Covariation of alpha 2-adrenoceptor density and function following irreversible antagonism with EEDQ.
1. Administration of the irreversible antagonist, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, (EEDQ, 2 mg kg-1, i.p.) to mice reduced binding of [3H]-RX 821002 (2-methoxy-idazoxan) to alpha 2-adrenoceptors in whole mouse brain by 75% 24 h later. The receptor binding returned over time only being reduced by 25% by 16 days post administration; the time taken for binding to return to 50% of control levels was estimated to be 5.25 days. 2. EEDQ administration also resulted in the loss of the sedative effect of the alpha 2-adrenoceptor agonist, medetomidine, measured by the holeboard test of directed exploration and locomotor activity. Agonist-induced sedation returned to control values by 8 days post EEDQ administration. 3. EEDQ administration also resulted in the loss of the hypothermic response to medetomidine (0.1 mg kg-1, i.p.). Medetomidine-induced hypothermia returned to control values by 12 days post EEDQ administration. 4. Pretreatment with the selective alpha 2-adrenoceptor antagonist, RX 821002 (0.1-3.0 mg kg-1, i.p.) 45 min before EEDQ prevented the loss of alpha 2-adrenoceptors as well as the blockade of medetomide-induced sedation and hypothermia by EEDQ. 5. The results of these experiments indicate that there is significant receptor reserve for alpha 2-adrenoceptor-mediated behavioural and physiological responses.
Durcan
M J
MJ
Laboratory of Clinical Studies, DICBR, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892.
Morgan
P F
PF
Van Etten
M L
ML
Linnoila
M
M
D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D004146:Dioxanes / Q000493:pharmacokinetics; D004347:Drug Interactions; D005106:Exploratory Behavior / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D019329:Idazoxan / Q000031:analogs & derivatives; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D020926:Medetomidine; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D011869:Radioligand Assay; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*
D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D011804:Quinolines; D018341:Receptors, Adrenergic, alpha-2; C000470:EEDQ; C058525:2-methoxyidazoxan; D020926:Medetomidine; D019329:Idazoxan