• DOI:10.1038/s41386-018-0116-7
• Corpus ID: 49426201

Harmony and heresy of an L-type calcium channel inhibitor: suppression of cocaine seeking via increased dopamine transmission in the nucleus accumbens

@article{SwinfordJackson2018HarmonyAH,
  title={Harmony and heresy of an L-type calcium channel inhibitor: suppression of cocaine seeking via increased dopamine transmission in the nucleus accumbens},
  author={Sarah E. Swinford-Jackson and R. Christopher Pierce},
  journal={Neuropsychopharmacology},
  year={2018},
  volume={43},
  pages={2335-2336}
}

• S. E. Swinford-Jackson, R. Pierce
• Published 9 June 2018
• Biology, Psychology
• Neuropsychopharmacology

Cocaine addiction exacts devastating personal, societal, and economic costs. However, despite decades of research and numerous clinical trials, FDA approved treatments for cocaine use disorder are nonexistent. Given these failures, a potentially efficient strategy for identifying effective treatments for cocaine addiction is to repurpose pharmacotherapies that have already been FDA approved for other indications. This approach is particularly advantageous when existing preclinical and/or clinical research supports the mechanism of the FDA approved drug as a modulator of cocaine-related behaviors. One example is drugs targeting L-type calcium channels (LTCC), which have been implicated in a number of neuropsychiatric disorders including drug addiction [1]. In rodent models, blockade of LTCCs has been shown to attenuate cocaine reinforcement [2] as well as the reinstatement of cocaine seeking [3], an animal model of relapse. In this issue of Neuropsychopharmacology, Addy et al. [4] explored the LTCC inhibitor isradipine (DynaCirc, Prescal), which is FDA approved for the treatment of hypertension, as a potential modulator of relapse-like behavior. In their model, rats were trained to self-administer cocaine and evaluated for cocaine cueevoked drug seeking following 10 days of forced abstinence. Systemic or intra-ventral tegmental area (VTA) administration of isradipine attenuated cocaine reinstatement. The current work also showed, importantly, that intra-VTA isradipine did not alter sucrose seeking, suggesting that the ability of this drug to suppress cocaine seeking is at least somewhat reinforcer specific and not due to general motor impairment. Interestingly, delivery of isradipine into the VTA immediately prior to a cocaine selfadministration session did not alter cocaine intake. To interpret these preclinical data in terms of translational potential, the LTCC inhibitor isradipine may help prevent cocaine relapse but apparently would not be efficacious as a cessation aid during periods of active drug taking. The mechanism(s) by which isradipine modulates cocaine seeking are not known, but one prominent mediator of cueelicited cocaine seeking is dopamine signaling. A substantial literature indicates that increased dopamine transmission in the nucleus accumbens promotes cocaine seeking [5] and LTCC inhibitors, either directly or indirectly, suppress dopamine transmission [6, 7]. Addy et al. [4] used fast scan cyclic voltammetry to measure phasic and tonic dopamine release in the nucleus accumbens of rats that experienced identical selfadministration training and forced abstinence as those evaluated for cocaineor sucrose seeking behavior. Surprisingly, intra-VTA administration of the same dose of isradipine that suppressed cocaine seeking actually increased phasic dopamine release relative to vehicle-treated rats. That is, in striking contradiction to cocaine reinstatement dogma, isradipine appears to attenuate cocaine seeking by enhancing phasic dopamine release in the accumbens. Tonic dopamine release in the nucleus accumbens also was higher after intra-VTA infusion of isradipine, even when factoring in the decreased tonic dopamine release induced by isradipine’s ethanol vehicle. Systemic administration of isradipine recapitulated the increase in both tonic and phasic dopamine release in the accumbens, but it is unclear whether this effect was solely mediated by LTCCs in the VTA or may have been modulated by LTCCs localized to other regions. Nonetheless, Addy et al. [4] further showed that the effect of systemic isradipine on cocaine reinstatement was due to increased dopamine release in the nucleus accumbens because isradipine failed to alter cocaine seeking in rats that received intra-accumbens infusion of flupenthixol, a dopamine receptor antagonist. Flupenthixol alone dose-dependently attenuates cocaine seeking, so the authors chose a dose of flupenthixol that did not alter cocaine seeking relative to vehicle. The effectiveness of a sub-threshold dose of flupenthixol to block the suppression of cocaine seeking by isradipine, particularly when dopamine release is elevated, raises a number of interesting questions about the expression and signaling of dopamine receptors during cocaine abstinence. An important caveat of these experiments is that dopamine release was measured in anesthetized rats; it will be essential to determine if the effects of isradipine on dopamine release remain consistent when assessed in awake, freely-moving rats and to measure dopamine release in the presence of cocaine-paired cues. Unlike many prior studies, which interrogated dopamine signaling in the context of reinstated drug seeking following extinction training, Addy et al. [4] assessed cocaine seeking following 10 days of forced abstinence. This is best characterized as an intermediate period of abstinence in which cue-evoked cocaine seeking is higher than immediately after cessation of cocaine-taking but is still not maximal, as seen at longer abstinence periods [8]. This well-described phenomenon, termed the incubation of cocaine craving, is known to be accompanied by myriad time-dependent changes in messenger RNA (mRNA) and protein expression [9], of which new potential mechanisms and/or targets are continuously being identified. It is conceivable that dopamine tone (not measured in this study) is modified during intermediate