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NEUROPHARMACOLOGY

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

Department of Pharmacology (G.A.C., L.D.V.d.K., H.X., Z.C., R.C., F.G., N.A.M., G.B.), Neuroscience Institute (G.A.C., L.D.V.d.K., C.J., N.A.M., G.B.), Loyola University Chicago, Maywood, Illinois

We previously demonstrated colocalization of serotonin 1A (5-HT_1A) and serotonin 2A (5-HT_2A) 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-HT_2A receptors has been implicated in several neuropsychiatric disorders, in this study we investigated whether acute in vivo activation of 5-HT_1A receptors in the PVN results in desensitization of 5-HT_2A receptor signaling. Functional desensitization of hypothalamic 5-HT_2A receptors was assessed via a reduction in oxytocin and adrenocorticotropin (ACTH) responses to the 5-HT_2A/2C receptor agonist (-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl [(-)DOI]. We report here that a single systemic injection of the 5-HT_1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino)-tetralin [(+)8-OH-DPAT] (200 µg/kg) significantly reduced the 5-HT_2A receptor-mediated oxytocin responses for at least 72 h. Direct intraparaventricular injection of (+)8-OH-DPAT (0.2 nmol) 24 h before a submaximal dose of (-)DOI (0.35 mg/kg) significantly inhibited the 5-HT_2A receptor-mediated increases in both oxytocin and ACTH (-39 and -16%, respectively). In addition, the (+)8-OH-DPAT-induced desensitization of the 5-HT_2A 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-HT_1A 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-HT_2A receptors after acute activation of 5-HT_1A receptors. These findings may provide insight into the long-term heterologous interactions between 5-HT_1A and 5-HT_2A receptor signaling that could occur in response to antidepressants, antipsychotics, or drugs of abuse that target these receptor subtypes.

Address correspondence to: Dr. George Battaglia, Department of Pharmacology, Loyola University of Chicago, Stritch School of Medicine, 2160 S. First Ave., Maywood, IL 60153. E-mail: gbattag{at}lumc.edu