2'-NH2-MPTP in Swiss Webster mice: evidence for long-term (6-month) depletions in cortical and hippocampal serotonin and norepinephrine, differential protection by selective uptake inhibitors or clorgyline and functional changes in central serotonin neurotransmission

AM Andrews and DL Murphy

Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland.

The i.p. administration of 1-methyl-4-(2'-aminophenyl)-1,2,3,6- tetrahydropyridine (2'-NH2-MPTP; 4 x 20 mg/kg) to Swiss Webster mice caused substantial decreases in cortical and hippocampal 5- hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid and norepinephrine (NE) measured 1 week post-treatment. Compared with the authors' previously reported results in C57BL/6 mice, these effects were significantly greater in hippocampus (80-90% vs. 60%) and of a similar magnitude in frontal cortex (60-75%). A long-term study showed that cortical and hippocampal 5-HT, 5-hydroxyindoleacetic acid and NE were still decreased 40% to 50% 6 months after treatment. Regional brain dopamine was essentially unchanged during the 6-month period. Pretreatment with the 5-HT-selective uptake inhibitors, fluoxetine or paroxetine, or with the NE-selective uptake inhibitor, desipramine, prevented decreases in cortical and hippocampal 5-HT and NE, respectively, 3 weeks after 2'-NH2-MPTP (4 x 20 mg/kg). In addition, pretreatment with the monoamine oxidase type-A inhibitor, clorgyline, also prevented the more modest decreases in 5-HT and NE caused by 4 x 15 mg/kg 2'-NH2-MPTP. Selegiline, a monoamine oxidase-B inhibitor, did not provide similar protection. Lastly, 2'-NH2-MPTP administered 3 weeks earlier, abolished hypothermia caused by the serotonin agonist, m- chlorophenylpiperazine, which provided preliminary evidence for an associated functional change in the central serotonergic system. Together, these data suggest that 2'-NH2-MPTP is a novel agent capable of producing long-lasting depletions in forebrain 5-HT and NE but not dopamine in two different strains of mice by some mechanisms that resemble those of the parent dopamine-depleting neurotoxin, MPTP.

Volume 267, Issue 3, pp. 1432-1439, 12/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				A. L. Numis, E. L. Unger, D. L. Sheridan, A. C. Chisnell, and A. M. Andrews The Role of Membrane and Vesicular Monoamine Transporters in the Neurotoxic and Hypothermic Effects of 1-Methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP) Mol. Pharmacol., September 1, 2004; 66(3): 718 - 727. [Abstract] [Full Text] [PDF]

				B. A. Luellen, D. B. Miller, A. C. Chisnell, D. L. Murphy, J. P. O'Callaghan, and A. M. Andrews Neuronal and Astroglial Responses to the Serotonin and Norepinephrine Neurotoxin: 1-Methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine J. Pharmacol. Exp. Ther., December 1, 2003; 307(3): 923 - 931. [Abstract] [Full Text] [PDF]

				E. L. Unger, P. Mazzola-Pomietto, D. L. Murphy, and A. M. Andrews 2'-NH2-MPTP [1-Methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine] Depletes Serotonin and Norepinephrine in Rats: A Comparison with 2'-CH3-MPTP [1-Methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine] J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 527 - 533. [Abstract] [Full Text] [PDF]