP alone. Thus, 2Ј-NH 2 -MPTP causes severe and immediate decrements in 5-HT and NE in frontal cortex and hippocampus, yet induces a modest GFAP response compared with other MPTP analogs that have their primary effect on DA. These results demonstrate the importance of obtaining quantitative assessments of GFAP to detect astroglial responses associated with selective damage to neurotransmitter systems with low-density innervation and suggest that serotonin may facilitate the astrocytic response to striatal injury.The irreversible Parkinsonian-like syndrome that rapidly developed in a group of Northern California substance abusers in the early 1980s fueled intense investigation of the causative agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a model of dopaminergic neurodegeneration. MPTP has since been shown to damage DA neurons of the nigrostriatal pathway in humans (Speciale, 2002) and experimental animals (Heikkila et al., 1984a). As such, MPTP has proven to be an important tool for modeling various aspects of DA degeneration occurring in idiopathic Parkinson's disease (Speciale, 2002).As part of the mechanistic evaluation of MPTP, many analogs were synthesized to elucidate structure-activity relationships (Youngster et al., 1989a;Maret et al., 1990). These studies focused primarily on the ability of MPTPrelated compounds to decrease DA in striatum. In fact, a number of analogs were shown to be at least as potent as MPTP in their ability to deplete DA and many of these possess a substituent at the 2Ј-position (Youngster et al., 1989b). However, a single 2Ј-substituted analog, 1-methyl-4-(2Ј-aminophenyl)-1,2,3,6-tetrahydropyridine (2Ј-NH 2 -MP...