(1-(2,5-DIMETHOXY-4 IODOPHENYL)-2-AMINOPROPANE)-INDUCED HEAD-TWITCHESIN THE RAT ARE MEDIATED BY 5-HYDROXYTRYPTAMINE (5-HT)(2A) RECEPTORS -MODULATION BY NOVEL 5-HT2A 2C ANTAGONISTS, D-1 ANTAGONISTS AND 5-HT1AAGONISTS/

In this study, the involvement of serotonergic and dopaminergic recept ors in the modulation of the head-twitch (HTW) response to the 5-hydro xytryptamine (5-HT)(2A)(5-HT2C agonist, 1-(2,5-dimethoxy-4-iodophenyl) -2-aminopropane, was characterized in rats using novel and selective l igands at 5-HT2A, 5-HT2C, D-1, D-2 and 5-HT1A receptors. HTW were dose -dependently inhibited by the 5-HT2A/2C antagonists, ritanserin, meter goline, mesulergine, mianserin, ICI 169,369 and LY 58,537, by the pref erential 5-HT2A antagonist, ketanserin and by the novel, selective 5-H T2A antagonist, SR 46349B. A further selective 5-HT2A antagonist, MDL 100,907, very potently abolished HTW (ED(50) = 0.005 mg/kg). The order of relative potency correlated highly with their affinity at 5-HT2A ( r = 0.83) but not 5-HT2C receptors (r = 0.06). In addition, the novel, selective 5-HT2C antagonist, SE 200,646A, failed to abolish HTW and t he 5-HT2C agonists/5-HT2A antagonists, 1-(3-chlorophenyl)piperazine an d 1-(3-trifluoromethylphenyl)piperazine, blocked, rather than elicited , HTW. The D1 antagonists, SCH 23390, NNC 112, NNC 756, SCH 39166 and A 69024, in this order of relative potency that correlated with their affinity at D-1 receptors (r = 0.98), blocked HTW. The D-2 antagonists , raclopride, eticlopride and haloperidol also blocked HTW. The 5-HT1A agonists, S 14671, S 14506, 8-hydroxy-2-(di-n-propylamino)tetralin, b uspirone, ipsapirone and (+)-flesinoxan, abolished HTW. The action of 8-hydroxy-2-(di-n-propylamino)tetralin was blocked by (-)-tertatolol ( ID50 = 4.5 mg/kg), a novel 5-HT1A receptor antagonist. Similarly, (-)- tertatolol attenuated the action of S 14506 and abolished that of S 14 671, buspirone and ipsapirone. A role of postsynaptic 5-HT1A receptors in the action of 5-HT1A agonists was suggested by the finding that pa rachlorophenylalanine (3 x 300 mg/kg, i.p.), which depleted cerebral p ools of 5-HT, did not modify the activity of ipsapirone. The present d ata demonstrate that 5-HT2A receptors mediate HTW in rats and that bot h D-1 and D-2 receptors as well as (postsynaptic) 5-HT1A receptors pla y a role in their expression.