Cholinergic Receptor Blockade in the VTA Attenuates Cue-Induced Cocaine-Seeking and Reverses the Anxiogenic Effects of Forced Abstinence.

Drug relapse after periods of abstinence is a common feature of substance abuse. Moreover, anxiety and other mood disorders are often co-morbid with substance abuse. Cholinergic receptors in the ventral tegmental area (VTA) are known to mediate drug-seeking and anxiety-related behavior in rodent models. However, it is unclear if overlapping VTA cholinergic mechanisms mediate drug relapse and anxiety-related behaviors associated with drug abstinence. We examined the effects of VTA cholinergic receptor blockade on cue-induced cocaine seeking and anxiety during cocaine abstinence. Male Sprague-Dawley rats were trained to self-administer intravenous cocaine (~0.5 mg/kg/infusion, FR1 schedule) for 10 days, followed by 14 days of forced abstinence. VTA infusion of the non-selective nicotinic acetylcholine receptor antagonist mecamylamine (0, 10, and 30 µg/side) or the non-selective muscarinic receptor antagonist scopolamine (0, 2.4 and 24 µg /side) significantly decreased cue-induced cocaine seeking. In cocaine naïve rats, VTA mecamylamine or scopolamine also led to dose-dependent increases in open arm time in the elevated plus maze (EPM). In contrast, rats that received I.V. cocaine, compared to received I.V. saline rats, displayed an anxiogenic response on day 14 of abstinence as reflected by decreased open arm time in the EPM. Furthermore, low doses of VTA mecamylamine (10 µg /side) or scopolamine (2.4 µg /side), that did not alter EPM behavior in cocaine naive rats, were sufficient to reverse the anxiogenic effects of cocaine abstinence. Together, these data point to an overlapping role of VTA cholinergic mechanisms to regulate relapse and mood disorder-related responses during cocaine abstinence.

The L-type calcium channel blocker, isradipine, attenuates cue-induced cocaine-seeking by enhancing dopaminergic activity in the ventral tegmental area to nucleus accumbens pathway.

Previous preclinical and clinical investigations have focused on the L-type calcium channel (LTCC) as a potential therapeutic target for substance abuse. While some clinical studies have examined the ability of LTCC blockers to alter cocaine's subjective effects, very few LTCC studies have examined cocaine relapse. Here, we examined whether ventral tegmental area (VTA)-specific or systemic administration of the LTCC inhibitor, isradipine, altered cocaine-seeking behavior in a rat model. Male Sprague-Dawley rats first received 10 days of cocaine self-administration training (2 h sessions), where active lever depression resulted in delivery of a ∼0.5 mg/kg cocaine infusion paired with a tone + light cue. Rats then underwent 10 days of forced abstinence, without access to cocaine or cocaine cues. Rats were then returned to the opertant chamber for the cue-induced cocaine-seeking test, where active lever depression in the original training context resulted in tone + light cue presentation. We found VTA specific or systemic isradipine administration robustly attenuated cocaine-seeking, without altering cocaine-taking nor natural reward seeking. Dopamine (DA) signaling in the nucleus accumbens (NAc) core is necessary and sufficient for cue-induced drug-seeking. Surprisingly in our study, isradipine enhanced tonic and phasic DA signaling in cocaine abstinent rats, with no change in sucrose abstinent nor naïve rats. Strikingly, isradipine's behavioral effects were dependent upon NAc core DA receptor activation. Together, our findings reveal a novel mechanism by which the FDA-approved drug, isradipine, could act to decrease cocaine relapse.