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

Abstract

Cocaine profoundly affects both cerebral blood vessels and neuronal activity in the brain. The vasoconstrictive effects of cocaine, concurrently with its effects on neuronal [Ca²⁺]_i accumulation are likely to jeopardize neuronal tissue that in the prefrontal cortex (PFC) could contribute to impaired self-regulation and compulsive cocaine consumption. Here we used optical imaging to study the cerebrovascular and neuronal effects of acute cocaine (1 mg/kg i.v.) and to examine whether selective blockade of L-type Ca²⁺ channels by Nifedipine (NIF) (0.5 mg/kg i.v.) would alleviate cocaine's effects on hemodynamics (measured with cerebral blood volume, HbT), oxygenation (measured with oxygenated hemoglobin, HbO₂) and neuronal [Ca²⁺]_i, which were concomitantly measured in the PFC of naive rats. Our results show that in the PFC acute cocaine significantly reduced flow delivery (HbT), increased neuronal [Ca²⁺]_i accumulation and profoundly reduced tissue oxygenation (HbO₂) and these effects were significantly attenuated by NIF pretreatment. They also show that cocaine-induced vasoconstriction is distinct from its increase of neuronal [Ca²⁺]_i accumulation though both of them contribute to hypoxemia and both effects were attenuated by NIF. These results provide evidence that blockade of voltage-gated L-type Ca²⁺ channels might be beneficial in preventing vasoconstriction and neurotoxic effects of cocaine and give support for further clinical investigations to determine their value in reducing cocaine's neurotoxicity in cocaine use disorders.