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Research ArticleArticle

Electrophysiological Comparison of 5-Hydroxytryptamine1A Receptor Antagonists on Dorsal Raphe Cell Firing

Lynn P. Martin, David M. Jackson, Carin Wallsten and Barbara L. Waszczak
Journal of Pharmacology and Experimental Therapeutics February 1999, 288 (2) 820-826;
Lynn P. Martin
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David M. Jackson
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Carin Wallsten
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Barbara L. Waszczak
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Abstract

Single-unit recording studies were undertaken in chloral hydrate-anesthetized rats to compare the effects on dorsal raphe cell firing of several putative 5-hydroxytryptamine (HT)1Areceptor antagonists, including WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide), p-MPPI (4-(2-methoxyphenyl)1-[2′-[N-(2′′-pyridinyl)-p-iodobenzamido]ethyl]piperazine), and two newly described 5-HT1A receptor antagonists, NDL-249 [(R)-3-(N-propylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide] and NAD-299 [(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide]. Consistent with a 5-HT1A receptor antagonist profile, pretreatment with an approximately equimolar (0.02–0.03 μmol/kg) i.v. dose of each compound caused a significant rightward shift in the dose-response curve for 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin]. Antagonist potency was clearly highest for NAD-299 and WAY 100635, which caused shifts roughly 3 times greater than those for eitherp-MPPI or NDL-249 (ED50 for 8-OH-DPAT, 1.3 ± 0.3 μg/kg; after NAD-299, 18.2 ± 1.0 μg/kg; after WAY 100635, 16.9 ± 2.9 μg/kg; after NDL-249, 6.0 ± 1.2 μg/kg; after p-MPPI, 4.7 ± 1.1 μg/kg). In separate studies, each of the antagonists was administered alone in increasing cumulative doses to evaluate whether they possessed intrinsic agonist activity in this system. At doses below 0.01 μmol/kg, none of the drugs altered firing by more than ±20% basal rates. At higher doses (>0.1 μmol/kg), WAY 100635, NDL-249, and NAD-299 caused a dose-dependent suppression of dorsal raphe cell firing (ED50 = 0.6 ± 0.2, 0.7 ± 0.3, and 0.9 ± 0.4 μmol/kg, respectively). However, the ED50 values for inhibition by these drugs were roughly 30 times higher than the doses that antagonized effects of 8-OH-DPAT. Moreover, the inhibition by all three antagonists (but not 8-OH-DPAT) was readily reversed byd-amphetamine (3.2 mg/kg i.v.), a releaser of norepinephrine, suggesting that these effects were likely due toalpha adrenergic receptor blockade rather than to 5-HT1A receptor agonism. Thus, it was concluded that WAY 100635, NAD-299, NDL-249, and p-MPPI all fulfill criteria as 5-HT1A receptor antagonists lacking intrinsic efficacy in the dorsal raphe system. The newly described compound NAD-299 exhibits antagonist potency comparable to that of WAY 100635 in this electrophysiological assay.

Footnotes

  • Send reprint requests to: Dr. Barbara L. Waszczak, Department of Pharmaceutical Sciences, 312 Mugar Hall, Northeastern University, 360 Huntington Ave., Boston, MA 02115. E-mail:b.waszczak{at}nunet.neu.edu

  • ↵1 This work was supported in part by Astra Arcus AB (Södertälje, Sweden) and by United States Public Health Service Grant NS23541 (B.L.W.).

  • Abbreviations:
    5-HT
    5-hydroxytryptamine
    8-OH-DPAT
    8-hydroxy-2-(di-n-propylamino) tetralin
    WAY 100635
    N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide
    p-MPPI
    4-(2-methoxyphenyl)1-[2′-[N-(2′′-pyridinyl)-p-iodobenzamido]ethyl]piperazine
    NDL-249
    (R)-3-(N-propylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide, NAD-299 (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide
    • Received April 2, 1998.
    • Accepted September 8, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 2
1 Feb 1999
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Research ArticleArticle

Electrophysiological Comparison of 5-Hydroxytryptamine1A Receptor Antagonists on Dorsal Raphe Cell Firing

Lynn P. Martin, David M. Jackson, Carin Wallsten and Barbara L. Waszczak
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 820-826;

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Research ArticleArticle

Electrophysiological Comparison of 5-Hydroxytryptamine1A Receptor Antagonists on Dorsal Raphe Cell Firing

Lynn P. Martin, David M. Jackson, Carin Wallsten and Barbara L. Waszczak
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 820-826;
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