Abstract

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) analog, 1-methyl-4-(2′-aminophenyl)-1,2,3,6-tetrahydropyridine (2′-NH₂-MPTP), depletes brain serotonin and norepinephrine in mice without affecting striatal dopamine. The present study was conducted to determine whether 2′-NH₂-MPTP would be similarly neurotoxic to rats. Four injections of 20 mg/kg 2′-NH₂-MPTP caused 80 to 90% depletions in serotonin and norepinephrine in frontal cortex and hippocampus in rats 1 week post-treatment. A lower dose of 2′-NH₂-MPTP (4 × 15 mg/kg) also produced large decrements in serotonin and norepinephrine levels and in serotonin transporter density measured 3 weeks after neurotoxin administration. Furthermore, this lower dose of 2′-NH₂-MPTP altered functional serotonin neurotransmission as evidenced by a 2-fold potentiation of 1-(3-chlorophenyl)-piperazine·2HCl-induced hyperthermia, an index of serotonergic denervation supersensitivity. At both doses, 2′-NH₂-MPTP was without effect on striatal dopamine. For comparison, additional rats were treated with a second 2′-substituted analog of MPTP, 1-methyl-4-(2′-methylphenyl)-1,2,3,6-tetrahydropyridine (2′-CH₃-MPTP), at 2 × 20 mg/kg. This dosing regimen causes substantial striatal dopamine depletion in mice. 2′-CH₃-MPTP had no effect on brain levels of serotonin, norepinephrine, or dopamine in rats. Together, these results demonstrate that rats are sensitive to the toxic effects of 2′-NH₂-MPTP but not to 2′-CH₃-MPTP at doses known to cause neurotoxicity in mice. Moreover, this study clearly shows that 2′-NH₂-MPTP can be utilized in rats as a tool to study the serotonergic and noradrenergic neurotransmitter systems.