T-Type Calcium Channel Antagonism Decreases Motivation for Nicotine and Blocks Nicotine- and Cue-Induced Reinstatement for a Response Previously Reinforced with Nicotine Jason M. Uslaner, Joshua D. Vardigan, Jason M. Drott, Victor N. Uebele, John J. Renger, Ariel Lee, Zhaoxia Li, A.D. Lê, and Pete H. Hutson Background: Recent evidence suggests an involvement of T-type calcium channels in the effects of drugs of abuse. Methods: We examined the influence of the novel, potent, and selective T-type calcium channel antagonist [2-(4-Cyclopropylphenyl)-N- ((1R)-1-{5-[2,2,2-trifluoroethyl]oxo}pyridine-2-yl)ethyl]acetamide] (TTA-A2) (.3, 1, or 3 mg/kg) on motivation for nicotine, as measured by nicotine self-administration on a progressive ratio (PR) schedule, and nicotine- and cue-induced reinstatement for a response previously reinforced with nicotine delivery (n = 11 or 12 Long Evans rats/group). Furthermore, we examined the specificity of the TTA-A2 effects by characterizing its influence on PR responding for food (in the absence or presence of nicotine-potentiated responding), food- versus nicotine-induced cue-potentiated reinstatement for a response previously reinforced by food administration (n = 11 or 12 Wistar Hannover rats/group), and its ability to induce a conditioned place aversion. Results: TTA-A2 dose-dependently decreased self-administration of nicotine on a PR schedule and the ability of both nicotine and a cue paired with nicotine to reinstate responding. The effects were specific for nicotine’s incentive motivational properties, as TTA-A2 did not influence responding for food on a PR schedule but did attenuate the ability of nicotine to potentiate responding for food. Likewise, TTA-A2 did not alter food-induced cue-potentiated reinstatement for a response previously reinforced by food but did decrease nicotine-induced cue-potentiated reinstatement. Finally, TTA-A2 did not produce an aversive state, as indicated by a lack of ability to induce conditioned place aversion. Conclusions: These data suggest that T-type calcium channel antagonists have potential for alleviating nicotine addiction by selectively decreasing the incentive motivational properties of nicotine. Key Words: Addiction, drug abuse, incentive salience, progressive ratio, relapse, self-administration T -type calcium channels are characterized by activation at low voltages, rapid inactivation, slow deactivation, and small single channel conductance (see [1,2] for reviews). Because of their involvement in burst firing (3,4) and pacemaker activity (5,6), these channels have been hypothesized to be involved in disorders hallmarked by alterations in electroenceph- alogram signaling (1). However, as selective antagonists for this channel have not been identified until recently (7,8), the hypoth- esis that T-type calcium channel antagonism might have thera- peutic utility for central nervous system disorders has remained untested (9). In addition to a potential role in sleep and seizure liability (4,10), T-type calcium channels might also be involved in the effects of drugs of abuse. For example, Newton et al. (11) showed that the mixed N-type and T-type calcium channel antagonist NP078585 reduced the reinforcing effects of alcohol, although these effects were attributed to the compound’s N-type channel activity. Biala and Budzynska (12) have found that the nonselective calcium channel antagonists nimodipine and fluna- rizine block nicotine-induced conditioned place preference. In a more recent publication, Urbano et al. (13) reported that injec- tions of cocaine given in a “binge-like” fashion elevated T-type current amplitudes and reduced the threshold for activating thalamic neurons. They proposed that such changes could lead to the thalamocortical dysfunctions observed in human cocaine abusers (14 –16). Finally, the marginally selective T-type calcium channel antagonists divalent nickel and sFTX-3.3 reduced nico- tine-induced calcium mobilization in substantia nigra pars com- pacta neurons (17), an effect that would be predicted to decrease nicotine-induced dopamine release in vivo. This is important because of the involvement of dopamine signaling in the abuse potential of nicotine and other addictive drugs (18 –20). Given this evidence, we were interested in examining the influence of a selective T-type calcium channel antagonist on the reinforcing and incentive motivational effects of nicotine. We have recently identified a potent, brain penetrant, state-depen- dent, selective antagonist, [2-(4-Cyclopropylphenyl)-N-((1R)-1- {5-[2,2,2-trifluoroethyl]oxo}pyridine-2-yl)ethyl]acetamide] (TTA- A2) (8,21,22). We tested the ability of TTA-A2 to influence nicotine self-administration on a progressive ratio (PR) schedule and nicotine-induced and cue-induced reinstatement for a re- sponse previously followed by nicotine administration. To char- acterize the selectivity of the observed effects and rule out potential confounds, we took advantage of the fact that nicotine increases the incentive motivational properties of nondrug re- wards by acting as a so-called reinfocement enhancer, an From the Department of Neuroscience (JMU, JDV, JMD, VNU, JJR, AL, PHH), Merck & Co., Inc., West Point, Pennsylvania; and Department of Neuro- science (ZL, ADL), Neurobiology of Alcohol Laboratory, Centre for Addic- tion and Mental Health, Toronto, Ontario, Canada. Address correspondence to Jason M. Uslaner, Ph.D., Merck & Co., Inc., WP46- 399, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486; E-mail: jason_uslaner@merck.com. Received Nov 6, 2009; revised May 3, 2010; accepted May 3, 2010. BIOL PSYCHIATRY 2010;68:712–718 0006-3223/$36.00 doi:10.1016/j.biopsych.2010.05.004 © 2010 Society of Biological Psychiatry