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.
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 microg/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.
Carrasco
Gonzalo A
GA
Department of Pharmacology, Loyola University of Chicago, Stritch School of Medicine, 2160 S. First Ave., Maywood, IL 60153, USA.
Van de Kar
Louis D
LD
Jia
Cuihong
C
Xu
Hao
H
Chen
Zhuo
Z
Chadda
Ritu
R
Garcia
Francisca
F
Muma
Nancy A
NA
Battaglia
George
G
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000494:pharmacology*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D007276:Injections, Intraventricular; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009490:Neurosecretory Systems / Q000187:drug effects* / Q000378:metabolism; D010121:Oxytocin / Q000097:blood; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk / Q000187:drug effects; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D044402:Receptor, Serotonin, 5-HT2A; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D010121:Oxytocin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000324:Adrenocorticotropic Hormone