ANTISENSE TECHNOLOGY REVEALS THE ALPHA(2A) ADRENOCEPTOR TO BE THE SUBTYPE MEDIATING THE HYPNOTIC RESPONSE TO THE HIGHLY SELECTIVE AGONIST, DEXMEDETOMIDINE, IN THE LOCUS-COERULEUS OF THE RAT

alpha(2) adrenergic agonists are used in the anesthetic management of the surgical patient for their sedative/hypnotic properties although t he alpha(2) adrenoceptor subtype responsible for these anesthetic effe cts is not known, Using a gene-targeting strategy, it is possible to s pecifically reduce the expression of the individual adrenoceptors expr essed in the central nervous system and to thereby determine their rol e in hypnotic action. Stably transfected cell lines (PC 124D for rat a lpha(2A); NIH3T3 for rat alpha(2C) adrenoceptors) were exposed to 5 mu M antisense oligodeoxynucleotides (ODNs) for alpha(2A) and alpha(2C) adrenergic receptor subtypes for 3 d. Individual receptor subtype expr ession, as determined by radiolabeled ligand binding, was selectively decreased only by the appropriate antisense ODNs and not by the ''scra mbled'' ODNs, These antisense ODNs were then administered three times, on alternate days, into the locus coeruleus of chronically cannulated rats and their hypnotic response to dexmedetomidine (an alpha(2) agon ist) was determined. Only the alpha(2A) antisense ODNs significantly c hange the hypnotic response causing both an increase in latency to, an d a decrease in duration of, the loss of righting reflex following dex medetomidine; hypnotic response had normalized 8 d after stopping the ODNs, Therefore, the alpha(2A) adrenoceptor subtype is responsible for the hypnotic response to dexmedetomidine in the locus coeruleus of th e rat.