Abstract
Serotonin-2C (5-HT2C) receptor antagonists and agonists have been shown to affect dopamine (DA) neurotransmission, with agonists selectively decreasing mesolimbic DA. As antipsychotic efficacy is proposed to be associated with decreased mesolimbic DA neurotransmission by virtue of DA D2 receptor antagonism, the 5-HT2C-selective receptor agonist, WAY-163909 [(7bR,10aR)-1,2, 3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7, 1hi]indole], was evaluated in animal models of schizophrenia and in vivo microdialysis and electrophysiology to determine the effects on mesolimbic and nigrostriatal DA neurotransmission. Similar to clozapine, WAY-163909 (1.7–30 mg/kg i.p.) decreased apomorphine-induced climbing with little effect on stereotypy and no significant induction of catalepsy. WAY-163909 (0.3–3 mg/kg s.c.) more potently reduced phencyclidine-induced locomotor activity compared with d-amphetamine with no effect on spontaneous activity. WAY-163909 (1.7–17 mg/kg i.p.) reversed MK-801 (5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate)- and DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-disrupted prepulse inhibition of startle (PPI) and improved PPI in DBA/2N mice. In conditioned avoidance responding, WAY-163909 (0.3–3 mg/kg i.p.; 1–17 mg/kg p.o.) reduced avoidance responding, an effect blocked by the 5-HT2B/2C receptor antagonist SB 206553 [5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole]. WAY-163909 (10 mg/kg s.c.) selectively decreased extracellular levels of DA in the nucleus accumbens without affecting the striatum. Likewise, in vivo electrophysiological recordings showed a decrease in the number of spontaneously firing DA neurons in the ventral tegmental area but not in the substantia nigra with both acute and chronic (21-day) administration of WAY-163909 (1–10 mg/kg i.p.). Thus, the profile of the 5-HT2C selective receptor agonist WAY-163909 is similar to that of an atypical antipsychotic and additionally may have rapid onset properties.
Footnotes
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Portions of this work were presented previously at the following meetings: Rosenzweig-Lipson S, Dunlop J, and McGonigle P (2000) Antiobesity-like effects of the selective 5-HT(2C) agonist WAY-161503. Experimental Biology 2000; 2000 Apr 15–18; San Diego, CA. ASBMB, Washington, DC; Grauer S, Brennan JA, Piesla MJ, et al. (2004) WAY-909, A 5-HT2C agonist, exhibits an atypical-like antipsychotic profile in a battery of rodent behavioral models. The 34th Annual Meeting of the Society for Neuroscience; 2004 Oct 23–27; San Diego, CA. Society for Neuroscience, Washington, DC; Rosenzweig-Lipson S, Beyer CE, Malberg J, et al. (2004) WAY-163909, A 5-HT2C selective agonist for the treatment of obesity, depression, and schizophrenia: lack of tolerance. The 35 Annual Meeting of the Society for Neuroscience; 2005 Nov 12–16; Washington, DC. Society for Neuroscience, Washington, DC; and Marquis KL, Grauer S, Brennan J et al. (2004) WAY-163909, a novel selective 5-HT2c agonist, exhibits an atypical-like antipsychotic profile: behavioral neurochemical, and electrophysiological evidence. The 43rd Annual Meeting of the American College of Neuropsychopharmacology; 2004 Dec 12–16; San Jaun, Puerto Rico. American College of Neuropsychopharmacology, Nashville, TN.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.106989.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine, serotonin; VTA, ventral tegmental area; SNC, substantia nigra pars compacta; WAY-163909, (7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole; DOI, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; MK-801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); SB206553, 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole; ANOVA, analysis of variance; MED, minimal effective dose; HPLC, high performance liquid chromatography; mPFC, medial prefrontal cortex; ACh, acetylcholine; IMER, immobilized enzyme reactor; ChO, choline oxidase; H2O2, hydrogen peroxide; CI, confidence interval; PCP, phencyclidine; PPI, prepulse inhibition of startle; NMDA, N-methyl-d-aspartate; mCPP, m-chlorophenylpiperazine.
- Received April 26, 2006.
- Accepted October 10, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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