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

Abstract

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.

Ca2+ channel blockade reduces cocaine’s vasoconstriction and neurotoxicity in the prefrontal cortex

“…Cocaine’s vasoconstriction effects are likely to reflect its sympathomimetic effects but its effects on L-type Ca channel’s function in blood vessels are also likely to contribute [ 58 ]. The mechanisms responsible for neuronal [Ca 2+ ] i accumulation are also likely to involve cocaine’s effects on L-type [Ca 2+ ] i channels in neurons, which are disrupted with chronic exposures [ 42 , 44 ].…”

“…Our findings have clinical implication for they provide further evidence of the potential of L-type Ca-channel blockers for the treatment of cocaine use disorders. Further preclinical evidence is expanding on the beneficial effects of L-type Ca-channel blockers in preventing cocaine intake and relapse [ 17 , 58 , 60 , 61 ]. To the extent that L-type Ca-channel blockers also block cocaine-induced vasoconstriction in the myocardium [ 62 , 63 ], they could also help prevent cocaine’s lethality.…”

Differential regulation of phasic dopamine release in the forebrain by the VTA noradrenergic receptor signaling

“…; Addy et al . ). Each trace consisted of 15 s of recording, with stimulation being performed at t = 5 s. Peak current associated with electrical stimulation of the VTA was recorded.…”

“…For evoking dopamine release, the VTA was stimulated with a biphasic square waveform (300 lA; 2 ms per phase; 24 pulses) with 60 Hz frequency corresponding to 'phasic' and 5 Hz corresponding to 'tonic' activity. Stimulation at 60 and 5 Hz has been shown to elicit markedly different responses in the forebrain, with 60 Hz stimulation evoking DA levels rising sharply over time proportionally to the number of pulses delivered, while 5 Hz stimulation causing a prolonged, but not elevated, response over time in the form of increased DAergic tone as opposed to a sharp stimulationevoked transient (Koranda et al 2014;Addy et al 2018). Each trace consisted of 15 s of recording, with stimulation being performed at t = 5 s. Peak current associated with electrical stimulation of the VTA was recorded.…”

Isradipine enhancement of virtual reality cue exposure for smoking cessation: Rationale and study protocol for a double-blind randomized controlled trial

“…The analytic plan for the primary outcome depends on several assumptions that will be checked prior to breaking the blind using dummy coded group labels (e.g., A vs. B). Although isradipine administration has demonstrated acute effects on cocaine-seeking behavior in rats after prolonged abstinence [51], an acute effect was not observed in the extinction of conditioned place preference in rats [11]. Given our experiment is modeled after the latter preclinical research, we are not predicting an acute effect of isradipine on session 1 craving.…”