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Research ArticleNEUROPHARMACOLOGY

Regional Patterns of Compensation following Genetic Deletion of Either 5-Hydroxytryptamine1A or 5-Hydroxytryptamine1B Receptor in the Mouse

Deborah A. Knobelman, René Hen, Julie A. Blendy and Irwin Lucki
Journal of Pharmacology and Experimental Therapeutics September 2001, 298 (3) 1092-1100;
Deborah A. Knobelman
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René Hen
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Julie A. Blendy
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Irwin Lucki
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Abstract

Plasticity in serotonergic transmission in serotonin or 5-hydroxytryptamine (5-HT) receptor mutants was examined by measuring the regulation of extracellular 5-HT levels in the striatum and ventral hippocampus of 5-HT1A and 5-HT1B receptor knockout mice using in vivo microdialysis. The efficacy of genetic deletion was verified by showing blunted regulation of extracellular 5-HT with selective 5-HT receptor agonists. 5-HT1A receptor knockout mice failed to demonstrate reduction of extracellular 5-HT in response to systemic administration of the 5-HT1A receptor agonist R-8-hydroxydipropylaminotetralin (R-8-OH-DPAT) and 5-HT1B receptor knockout mice failed to demonstrate reduction of extracellular 5-HT in response to systemic administration of the 5-HT1B receptor agonist CP 94,253. Plasticity also developed to deletion of the complementary autoreceptor. 5-HT1A receptor knockout mice demonstrated a significantly greater response to CP 94,253 in the striatum, but not the ventral hippocampus, suggesting the development of enhanced sensitivity of striatal 5-HT1B receptors. In 5-HT1B receptor knockout mice, R-8-OH-DPAT evoked a significantly diminished response in the ventral hippocampus, but not the striatum, suggesting the potential desensitization of 5-HT1A receptors in the median raphe nucleus. The pattern of regional compensations between somatodendritic and terminal autoreceptors was confirmed by pharmacological challenges using the selective serotonin reuptake inhibitor fluoxetine combined with either a 5-HT1A (WAY 100635) or a 5-HT1B/1D (GR 127935) receptor antagonist. The regional pattern of compensation may be determined by the preferential role of 5-HT1A or 5-HT1B receptors in regulating 5-HT release. Taken together, these results demonstrate the development of regional plasticity between complementary somatodendritic and terminal autoreceptors after the genetic deletion of 5-HT1A or 5-HT1B receptors.

Footnotes

  • This research was supported by U.S. Public Health Service Grant MH 48125 and by National Research Service Award MH 12147 (to D.A.K.). This research was submitted in partial fulfillment of the requirements for the Ph.D. degree in the Department of Pharmacology at the University of Pennsylvania (to D.A.K.).

  • Abbreviations:
    5-HT
    serotonin or 5-hydroxytryptamine
    DR
    dorsal raphe nucleus
    MR
    median raphe nucleus
    SSRI
    selective serotonin reuptake inhibitor
    8-OH-DPAT
    8-hydroxydipropylaminotetralin
    PCR
    polymerase chain reaction
    bp
    base pair
    ANOVA
    analysis of variance
    AUC
    area under the curve
    • Received January 31, 2001.
    • Accepted May 21, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 3
1 Sep 2001
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Research ArticleNEUROPHARMACOLOGY

Regional Patterns of Compensation following Genetic Deletion of Either 5-Hydroxytryptamine1A or 5-Hydroxytryptamine1B Receptor in the Mouse

Deborah A. Knobelman, René Hen, Julie A. Blendy and Irwin Lucki
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 1092-1100;

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Research ArticleNEUROPHARMACOLOGY

Regional Patterns of Compensation following Genetic Deletion of Either 5-Hydroxytryptamine1A or 5-Hydroxytryptamine1B Receptor in the Mouse

Deborah A. Knobelman, René Hen, Julie A. Blendy and Irwin Lucki
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 1092-1100;
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