5-HT2A receptor blockade and 5-HT2C receptor activation interact to reduce cocaine hyperlocomotion and fos protein expression in the caudate-putamen
Article first published online: 11 SEP 2012
Copyright © 2012 Wiley Periodicals, Inc.
Volume 66, Issue 12, pages 989–1001, December 2012
How to Cite
Pockros, L. A., Pentkowski, N. S., Conway, S. M., Ullman, T. E., Zwick, K. R. and Neisewander, J. L. (2012), 5-HT2A receptor blockade and 5-HT2C receptor activation interact to reduce cocaine hyperlocomotion and fos protein expression in the caudate-putamen. Synapse, 66: 989–1001. doi: 10.1002/syn.21592
- Issue published online: 13 OCT 2012
- Article first published online: 11 SEP 2012
- Accepted manuscript online: 10 AUG 2012 08:49AM EST
- Manuscript Accepted: 7 AUG 2012
- Manuscript Revised: 2 AUG 2012
- Manuscript Received: 21 MAY 2012
- NIDA. Grant Number: R01DA011064
- NIDA Individual National Research Service Award. Grant Number: DA025413
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. Synapse, 2012. © 2012 Wiley Periodicals, Inc.