Abstract
These studies investigated the effects of antagonists selective for the 5-HT2A, 5-HT2B, or 5-HT2C receptor subtypes on behaviors elicited or maintained by cocaine. The selective 5-HT2A receptor antagonist M100,907 (0.5 mg/kg, SC) attenuated the locomotor activity elicited by 10 mg/kg cocaine, whereas the selective 5-HT2C receptor antagonist SB242,084 (0.5 mg/kg IP) potentiated the locomotor stimulant effect of 10 mg/kg cocaine. The selective 5-HT2B antagonist SB215,505 (3 mg/kg PO) did not alter cocaine-induced locomotor activity. In a second series of experiments, the effects of M100,907 and SB242,084 were examined in rats self-administering cocaine intravenously according to a progressive ratio schedule. M100,907 (0.5–2 mg/kg) did not alter responding for cocaine at an infusion dose of 0.25 mg. Similarly M100,907 (0.5 mg/kg) failed to alter responding for cocaine at infusion doses of 0.0625, 0.125 and 0.25 mg. SB242,084 (0.5–1 mg/kg) increased responding for cocaine with the infusion dose set at 0.125 mg. Examination of the effects of SB242,084 (0.5 mg/kg) on the cocaine dose response curve revealed significant increases in responding at the lowest doses of 0.0625 and 0.125 but not 0.25 mg. After completion of the self-administration experiments responding was extinguished. M100,907 (0.5 mg/kg) attenuated the ability of experimenter administered cocaine (10 mg/kg and 20 mg/kg) to reinstate lever pressing, whereas the priming effect of cocaine (10 mg/kg) was enhanced by SB242,084. These results indicate distinct, and in some cases opposite, effects of a 5-HT2A compared with a 5-HT2C receptor antagonist on various cocaine-mediated behavioral effects.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Abramowski D, Rigo M, Duc D, Hoyer D, Staufenbiel M . (1995): Localization of the 5-hydroxytryptamine2C protein in human and rat brain using specific antisera. Neuropharmacology 34: 1636–1645
Arnold JM, Roberts DCS . (1997): A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57: 441–447
Barnes NM, Sharp T . (1999): A review of central 5-HT receptors and their function. Neuropharmacology 38: 1083–1152
Boess FG, Martin I L . (1994): Molecular biology of 5-HT receptors. Neuropharmacology 33: 275–317
Bradberry CW, Nobileeti JB, Elsworth JD, Murphy B, Jatlow P, Roth RH . (1993): Cocaine and cocaethylene: Microdialysis comparison of drug brain levels and effects on dopamine and serotonin. J Neurochem 60: 1429–1435
Caine SB, Koob GF . (1994): Effects of dopamine D1 and D2 antagonists on cocaine self-administration under different schedules of reinforcement in the rat. J Pharmacol Exp Ther 270: 209–218
Callahan PM, Appel JB, Cunningham KA . (1991): Dopamine D1 and D2 mediation of the discriminative stimulus properties of d-amphetamine and cocaine. Psychopharmacology (Berl) 103: 50–55
Carroll ME, Lac ST, Asencio M, Kragh R . (1990): Fluoxetine reduces intravenous cocaine self-administration in rats. Pharmacol Biochem Behav 35: 237–244
de Wit H, Stewart J . (1981): Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology (Berl) 75: 134–143
de Wit H, Stewart J . (1983): Drug reinstatement of heroin-reinforced responding in the rat. Psychopharmacology (Berl) 79: 23–31
Di Ciano P, Coury A, Depoortere RY, Egilmez Y, Lane JD, Emmett-Oglesby M, Lepiane FG, Phillips AG, Blaha CD . (1995): Comparison of changes in extracellular dopamine concentrations in the nucleus accumbens during intravenous self-administration of cocaine or d-amphetamine. Behav Pharmacol 6: 311–322
Di Giovanni G, Di Matteo V, La Grutta V, Esposito E . (2001): m-Chlorophenylpiperazine excites non-dopaminergic neurons in the rat substantia nigra and ventral tegmental area by activating serotonin-2C receptors. Neuroscience 103: 111–116
Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E . (1999): SB242,084 a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system. Neuropharmacology 38: 1195–1205
Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E . (2000): Biochemical and electrophysiological evidence that Ro60–0175 inhibits mesolimbic dopaminergic function through serotonin2C receptors. Brain Res 865: 85–90
Doherty MD, Pickel V M . (2000): Ultrastructural localization of the serotonin 2A receptor in dopaminergic neurons in the ventral tegmental area. Brain Res 864: 176–185
Eberle-Wang K, Mikeladze Z, Uryu K, Chesselet MF . (1997): Pattern of expression of serotonin2C receptor messenger RNA in the basal ganglia of adult rats. J Comp Neurol 384: 233–247
Grottick AJ, Fletcher PJ, Higgins GA . (2000): Studies to investigate the role of 5-HT2C receptors on cocaine- and food-maintained behavior. J Pharmacol Exp Ther 295: 1183–1191
Higgins GA, Ouagazzal AM, Grottick AJ . (2001): Influence of the 5-HT2C receptor antagonist SB242,084 on behaviour produced by the 5-HT2 agonist Ro60–0175 and the indirect 5-HT agonist dexfenfluramine. Br J Pharmacol 133: 459–466
Kehne JH, Baron BM, Carr AA, Chaney SF, Elands J, Fe DJ, Frank RA, Van Giersbergen PLM, McCloskey TC, Johnson MP, McCarty DR, Poirot M . (1996): Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100,907 as a potent 5-HT2A antagonist with a favorable CNS profile. J Pharmacol Exp Ther 277: 968–981
Kelly PH, Iversen SD . (1976): Selective 6-OHDA-induced destruction of mesolimbic dopamine neurons: Abolition of psychostimulant-induced locomotor activity in rats. Eur J Pharmacol 40: 45–56
Kennett GA, Trail B, Bright F . (1998): Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated. Neuropharmacology 37: 1603–1610
Kennett GA, Wood MD, Bright F, Trail B, Riley G, Holland V, Avenell KY, Stean T, Upton N, Bromidge S, Forbes IT, Brown AM, Middlemiss DN, Blackburn TP . (1997): SB242,084, a selective and brain penetrant 5-HT2C receptor antagonist. Neuropharmacology 36: 609–620
Koe BK . (1976): Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain. J Pharmacol Exp Ther 199: 649–661
Krebs-Thomson K, Paulus MP, Geyer MA . (1998): Effects of hallucinogens on locomotor and investigatory activity and patterns:influence of 5-HT2A and 5-HT2C receptors. Neuropsychopharmacology 18: 339–351
Lacosta S, Roberts DCS . (1993): MDL 72222, ketanserin and methysergide pretreatments fail to alter breaking points on a progressive ratio schedule reinforced by intravenous cocaine. Pharmacol Biochem Behav 44: 161–165
Loh EA, Roberts DCS . (1990): Break points on a progressive ratio schedule reinforced by intravenous cocaine increase following depletion of forebrain serotonin. Psychopharmacology (Berl) 101: 262–266
Lopez-Gimenez JF, Mengod G, Palacios JM, Vilaro MT . (1997): Selective visualization of rat brain 5-HT2A receptors by autoradiography with [3H] MDL100,907. Naunyn-Schmiedeberg's Arch Pharmacol 356: 446–454
Maldonado R, Robledo P, Chover AJ, Caine SB, Koob GF . (1993): D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat. Pharmacol Biochem Behav 45: 239–242
Martin JR, Bos M, Jenck F, Moreau J-L, Mutel V, Sleight AJ, Wichmann J, Andrews JS, Berendsen HHG, Broekkamp CLE, Ruight GSF, Kohler C, van Delft AML . (1998): 5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential. J Pharmacol Exp Ther 286: 913–924
McCreary AC, Cunningham KA . (1999): Effects of the 5-HT2C/2B antagonist SB206,553 on hyperactivity induced by cocaine. Neuropsychopharmacology 20: 556–564
McElvain JS, Schenk JO . (1992): A multisubstrate mechanism of striatal dopamine uptake and its inhibition by cocaine. Biochem Pharmacol 43: 2189–2199
McGregor A, Lacosta S, Roberts DCS . (1993): L-Tryptophan decreases the breaking point under a progressive ratio schedule of intravenous cocaine reinforcement in the rat. Pharmacol Biochem Behav 44: 651–655
McMahon LR, Cunningham KA . (2001): Antagonism of 5-hydroxytryptamine2A receptors attenuates the behavioral effects of cocaine in rats. J Pharmacol Exp Ther 297: 357–363
McMahon LR, Filip M, Cunningham KA . (2001): Differential regulation of the mesoaccumbens circuit by serotonin 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors. J Neurosci 21: 7781–7787
Moser PC, Moran PM, Frank RA, Kehne JH . (1996): Reversal of amphetamine-induced behaviours by MDL 100,907 a selective 5-HT2A antagonist. Behav Brain Res 73: 163–167
Nebigil CG, Choi D-S, Dierich A, Hickel P, Le Meur M, Messaddeq N, Launay J-M, Maroteaux L . (2000): Serotonin 2B receptor is required for heart development. Proc. Natl. Acad. Sci. 97: 9508–9513
Neisewander JL, O′Dell LE, Redmond JC . (1995): Localization of dopamine receptor subtypes occupied by intra-accumbens antagonists that reverse cocaine-induced locomotion. Brain Res 671: 201–212
O′Neill MF, Heron-Maxwell CL, Shaw G . (1999): 5-HT2 receptor antagonism reduces hyperactivity induced by amphetamine, cocaine and MK-801 but not D1 agnoist C-APB. Pharmacol Biochem Behav 63: 237–243
Peltier R, Schenk S . (1993): Effects of serotonergic manipulations on cocaine self-administration in rats. Psychopharmacol 110: 390–394
Pettit HO, Ettenberg A, Bloom FE, Koob GF . (1984): Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats. Psychopharmacology (Berl) 84: 167–173
Pettit HO, Justice JB . (1991): Effect of dose on cocaine self-administration behavior and dopamine levels in the nucleus accumbens. Brain Res 539: 94–102
Pompeiano M, Palacios JM, Mengod G . (1994): Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors. Mol Brain Res 23: 163–178
Reavill C, Kettle A, Holland V, Riley G, Blackburn T . (1999): Attenuation of haloperidol-induced catalepsy by a 5-HT2C receptor antagonist. Br J Pharmacol 126: 572–574
Richardson NR, Roberts DCS . (1991): Fluoxetine pretreatment reduces breaking points on a progressive ratio schedule reinforced by intravenous cocaine self-administration in the rat. Life Sci 49: 833–840
Roberts DCS, Corcoran ME, Fibiger HC . (1977): On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine. Pharmacol Biochem Behav 6: 615–620
Roberts DCS, Loh EA, Baker GB, Vickers G . (1994): Lesions of central serotonin systems affect responding on a progressive ratio schedule reinforced either by intravenous cocaine or by food. Pharmacol Biochem Behav 49: 177–182
Schenk S, Partridge B . (1999): Cocaine-seeking produced by experimenter-administered drug injections: dose-effect relationships in rats. Psychopharmacology (Berl) 147: 285–290
Schmidt CJ, Sorensen SM, Kehne JH, Carr AA, Palfreyman MG . (1995): The role of 5-HT2A receptors in antipsychotic activity. Life Sci 56: 2209–2222
Sipes TE, Geyer MA . (1995): DOI disruption of prepulse inhibition of startle in the rat is mediated by5-HT2A and not by 5-HT2C receptors. Behav Pharmacol 6: 839–842
Tsibulsky V, Dashevsky B, Frank RA . (1995): D2 and 5-HT2 modulation of psychostimulant-induced facilitation of brain stimulation reward. Drug Dev Res 34: 297–305
Acknowledgements
PJF is a Career Scientist of the Ontario Ministry of Health. The work in his laboratory was supported by an operating grant from the Canadian Institutes of Health Research. Shannon Robinson and Judy Sinyard are thanked for the assistance in running the self-administration experiments. We also thank Drs. Mark Duxon and Derek Middlemiss (GlaxoSmithKline) for the generous supply of SB215505, and Juergen Wichmann and Philippe Guerry for the synthesis of SB242,084 and M100,907.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fletcher, P., Grottick, A. & Higgins, G. Differential Effects of the 5-HT2A Receptor Antagonist M100,907 and the 5-HT2C Receptor Antagonist SB242,084 on Cocaine-induced Locomotor Activity, Cocaine Self-administration and Cocaine-induced Reinstatement of Responding. Neuropsychopharmacol 27, 576–586 (2002). https://doi.org/10.1016/S0893-133X(02)00342-1
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1016/S0893-133X(02)00342-1
Keywords
This article is cited by
-
5-Hydroxytryptamine receptor 2C
AfCS-Nature Molecule Pages (2008)
