The time-course for up- and down-regulation of the cortical 5-hydroxytryptamine (5-HT)2A receptor density predicts 5-HT2A receptor-mediated behavior in the rabbit.
5-Hydroxytryptamine (serotonin; 5-HT)2 receptor agonists such as (+/-)-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) injected systemically or directly into frontal cortex, elicit stereotyped head movements that are mediated by 5-HT2A receptors. Chronic administration of 5-HT2A receptor antagonists can produce either a down-regulation, e.g., d-2-bromolysergic acid diethylamide (BOL) or an up-regulation, e.g., alpha-phenyl-10(2-phenylethyl)-4-piperidinemethanol (MDL11,939) of cortical 5-HT2A receptors in the rabbit with no change in the density of the 5-HT2C receptor. We examined the degree to which the time course for the onset and offset of changes in cortical 5-HT2A receptor density was correlated with functional changes as measured by the magnitude of DOI elicited, 5-HT2A receptor-mediated head movements (head bobs). First, the magnitude of DOI-elicited head bobs was measured over 1 to 8 days after chronic BOL (5.8 micromol/kg), MDL11,939 (10 micromol/kg), or vehicle administration. Second, rabbits were injected with BOL, MDL11,939, or vehicle once daily for 8 days, and then, 1 to 8 days after the cessation of drug or vehicle, DOI-elicited head bobs were determined. Samples of frontal cortex were obtained for each animal immediately following behavioral testing, and 5-HT2A receptor density was measured using [3H]ketanserin. Thus, each animal provided a value for receptor density and number of head bobs, and these two measures showed a high degree of correlation between 0.94 for BOL and 0.95 for MDL11,939. This study establishes that the density of 5-HT2A receptors in cortex reflects their functional status.
Dave
Kuldip D
KD
Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15th Street, 8th Floor, NCB, Mail stop 488, Philadelphia, PA 19102, USA. kuldip.dave@drexel.edu
Harvey
John A
JA
Aloyo
Vincent J
VJ
D000662:Amphetamines / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation; D007276:Injections, Intraventricular; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011817:Rabbits; D044402:Receptor, Serotonin, 5-HT2A / Q000008:administration & dosage; D058830:Serotonin 5-HT2 Receptor Antagonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation
D000662:Amphetamines; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D017366:Serotonin Receptor Agonists; C066169:alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine