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 language||English (US)|
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Mar 2007|
All Science Journal Classification (ASJC) codes
- Molecular Medicine