T-Type Calcium Channel Antagonism Decreases Motivation for Nicotine and Blocks Nicotine- and Cue-Induced Reinstatement for a Response Previously Reinforced with Nicotine

doi:10.1016/j.biopsych.2010.05.004

Biological Psychiatry

Volume 68, Issue 8, 15 October 2010, Pages 712-718

https://doi.org/10.1016/j.biopsych.2010.05.004 Get rights and content

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.

Section snippets

Animals

Male Long Evans rats (250–275 g) purchased from Charles River Laboratories (Wilmington, Massachusetts) were housed singly in a humidity- and temperature-regulated vivarium on a 12/12 hour reverse light/dark cycle. Water and chow were available ad libitum until training and subsequently rats were fed 25 g chow per day following their daily operant session.

Apparatus

Nicotine self-administration occurred in operant chambers controlled by a computer interface system (Med Associates, St. Albans, Vermont).

Experiment 1: Influence of TTA-A2 on Responding for Nicotine on a PR Schedule and Nicotine and Cue-Induced Reinstatement

The TTA-A2 dose dependently decreased responding for nicotine on a PR schedule as revealed by a main effect of group on reinforcers [F(3,41) = 3.8, p < .02]. Post hoc tests showed that administration of 3 mg/kg TTA-A2 significantly reduced the number of nicotine infusions earned (p = .015; Figure 1). Analysis of variance revealed no effect of TTA-A2 on inactive lever presses [F(3,41) = 2.5, p > .05].

The TTA-A2 also reduced the ability of a nicotine priming injection to reinstate responding (

Discussion

We report three novel findings. First, TTA-A2 dose-dependently decreased motivation for nicotine as measured by responding for intravenous nicotine on a PR schedule. Second, TTA-A2 attenuated the ability of: 1) a nicotine-priming injection and 2) the presentation of conditioned stimuli previously paired with nicotine to promote reinstatement in animals extinguished to lever pressing for intravenous nicotine. Third, TTA-A2 failed to modulate PR responding for food or the ability of food to

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For example, when TTA-A2 was administered in conjunction with cocaine or amphetamine to mice previously given repeated daily injections of either amphetamine or cocaine, expression of locomotor sensitization was blocked (Gangarossa et al., 2014). Further, in a nicotine self-administration model, rats given TTA-A2 showed reduced motivation to self-administer nicotine and motivation was not reinstated when either a priming dose of nicotine or a nicotine associated cue was presented (Uslaner et al., 2010). In addition, TTA-A2 appeared to selectively block drug-related behaviors in the tasks tested without impairing the response to a natural food reward.
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However, because of the lack of selective antagonists for the T-type calcium channel, the hypothesis that selective compounds might produce effects in preclinical assays predictive of antipsychotic potential has hitherto been untested. We have recently described a potent, brain penetrant, state dependent, selective T-type calcium channel antagonist, TTA-A2 (Barrow et al., 2007; Kraus et al., 2010; Uebele et al., 2009a, 2009b; Uslaner et al., 2010), and in the present study characterized its antipsychotic potential preclinically. First, we examined the effects of TTA-A2 on amphetamine- and MK-801-induced psychomotor activity and conditioned avoidance responding, assays sensitive to antipsychotics (Arnt, 1995; Arnt et al., 1997; Wadenberg and Hicks, 1999).
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Archival ReportT-Type Calcium Channel Antagonism Decreases Motivation for Nicotine and Blocks Nicotine- and Cue-Induced Reinstatement for a Response Previously Reinforced with Nicotine

Background

Methods

Results

Conclusions

Section snippets

Animals

Apparatus

Experiment 1: Influence of TTA-A2 on Responding for Nicotine on a PR Schedule and Nicotine and Cue-Induced Reinstatement

Discussion

Cell Calcium

Neuron

J Neurosci Methods

Eur J Pharmacol

Biol Psychiatry

Psychiatry Res

Brain Res Brain Res Rev

Drug Alcohol Depend

Curr Opin Neurobiol

Pharmacol Biochem Behav

Behav Brain Res

Trends Pharmacol Sci

Physiol Behav

Pharmacol Biochem Behav

Neuropharmacology

Low-threshold calcium currents in central nervous system neurons

Annu Rev Physiol

Electrophysiology of mammalian inferior olivary neurones in vitroDifferent types of voltage-dependent ionic conductances

J Physiol

Mechanisms of oscillatory activity in guinea-pig nucleus reticularis thalami in vitro: A mammalian pacemaker

J Physiol

Archival Report
T-Type Calcium Channel Antagonism Decreases Motivation for Nicotine and Blocks Nicotine- and Cue-Induced Reinstatement for a Response Previously Reinforced with Nicotine