Single exposure to a serotonin 1A receptor agonist, (+)8-hydroxy-2-(di-n- propylamino)-tetralin, produces a prolonged heterologous desensitization of serotonin 2A receptors in neuroendocrine neurons in vivo

Gonzalo A. Carrasco, Louis D. Van De Kar, Cuihong Jia, Hao Xu, Zhuo Chen, Ritu Chadda, Francisca Garcia, Nancy A. Muma, George Battaglia

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15 Scopus citations

Abstract

We previously demonstrated colocalization of serotonin 1A (5-HT 1A) and serotonin 2A (5-HT2A) receptors in oxytocin and corticotropin-releasing factor neurons in the hypothalamic paraventricular nucleus (PVN). Because a functional imbalance between hypothalamic 5-HT 1A and 5-HT2A receptors has been implicated in several neuropsychiatric disorders, in this study we investigated whether acute in vivo activation of 5-HT1A receptors in the PVN results in desensitization of 5-HT2A receptor signaling. Functional desensitization of hypothalamic 5-HT2A receptors was assessed via a reduction in oxytocin and adrenocorticotropin (ACTH) responses to the 5-HT2A/2C receptor agonist (-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl[(-)DOI]. We report here that a single systemic injection of the 5-HT1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino)-tetralin [(+)8-OH-DPAT] (200 μg/kg) significantly reduced the 5-HT2A receptor-mediated oxytocin responses for at least 72 h. Direct intraparaventricular injection of (+)8-OHDPAT (0.2 nmol) 24 h before a submaximal dose of (-)DOI (0.35 mg/kg) significantly inhibited the 5-HT2A receptor-mediated increases in both oxytocin and ACTH (-39 and -16%, respectively). In addition, the (+)8-OH-DPAT-induced desensitization of the 5-HT2A receptor-mediated oxytocin but not the ACTH response was inhibited in rats pretreated with either a systemic (0.1 mg/kg) or intraparaventricular (10 nmol) injection of the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635). This is the first in vivo demonstration of a prolonged heterologous intracellular desensitization of 5-HT2A receptors after acute activation of 5-HT1A receptors. These findings may provide insight into the long-term heterologous interactions between 5-HT1A and 5-HT 2A receptor signaling that could occur in response to antidepressants, antipsychotics, or drugs of abuse that target these receptor subtypes.

Original languageEnglish (US)
Pages (from-to)1078-1086
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume320
Issue number3
DOIs
StatePublished - Mar 2007

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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