The effects of α2‐adrenoceptor antagonists on the inhibition of 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI)‐induced head shakes by 5‐HT1A receptor agonists in the mouse

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Abstract
8‐Hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT), gepirone, buspirone and ipsapirone dose‐dependently antagonized the head‐shakes induced by 1‐(2,5‐dimethoxy 4‐iodophenyl)‐2‐amino propane hydrochloride (DOI) (1.0 mg kg−1) in mice, when these agents were given i.p. 10 min beforehand. para‐Chlorophenylalanine (pCPA) abolished the effect of 8‐OH‐DPAT (0.1 mg kg−1) and of buspirone (1.0 mg kg−1). (±)‐Pindolol (5.0 mg kg−1) also antagonized the effect of 8‐OH‐DPAT(0.1 mg kg−1). The α2‐adrenoceptor antagonists, RX811059 (1.0 mg kg−1), idazoxan (0.5 mg kg−1), yohimbine (1.0 mg kg−1) and 1‐(2‐pyrimidinyl)‐piperazine (1‐PP) (2.0 mg kg−1) i.p. prevented the antagonistic effect of 8‐OH‐DPAT (0.1 mg kg−1) on DOI‐head‐shakes. Orally‐administered buspirone, given 60 min beforehand, only reduced DOI‐head‐shakes at doses of 60 mg kg−1 and above. However, when buspirone (1.0 mg kg−1) was administered orally twice daily for 21 days, DOI‐head‐shakes were significantly reduced when tested 60 min after the first daily dose on days 5, 12 and 21 and 48 h after withdrawal. A single oral dose of buspirone (1.0 mg kg−1) strongly antagonized DOI‐head‐shakes when given 24 h after the last of 4 daily doses of 1‐PP (2.0 mg kg−1, p.o.) but had no effect on DOI‐head‐shakes 24 h after the last of 4 daily doses of water (p.o.). A single oral dose of 1‐PP (2.0 mg kg−1) abolished the inhibitory effect of i.p. buspirone (1.0 mg kg−1) on DOI‐head‐shakes in mice which had received water (p.o.) daily on the 4 previous days but not in mice which had received 1‐PP (2.0 mg kg−1, p.o.) on these days. The ability of 5‐HT1A receptor agonists to antagonize DOI‐head‐shakes may be due to an effect at presynaptic 5‐HT receptors. It is suggested that 1‐PP, formed from buspirone, may act at α2‐adrenoceptors to prevent acutely administered oral buspirone from antagonizing DOI‐head shakes, but that tolerance occurs to this effect of 1‐PP, thus revealing the inhibitory effect of buspirone when the latter is given repeatedly.