Sustained Depletion of Cortical and Hippocampal Serotonin and Norepinephrine but Not Striatal Dopamine by 1‐Methyl‐4‐(2′‐Aminophenyl)‐1,2,3,6‐Tetrahydropyridine (2′‐NH2‐MPTP): A Comparative Study with 2′‐CH3‐MPTP and MPTP

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Abstract
Unlike 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), which produces consistent decreases in levels of striatal dopamine (DA) with considerably smaller and more variable effects on mouse brain levels of serotonin (5‐HT) and norepinephrine (NE), a novel amine‐substituted MPTP analogue, 1‐methyl‐4‐(2′‐aminophenyl)‐1,2,3,6‐tetrahydropyridine (2′‐NH2‐MPTP), administered in a standard mouse dosing paradigm for MPTP (20 mg/kg X 4) did not affect striatal DA but led to marked reductions (60–70%) in levels of 5‐HT, 5‐hydroxyindoleacetic acid (5‐HIAA), and NE measured in frontal cortex and hippocampus 1 week after treatment. Another 2′‐substituted MPTP analogue, 1‐methyl‐4‐(2′‐methylphenyl)‐1,2,3,6‐tetrahydropyridine, affected cortical and hippocampal 5‐HT, 5‐HIAA, and NE only minimally, while markedly reducing the DA content in striatum (90%), thus indicating that the substituent (‐NH2 versus ‐CH3) at the 2’position is important for the differential effects of these MPTP analogues. In a replication study with a 3‐week end point, hippocampal and cortical 5‐HT, 5‐HIAA, and NE levels remained depressed with no indication of recovery. These results suggest that 2′‐NH2‐MPTP may be a novel, regionally selective neurotoxin for serotonergic and norad‐renergic nerve terminals.