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

Authors

  • Lara A. Pockros,

    1. Department of Psychology, Arizona State University, 950 S. McAllister, Tempe, Arizona 85287-1104
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  • Nathan S. Pentkowski,

    1. Department of Psychology, Arizona State University, 950 S. McAllister, Tempe, Arizona 85287-1104
    2. School of Life Sciences, Arizona State University, 427 East Tyler Mall, Tempe, Arizona 85287-4501
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  • Sineadh M. Conway,

    1. School of Life Sciences, Arizona State University, 427 East Tyler Mall, Tempe, Arizona 85287-4501
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  • Teresa E. Ullman,

    1. School of Life Sciences, Arizona State University, 427 East Tyler Mall, Tempe, Arizona 85287-4501
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  • Kimberly R. Zwick,

    1. School of Life Sciences, Arizona State University, 427 East Tyler Mall, Tempe, Arizona 85287-4501
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  • Janet L. Neisewander

    Corresponding author
    1. Department of Psychology, Arizona State University, 950 S. McAllister, Tempe, Arizona 85287-1104
    2. School of Life Sciences, Arizona State University, 427 East Tyler Mall, Tempe, Arizona 85287-4501
    • School of Life Sciences, Arizona State University, 427 East Tyler Mall, Tempe, Arizona 85287-4501, USA
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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. Synapse, 2012. © 2012 Wiley Periodicals, Inc.

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