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Research ArticleArticle

Pindolol Suppresses Serotonergic Neuronal Activity and Does Not Block the Inhibition of Serotonergic Neurons Produced by 8-Hydroxy-2-(di-n-propylamino)tetralin in Awake Cats

Casimir A. Fornal, Francisco J. Martin, Christine W. Metzler and Barry L. Jacobs
Journal of Pharmacology and Experimental Therapeutics October 1999, 291 (1) 229-238;
Casimir A. Fornal
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Francisco J. Martin
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Christine W. Metzler
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Barry L. Jacobs
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Abstract

Clinical studies have shown that pindolol can enhance the effects of antidepressant drugs, presumably by acting as an antagonist at somatodendritic 5-hydroxytryptamine (5-HT)1A autoreceptors, which regulate the firing rate of central serotonergic neurons. The current study characterized the action of pindolol on the single-unit activity of serotonergic neurons in the dorsal raphe nucleus of freely moving cats. (±)-Pindolol produced a dose-dependent inhibition of neuronal activity after i.v. (ED50 = 0.25 mg/kg) and s.c. (ED50 = 1.23 mg/kg) administration. The active enantiomer (−)-pindolol (1 mg/kg i.v.) also suppressed neuronal activity (maximal decrease, 88%). Upon p.o. administration, (±)-pindolol (10 mg/kg) produced a marked, long-acting suppression of neuronal activity similar to that observed after s.c. administration. In all cases, the reduction in firing rate produced by pindolol was completely reversed by low doses ofN-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635) (0.1 mg/kg i.v. or 0.2 mg/kg s.c.), a selective 5-HT1A antagonist. Systemic administration of (−)-tertatolol (1–5 mg/kg i.v.), another β-adrenoceptor blocker/putative 5-HT1A antagonist, had no significant effect on neuronal activity. The ability of i.v. (±)-pindolol (0.1–1 mg/kg) to reverse the suppression of serotonergic neuronal activity produced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (10 μg/kg i.v.), a selective 5-HT1A agonist, also was examined. (±)-Pindolol had no appreciable effect on the action of 8-OH-DPAT. In contrast, the 5-HT1A antagonist drugs WAY-100635 (0.1 mg/kg i.v.), 4-fluoro-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl benzamide (0.1 mg/kg, i.v.),N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropanamide [(S)-WAY-100135] (0.5 mg/kg i.v.), and (−)-tertatolol (1–5 mg/kg i.v.) reversed the effect of 8-OH-DPAT to varying degrees. Overall, these results indicate that pindolol acts as an agonist rather than an antagonist at 5-HT1A autoreceptors in awake animals.

Footnotes

  • Send reprint requests to: Dr. Casimir A. Fornal, Program in Neuroscience, Department of Psychology, Green Hall, Princeton University, Princeton, NJ 08544. E-mail: Fornal{at}princeton.edu

  • ↵1 This work was supported by a grant from the National Institute of Mental Health (MH-23433).

  • ↵2 Recipient of a Formacion de Personal Investigador Postdoctoral Fellowship from the Spanish government. Present address: Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, Santander, Cantabria, Spain.

  • Abbreviations:
    5-HT
    5-hydroxytryptamine
    SSRI
    selective serotonin reuptake inhibitor
    DRN
    dorsal raphe nucleus
    WAY-100635
    N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide
    8-OH-DPAT
    8-hydroxy-2-(di-n-propylamino)tetralin
    p-MPPI
    4-fluoro-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl benzamide
    (S)-WAY-100135
    N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropanamide
    LSD
    d-lysergic acid diethylamide
    • Received March 11, 1999.
    • Accepted May 25, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 1
1 Oct 1999
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Research ArticleArticle

Pindolol Suppresses Serotonergic Neuronal Activity and Does Not Block the Inhibition of Serotonergic Neurons Produced by 8-Hydroxy-2-(di-n-propylamino)tetralin in Awake Cats

Casimir A. Fornal, Francisco J. Martin, Christine W. Metzler and Barry L. Jacobs
Journal of Pharmacology and Experimental Therapeutics October 1, 1999, 291 (1) 229-238;

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Research ArticleArticle

Pindolol Suppresses Serotonergic Neuronal Activity and Does Not Block the Inhibition of Serotonergic Neurons Produced by 8-Hydroxy-2-(di-n-propylamino)tetralin in Awake Cats

Casimir A. Fornal, Francisco J. Martin, Christine W. Metzler and Barry L. Jacobs
Journal of Pharmacology and Experimental Therapeutics October 1, 1999, 291 (1) 229-238;
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