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.
Footnotes
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Financial support was provided by the National Institute of Mental Health Intramural Program and by the Pennsylvania State University. E.L.U. was supported by a Life Sciences Consortium graduate fellowship from the Pennsylvania State University.
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Portions of this work have been presented as abstracts at the following meetings: Andrews AM, Mazzola-Pomietto P, and Murphy, DL (1996)2′-NH2-MPTP selectively depletes cortical and hippocampal 5-HT and NE in the rat: a cross-species comparison versus MPTP and 2′-CH3-MPTP, in 1996 Annual Meeting of the American College of Neuropsychopharmacology; 20 December 1996, San Juan, Puerto Rico; Andrews AM, Mazzola-Pomietto P, and Murphy DL: 2′-NH2-MPTP selectively depletes cortical and hippocampal 5-HT and NE in the rat: a comparison with 2′-CH3-MPTP (1997), in Joint Meeting of the International Society for Neurochemistry & the American Society for Neurochemistry; 22 July 1997, Boston, MA.
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DOI: 10.1124/jpet.102.037614
- Abbreviations:
- 2′-NH2-MPTP
- 1-methyl-4-(2′-aminophenyl)-1,2,3,6-tetrahydropyridine
- MPTP
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- 5-HT
- 5-hydroxytryptamine (serotonin)
- NE
- norepinephrine
- DA
- dopamine
- MAO
- monoamine oxidase
- MPP+
- 1-methyl 4-phenylpyridinium
- VMAT
- vesicular monoamine transporter
- m-CPP
- 1-(3-chlorophenyl)-piperazine·2HCl
- [125I]RTI-55
- [125I]3β-(4-trimethylstannylphenyl)-tropane-2β-carboxylic acid methyl ester
- GBR12935
- 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)homopiperazine
- HPLC
- high-performance liquid chromatography
- 2′-CH3-MPTP
- 1-methyl-4-(2′-methylphenyl)-1,2,3,6-tetrahydropyridine
- 5-HIAA
- 5-hydroxyindoleacetic acid
- DOPAC
- 3,4-dihydroxyphenylacetic acid
- HVA
- homovanillic acid
- Received April 17, 2002.
- Accepted June 20, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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