DETERMINATION OF THE ROLE OF THE 5-HT(6) RECEPTOR IN THE RAT-BRAIN - A STUDY USING ANTISENSE OLIGONUCLEOTIDES

The purpose of the present study was to determine possible physiologic al functions of the 5-ht(6) receptor using antisense oligonucleotides (AOs) in male rats. Repeated intracerebroventricular treatment with AO s but not with a scrambled form of the antisense sequence (SO) gave ri se to a specific behavioral syndrome of yawning, stretching and chewin g and caused a 30% reduction in the number of [H-3]-lysergic acid diet hylamide binding sites (measured in the presence of 300 nM spiperone). Neither sequence, however, had any effect on other parameters measure d (e.g., locomotor activity, body weight, food intake, body temperatur e and nociception). The specific behavioral syndrome did not appear to be caused by modulation of dopaminergic neurotransmission since no ch anges in the tissue levels of either dopamine or its metabolites 3,4-d ihydroxyphenylacetic acid and homovanillic acid were seen. Furthermore , haloperidol (0.03 mg/kg s.c.) did not reduce the number of yawns or stretches. An increase in cholinergic neurotransmission did appear to be involved since the behavioral syndrome was dose-dependently antagon ized by atropine. The present study suggests that 5-ht(6) receptors ar e functionally expressed in the rat brain, where one of their function s appears to be the control of cholinergic neurotransmission.