Isradipine, an L-type calcium channel inhibitor, attenuates cue-associated methamphetamine-seeking in mice

Abstract

Methamphetamine (meth) is an addictive psychostimulant and there are no FDA-approved treatment options for patients suffering from meth use disorders. In addition to being addictive, meth is also neurotoxic and chronic administration results in degeneration of substantia nigra pars compacta (SNc) dopamine and locus coeruleus (LC) norepinephrine neurons in mice. Optimal treatment strategies for meth use disorders would attenuate maladaptive meth-seeking behavior as well as provide neuroprotection. The L-type calcium channel inhibitor isradipine and the monoamine oxidase (MAO) inhibitor rasagiline both prevent chronic meth-induced SNc and LC degeneration but effects on meth-seeking are unknown. To test whether these clinically available compounds can mitigate meth-seeking, mice were implanted with chronic indwelling jugular vein catheters and allowed to self-administer meth (0.1 mg/kg/infusion) for 10 consecutive days (2-hrs/day) on a fixed ratio (FR) 1 schedule of reinforcement with meth infusions paired to a cue light. One day after the last self-administration session mice were tested for cue-associated meth-seeking behavior wherein the meth-associated cue light was contingently presented but meth reinforcement withheld. Isradipine (3 mg/kg) attenuated cue-associated meth-seeking in both male and female mice. In contrast, rasagiline (1 mg/kg) had no effect on seeking in either sex. These results suggest that isradipine may have the potential to serve as a dual-purpose pharmacotherapy for meth use disorders by attenuating seeking behavior and providing neuroprotection.