Serotonin 5-HT2A receptors underlie increased motor behaviors induced in dopamine-depleted rats by intrastriatal 5-HT2A/2C agonism.
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-HT(2) 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-HT(2) receptor agonism in the neonatal DA-depleted rat. Male Sprague-Dawley rats were treated with 6-hydroxydopamine (6-OHDA; 60 microg in 5 microl 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 microg/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-HT(2) antagonist ketanserin (1.0 microg) and the 5-HT(2A)-preferring antagonist M100907 [(R)(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol; 1.0 microg] 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 microg]. 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.
Bishop
Christopher
C
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, USA.
Tessmer
Jennifer L
JL
Ullrich
Thomas
T
Rice
Kenner C
KC
Walker
Paul D
PD
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology
D000662:Amphetamines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; D016627:Oxidopamine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D004298:Dopamine