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NEUROPHARMACOLOGY

Serotonin 5-HT_2A Receptors Underlie Increased Motor Behaviors Induced in Dopamine-Depleted Rats by Intrastriatal 5-HT2A/2C Agonism

Departments of Anatomy and Cell Biology (C.B., P.D.W.) and Psychiatry and Behavioral Neurosciences (J.L.T.), Wayne State University School of Medicine, Detroit, Michigan; and Laboratory of Medicinal Chemistry (T.U., K.C.R.), National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland

Gene expression studies have suggested that dopamine (DA) depletion increases the sensitivity of striatal direct pathway neurons to the effects of serotonin (5-HT) via the 5-HT₂ receptor. The present study examined the possible influence(s) of 5-HT_2A or 5-HT_2C receptor-mediated signaling locally within the striatum on motor behavior triggered by 5-HT₂ receptor agonism in the neonatal DA-depleted rat. Male Sprague-Dawley rats were treated with 6-hydroxydopamine (6-OHDA; 60 µg in 5 µl per lateral ventricle) on postnatal day 3 to achieve near-total DA depletion bilaterally. Sixty days later, sham-operated (saline-injected) or 6-OHDA-treated rats were challenged with the 5-HT_2A/2C agonist DOI [(±)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane] or saline either by systemic treatment or bilateral intrastriatal infusion. Motor behavior was quantified for 60 min after agonist injection using computerized activity monitors. Systemic DOI treatment (0.2 or 2.0 mg/kg i.p.) was more effective in inducing motor activity in the DA-depleted group compared with intact controls. Intrastriatal DOI infusion (1.0 or 10.0 µg/side) also produced a significant rise in motor activity in the DA-depleted group during the 30- to 60-min period of behavioral analysis but did not influence behavior in intact animals. The effects of intrastriatal DOI infusion were blocked by intrastriatal coinfusion of the 5-HT₂ antagonist ketanserin (1.0 µg) and the 5-HT_2A-preferring antagonist M100907 [(R)(+)--(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol; 1.0 µg] but not the 5-HT_2C-preferring antagonist RS102221 [8-[5-(2,4-dimethoxy-5-(4-trifluoromethylsulfo-amido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione; 1.0 µg]. Such results support the hypothesis that 5-HT_2A receptor-mediated signaling events are strengthened within the striatum under conditions of DA depletion to provide a more potent regulation of motor activity.

Address correspondence to: Dr. Paul D. Walker, Department of Anatomy and Cell Biology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201. E-mail: pdwalker{at}med.wayne.edu