tetrahydropyridine] Depletes Serotonin and Norepinephrine in Rats: A Comparison with 2 -CH3-MPTP [1-Methyl-4-(2 - methylphenyl)-1,2,3,6-tetrahydropyridine]

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) analog, 1-methyl-4-(2 -aminophenyl)-1,2,3,6-tetrahydropyridine (2 -NH2MPTP), 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 -CH3MPTP 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. Neurodegeneration in monoamine neurotransmitter systems is known to occur in disorders such as Parkinson’s and Alzheimer’s diseases, and as part of the normal aging process (Gottfries, 1990; Palmer and DeKosky, 1993; Melamed et al., 1996; Miyawaki et al., 1997; Hornykiewicz, 1998; Meltzer et al., 1998; Perl et al., 1998; Parvizi et al., 2001). In this regard, selective neurotoxins are useful tools for studying neurodegenerative mechanisms. Studies on 1-methyl-4-(2 -aminophenyl)1,2,3,6-tetrahydropyridine (2 -NH2-MPTP) have shown that this unique analog of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is capable of selectively destroying serotonin [5-hydroxytryptamine (5-HT)] and norepinephrine (NE) nerve terminals in mice while having no effect on striatal dopamine (DA) (Andrews and Murphy, 1993c). Depletions in 5-HT and NE in mice are most pronounced in frontal cortex and hippocampus and are selectively attenuated by 5-HT or NE uptake inhibitors, respectively (Andrews and Murphy, 1993a,b). 2 NH2-MPTP-induced neurotoxicity is also dependent on metabFinancial 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. Portions of this work have been presented as abstracts at the following meetings: Andrews AM, Mazzola-Pomietto P, and Murphy, DL (1996) 2 -NH2MPTP 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. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. 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; [I]RTI-55, [I]3 -(4-trimethylstannylphenyl)-tropane2 -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, 3,4dihydroxyphenylacetic acid; HVA, homovanillic acid. 0022-3565/02/3032-527–533$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 303, No. 2 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 37614/1014525 JPET 303:527–533, 2002 Printed in U.S.A.