(1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane)-induced head-twitches in the rat are mediated by 5-hydroxytryptamine (5-HT) 2A receptors: modulation by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists

R Schreiber, M Brocco, V Audinot, A Gobert, S Veiga and MJ Millan

Department of Psychopharmacology, Centre de Recherches Croissy, Croissy- sur-Seine, France.

In this study, the involvement of serotonergic and dopaminergic receptors in the modulation of the head-twitch (HTW) response to the 5- hydroxytryptamine (5-HT)2A/5-HT2C agonist, 1-(2,5-dimethoxy-4- iodophenyl)-2-aminopropane, was characterized in rats using novel and selective ligands at 5-HT2A, 5-HT2C, D1, D2 and 5-HT1A receptors. HTW were dose-dependently inhibited by the 5-HT2A/2C antagonists, ritanserin, metergoline, mesulergine, mianserin, ICI 169,369 and LY 58,537, by the preferential 5-HT2A antagonist, ketanserin and by the novel, selective 5-HT2A antagonist, SR 46349B. A further selective 5- HT2A antagonist, MDL 100,907, very potently abolished HTW (ED50 = 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, SB 200,646A, failed to abolish HTW and the 5-HT2C agonists/5-HT2A antagonists, 1-(3- chlorophenyl)piperazine and 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 D1 receptors (r = 0.98), blocked HTW. The D2 antagonists, raclopride, eticlopride and haloperidol also blocked HTW. The 5-HT1A agonists, S 14671, S 14506, 8-hydroxy-2-(di-n- propylamino)tetralin, buspirone, 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 14671, buspirone and ipsapirone. A role of postsynaptic 5-HT1A receptors in the action of 5-HT1A agonists was suggested by the finding that parachlorophenylalanine (3 x 300 mg/kg, i.p.), which depleted cerebral pools of 5-HT, did not modify the activity of ipsapirone. The present data demonstrate that 5-HT2A receptors mediate HTW in rats and that both D1 and D2 receptors as well as (postsynaptic) 5-HT1A receptors play a role in their expression.

Volume 273, Issue 1, pp. 101-112, 04/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				W. J. Thomsen, A. J. Grottick, F. Menzaghi, H. Reyes-Saldana, S. Espitia, D. Yuskin, K. Whelan, M. Martin, M. Morgan, W. Chen, et al. Lorcaserin, a Novel Selective Human 5-Hydroxytryptamine2C Agonist: in Vitro and in Vivo Pharmacological Characterization J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 577 - 587. [Abstract] [Full Text] [PDF]

				M. J. Millan, P. Svenningsson, C. R. Ashby Jr., M. Hill, M. Egeland, A. Dekeyne, M. Brocco, B. Di Cara, F. Lejeune, N. Thomasson, et al. S33138 [N-[4-[2-[(3aS,9bR)-8-Cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], a Preferential Dopamine D3 versus D2 Receptor Antagonist and Potential Antipsychotic Agent. II. A Neurochemical, Electrophysiological and Behavioral Characterization in Vivo J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 600 - 611. [Abstract] [Full Text] [PDF]

				K. D. Dave, J. A. Harvey, and V. J. Aloyo The Time-Course for Up- and Down-Regulation of the Cortical 5-Hydroxytryptamine (5-HT)2A Receptor Density Predicts 5-HT2A Receptor-Mediated Behavior in the Rabbit J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 327 - 335. [Abstract] [Full Text] [PDF]

				M. A. Benneyworth, Z. Xiang, R. L. Smith, E. E. Garcia, P. J. Conn, and E. Sanders-Bush A Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 2 Blocks a Hallucinogenic Drug Model of Psychosis Mol. Pharmacol., August 1, 2007; 72(2): 477 - 484. [Abstract] [Full Text] [PDF]

				M. Filip, M. J. Bubar, and K. A. Cunningham Contribution of Serotonin (5-Hydroxytryptamine; 5-HT) 5-HT2 Receptor Subtypes to the Hyperlocomotor Effects of Cocaine: Acute and Chronic Pharmacological Analyses J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 1246 - 1254. [Abstract] [Full Text] [PDF]

				G. V. Williams, S. G. Rao, and P. S. Goldman-Rakic The Physiological Role of 5-HT2A Receptors in Working Memory J. Neurosci., April 1, 2002; 22(7): 2843 - 2854. [Abstract] [Full Text] [PDF]

				L. Renyi, J. L. Evenden, C. J. Fowler, E. Jerning, D. Kelder, D. Lake-Bakaar, L.-G. Larsson, N. Mohell, M. Sallemark, and S. B. Ross The Pharmacological Profile of (R)-3,4-Dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran-5-carboxamide, a Selective 5-Hydroxytryptamine1A Receptor Agonist J. Pharmacol. Exp. Ther., December 1, 2001; 299(3): 883 - 893. [Abstract] [Full Text] [PDF]

				V. J. Aloyo, K. D. Dave, T. Rahman, and J. A. Harvey Selective and Divergent Regulation of Cortical 5-HT2A Receptors in Rabbit J. Pharmacol. Exp. Ther., December 1, 2001; 299(3): 1066 - 1072. [Abstract] [Full Text] [PDF]

				L. D. Van de Kar, A. Javed, Y. Zhang, F. Serres, D. K. Raap, and T. S. Gray 5-HT2A Receptors Stimulate ACTH, Corticosterone, Oxytocin, Renin, and Prolactin Release and Activate Hypothalamic CRF and Oxytocin-Expressing Cells J. Neurosci., May 15, 2001; 21(10): 3572 - 3579. [Abstract] [Full Text] [PDF]

				M. J. Millan Improving the Treatment of Schizophrenia: Focus on Serotonin (5-HT)1A Receptors J. Pharmacol. Exp. Ther., December 1, 2000; 295(3): 853 - 861. [Abstract] [Full Text]

				M. J. Millan, F. Lejeune, and A. Gobert Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex: relevance to the actions of antidepressant agents J Psychopharmacol, March 1, 2000; 14(2): 114 - 138. [Abstract] [PDF]

				M. J. Millan, A. Gobert, K. Bervoets, J.-M. Rivet, S. Veiga, and M. Brocco Induction of Spontaneous Tail-Flicks in Rats by Blockade of Transmission at N-Methyl-D-Aspartate Receptors: Roles of Multiple Monoaminergic Receptors in Relation to the Actions of Antipsychotic Agents J. Pharmacol. Exp. Ther., February 1, 2000; 292(2): 672 - 683. [Abstract] [Full Text]

				M. J. Millan, M. Brocco, J.-M. Rivet, V. Audinot, A. Newman-Tancredi, L. Maiofiss, S. Queriaux, N. Despaux, J.-L. Peglion, and A. Dekeyne S18327 (1-{2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperid-1-yl]ethyl}3-phenyl imidazolin-2-one), a Novel, Potential Antipsychotic Displaying Marked Antagonist Properties at alpha 1- and alpha 2-Adrenergic Receptors: II. Functional Profile and a Multiparametric Comparison with Haloperidol, Clozapine, and 11 Other Antipsychotic Agents J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 54 - 66. [Abstract] [Full Text]

				N. A. Darmani and B. Ahmad Long-Term Sequential Determination of Behavioral Ontogeny of 5-HT1A and 5-HT2 Receptor Functions in the Rat J. Pharmacol. Exp. Ther., January 1, 1999; 288(1): 247 - 253. [Abstract] [Full Text]

				M. J. Millan, A. Newman-Tancredi, M. Brocco, A. Gobert, F. Lejeune, V. Audinot, J.-M. Rivet, R. Schreiber, A. Dekeyne, M. Spedding, et al. S 18126 ({2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl methyl]indan-2-yl}), a Potent, Selective and Competitive Antagonist at Dopamine D4 Receptors: An In Vitro and In Vivo Comparison with L 745,870 (3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2,3b]pyridine) and Raclopride J. Pharmacol. Exp. Ther., October 1, 1998; 287(1): 167 - 186. [Abstract] [Full Text]

				M. J. Millan, R. Schreiber, A. Dekeyne, J.-M. Rivet, K. Bervoets, M. Mavridis, C. Sebban, S. Maurel-Remy, A. Newman-Tancredi, M. Spedding, et al. S 16924 ((R)-2-{1-[2-(2,3-Dihydro-Benzo[1,4] Dioxin-5-Yloxy)-Ethyl]-Pyrrolidin-3yl}-1-(4-Fluoro-Phenyl)-Ethanone), a Novel, Potential Antipsychotic with Marked Serotonin (5-HT)1A Agonist Properties: II. Functional Profile in Comparison to Clozapine and Haloperidol J. Pharmacol. Exp. Ther., September 1, 1998; 286(3): 1356 - 1373. [Abstract] [Full Text]

				L. J. Bristow, N. Collinson, G. P. Cook, N. Curtis, S. B. Freedman, J. J. Kulagowski, P. D. Leeson, S. Patel, C. I. Ragan, M. Ridgill, et al. L-745,870, a Subtype Selective Dopamine D4 Receptor Antagonist, Does Not Exhibit a Neuroleptic-Like Profile in Rodent Behavioral Tests J. Pharmacol. Exp. Ther., December 1, 1997; 283(3): 1256 - 1263. [Abstract] [Full Text]

				D. L. Willins and H. Y. Meltzer Direct Injection of 5-HT2A Receptor Agonists into the Medial Prefrontal Cortex Produces a Head-Twitch Response in Rats J. Pharmacol. Exp. Ther., August 1, 1997; 282(2): 699 - 706. [Abstract] [Full Text]

				M. S. Kleven, M.-B. Assié, and W. Koek Pharmacological Characterization of In Vivo Properties of Putative Mixed 5-HT1A Agonist/5-HT2A/2C Antagonist Anxiolytics. II. Drug Discrimination and Behavioral Observation Studies in Rats J. Pharmacol. Exp. Ther., August 1, 1997; 282(2): 747 - 759. [Abstract] [Full Text]

				A. Kulikov, S. Aguerre, O. Berton, A. Ramos, P. Mormede, and F. Chaouloff Central Serotonergic Systems in the Spontaneously Hypertensive and Lewis Rat Strains that Differ in the Elevated Plus-Maze Test of Anxiety J. Pharmacol. Exp. Ther., May 1, 1997; 281(2): 775 - 784. [Abstract] [Full Text]