Sustained treatment with a 5-HT(2A) receptor agonist causes functional desensitization and reductions in agonist-labeled 5-HT(2A) receptors despite increases in receptor protein levels in rats.
Adaptive changes in serotonin2A (5-HT(2A)) receptor signaling are associated with the clinical response to a number of psychiatric drugs including atypical antipsychotics and selective serotonin reuptake inhibitors. The present study examined possible mechanisms of agonist-induced desensitization of 5-HT(2A) receptors in rat hypothalamic paraventricular nucleus (PVN) after 4 and 7 days of treatment with 1mg/kg (-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). The magnitude of 5-HT(2A) receptor-mediated oxytocin release decreased 78% after 4 days and 61% after 7 days of DOI treatment. Similarly, the magnitude of ACTH release following 1mg/kg DOI decreased by 31% after 4 days and 38% after 7 days of DOI treatment. Treatment with DOI for either 4 or 7 days caused a significant decrease (by approximately 50%) in the high-affinity 5-HT(2A) receptor binding as measured by (125)I-DOI binding compared to saline-treated control rats. In contrast, western blot analysis demonstrated a significant increase in 5-HT(2A) receptor protein levels with 4 or 7 days of DOI treatment to 167% and 191% of control levels, respectively. Real time quantitative RT-PCR analysis revealed a small but nonsignificant increase in the levels of 5-HT(2A) mRNA following treatment with DOI for 4 or 7 days. Taken together, the 5-HT(2A) receptor-stimulated hormone responses, agonist binding data and western blot data suggest that although agonist treatment increases the levels of 5-HT(2A) receptor protein in the cell membrane, there is a reduction in the population of 5-HT(2A) receptors capable of high-affinity binding and mediating a functional response.
Shi
Ju
J
Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153, USA.
Landry
Michelle
M
Carrasco
Gonzalo A
GA
Battaglia
George
G
Muma
Nancy A
NA
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000662:Amphetamines / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008297:Male; D010121:Oxytocin / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013997:Time Factors
D000662:Amphetamines; D007456:Iodine Isotopes; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D017366:Serotonin Receptor Agonists; D010121:Oxytocin; D000324:Adrenocorticotropic Hormone; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine