T-type calcium channel antagonism decreases motivation for nicotine and blocks nicotine- and cue-induced reinstatement for a response previously reinforced with nicotine.
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.
Uslaner
Jason M
JM
Department of Neuroscience, Merck & Co., Inc., West Point, Pennsylvania 19486, USA. jason_uslaner@merck.com
Vardigan
Joshua D
JD
Drott
Jason M
JM
Uebele
Victor N
VN
Renger
John J
JJ
Lee
Ariel
A
Li
Zhaoxia
Z
Lê
A D
AD
Hutson
Pete H
PH
D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004305:Dose-Response Relationship, Drug; D005108:Extinction, Psychological / Q000187:drug effects*; D005502:Food; D008297:Male; D009042:Motivation / Q000187:drug effects*; D009538:Nicotine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012646:Self Administration
C553486:2-(4-cyclopropylphenyl)-N-(1-(5-((2,2,2-trifluoroethyl)oxo)pyridin-2-yl)ethyl)acetamide; D044482:Benzeneacetamides; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D011725:Pyridines; D009538:Nicotine