Isradipine, an L-type calcium channel blocker, attenuates cocaine effects in mice by reducing central glutamate release.

ABSTRACT

Substance abuse disorder is a chronic condition for which pharmacological treatment options remain limited. L-type calcium channels (LTCC) have been implicated in drug-related plasticity and behavior. Specifically, dopaminergic neurons in the mesocorticolimbic pathway express Cav1.2 and Cav1.3 channels, which may regulate dopaminergic activity associated with reward behavior. Therefore, this study aimed to investigate the hypothesis that pre-administration of the LTCC blocker, isradipine can mitigate the effects of cocaine by modulating central glutamatergic transmission. For that, we administered isradipine at varying concentrations (1, 7.5, and 15 µg/µL) via intracerebroventricular injection in male Swiss mice. This pretreatment was carried out prior to subjecting animals to behavioral assessments to evaluate cocaine-induced locomotor sensitization and conditioned place preference (CPP). The results revealed that isradipine administered at a concentration of 1 µg/µL effectively attenuated both the sensitization and CPP induced by cocaine (15 mg/kg, via i. p.). Moreover, mice treated with 1 µg/µL of isradipine showed decreased presynaptic levels of glutamate and calcium in the cortex and hippocampus as compared to control mice following cocaine exposure. Notably, the gene expression of ionotropic glutamate receptors, AMPA, and NMDA, remained unchanged, as did the expression of Cav1.2 and Cav1.3 channels. Importantly, these findings suggest that LTCC blockage may inhibit behavioral responses to cocaine, most likely by decreasing glutamatergic input in areas related to addiction.