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The Journal of Neuroscience, November 5, 2008, 28(45):11712-11719; doi:10.1523/JNEUROSCI.3621-08.2008

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Behavioral/Systems/Cognitive
A Blocker of N- and T-type Voltage-Gated Calcium Channels Attenuates Ethanol-Induced Intoxication, Place Preference, Self-Administration, and Reinstatement

Philip M. Newton,¹ Lily Zeng,¹ Victoria Wang,¹ Jacklyn Connolly,¹ Melisa J. Wallace,¹ Chanki Kim,² Hee-Sup Shin,² Francesco Belardetti,³ Terrance P. Snutch,^3,4 and Robert O. Messing¹

¹Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608, ²Center for Neural Science, Korea Institute of Science and Technology, 136-791 Seoul, Republic of Korea, ³Neuromed Pharmaceuticals, Vancouver, British Columbia, Canada V6T 1Z3, and ⁴Michael Smith Laboratories, University of British Columbia, British Columbia, Canada V6T 1Z4

Correspondence should be addressed to Dr. Robert O. Messing, Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608. Email: romes{at}gallo.ucsf.edu

There is a clear need for new therapeutics to treat alcoholism. Here, we test our hypothesis that selective inhibitors of neuronal calcium channels will reduce ethanol consumption and intoxication, based on our previous studies using knock-out mice and cell culture systems. We demonstrate that pretreatment with the novel mixed N-type and T-type calcium channel antagonist 1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine (NP078585) reduced ethanol intoxication. NP078585 also attenuated the reinforcing and rewarding properties of ethanol, measured by operant self-administration and the expression of an ethanol conditioned place preference, and abolished stress-induced reinstatement of ethanol seeking. NP078585 did not affect alcohol responses in mice lacking N-type calcium channels. These results suggest that selective calcium channel inhibitors may be useful in reducing acute ethanol intoxication and alcohol consumption by human alcoholics.

Key words: alcoholism; calcium channel; N type; T type; conotoxin; addiction; relapse

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Received July 31, 2008; revised Sept. 18, 2008; accepted Sept. 20, 2008.

Correspondence should be addressed to Dr. Robert O. Messing, Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608. Email: romes{at}gallo.ucsf.edu

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