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5‐HT 2A receptor blockade and 5‐HT 2C receptor activation interact to reduce cocaine hyperlocomotion and fos protein expression in the caudate‐putamen
Author(s) -
Pockros Lara A.,
Pentkowski Nathan S.,
Conway Sineadh M.,
Ullman Teresa E.,
Zwick Kimberly R.,
Neisewander Janet L.
Publication year - 2012
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.21592
Subject(s) - striatum , chemistry , agonist , pharmacology , c fos , antagonist , hypoactivity , dopamine , saline , receptor , neuroscience , psychology , endocrinology , medicine , biochemistry , gene expression , gene
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. Synapse, 2012. © 2012 Wiley Periodicals, Inc.