title: 5-HT(2A) receptor blockade and 5-HT(2C) receptor activation interact to reduce cocaine hyperlocomotion and Fos protein expression in the caudate-putamen.
abstract: Both the 5-HT(2A) receptor (R) antagonist M100907 and the 5-HT(2C) R agonist MK212 attenuate cocaine-induced dopamine release and hyperlocomotion. This study examined whether these drugs interact to reduce cocaine hyperlocomotion and Fos expression in the striatum and prefrontal cortex. We first determined from dose-effect functions a low dose of both M100907 and MK212 that failed to alter cocaine (15 mg/kg, i.p.) hyperlocomotion. Subsequently, we examined whether these subthreshold doses given together would attenuate cocaine hyperlocomotion, consistent with a 5-HT(2A)/5-HT(2C) R interaction. Separate groups of rats received two sequential drug injections 5 min apart immediately before a 1-h locomotion test as follows: (1) saline + saline, (2) saline + cocaine, (3) 0.025 mg/kg M100907 + cocaine, (4) 0.125 mg/kg MK212 + cocaine, or (5) cocktail combination of 0.025 mg/kg M100907 and 0.125 mg/kg MK212 + cocaine. Brains were extracted for Fos immunohistochemistry 90 min after the second injection. We next examined the effects of 0.025 mg/kg M100907 and 0.125 mg/kg MK212, alone and in combination, on spontaneous locomotor activity. While neither drug given alone produced any effects, the M100907/MK212 cocktail attenuated cocaine hyperlocomotion as well as cocaine-induced Fos expression in the dorsolateral caudate-putamen (CPu), but had no effect on spontaneous locomotion. The findings suggest that 5-HT(2A) Rs and 5-HT(2C) Rs interact to attenuate cocaine hyperlocomotion and Fos expression in the CPu, and that the CPu is a potential locus of the interactive effects between these 5-HT(2) R subtypes on behavior. Further research investigating combined 5-HT(2A) R antagonism and 5-HT(2C) R agonism as a treatment for cocaine dependence is warranted.
authors.affiliation: Department of Psychology, Arizona State University, 950 S. McAllister, Tempe, Arizona 85287-1104, USA.
authors.forename: Lara A
authors.initials: LA
authors.lastname: Pockros
authors.forename: Nathan S
authors.initials: NS
authors.lastname: Pentkowski
authors.forename: Sineadh M
authors.initials: SM
authors.lastname: Conway
authors.forename: Teresa E
authors.initials: TE
authors.lastname: Ullman
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Zwick
authors.forename: Janet L
authors.initials: JL
authors.lastname: Neisewander
mesh_terms: D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D005464:Fluorobenzenes / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D011699:Putamen / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology; 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 / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology
chemical_list: D005464:Fluorobenzenes; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D011719:Pyrazines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; C014896:6-chloro-2-(1-piperazinyl)pyrazine; C079049:volinanserin; D003042:Cocaine