5-HT2A receptor blockade and 5-HT2C receptor activation interact to reduce cocaine hyperlocomotion and fos protein expression in the caudate-putamen

Lara A. Pockros, Nathan S. Pentkowski, Sineadh M. Conway, Teresa E. Ullman, Kimberly R. Zwick, Janet Neisewander

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Both the 5-HT2A receptor (R) antagonist M100907 and the 5-HT2CR 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-HT2A/5-HT2CR 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-HT2ARs and 5-HT2CRs 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-HT2R subtypes on behavior. Further research investigating combined 5-HT2AR antagonism and 5-HT2CR agonism as a treatment for cocaine dependence is warranted.

Original languageEnglish (US)
Pages (from-to)989-1001
Number of pages13
JournalSynapse
Volume66
Issue number12
DOIs
Publication statusPublished - Dec 2012

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Keywords

  • Cocaine
  • Locomotion
  • M100907
  • MK212
  • Serotonin

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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