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.
Highlights
Cocaine is a highly addictive drug and one associated with significant neurotoxicity, including cerebral strokes, transient ischemic attacks as well as seizures [1,2,3,4]
We showed that in rodents chronically exposed to cocaine, an acute dose of cocaine triggered a long lasting reduction in cerebral blood flow (CBF) and persistent increases in deoxygenated hemoglobin ([HbR]) and in intracellular calcium concentrations ([Ca2+]i), which we measured in the somatosensory cortex and that were associated with behavioral manifestations of temporal paralysis [14, 15]
While cocaine’s dopamine-enhancing properties are believed to underlie its rewarding and addictive effects, its vasoconstrictive effects [29] alongside neuronal Ca accumulation [11, 24] and disruption of neurovascular coupling [30] are likely to damage neuronal tissue and in the prefrontal cortex (PFC) contribute to impairments in executive function that facilitate compulsive drug taking [8]
Summary
Cocaine is a highly addictive drug and one associated with significant neurotoxicity, including cerebral strokes, transient ischemic attacks as well as seizures [1,2,3,4]. The mechanisms associated with cocaine-induced CBF reductions and ischemia are not well understood, but may result from direct vasoconstriction elicited by cocaine-induced [Ca2+]i increases in vascular smooth muscle cells [10] and/or by parallel increases in neuronal activity that exacerbate tissue hypoxemia [11]. We showed that in rodents chronically exposed to cocaine, an acute dose of cocaine triggered a long lasting reduction in CBF and persistent increases in deoxygenated hemoglobin ([HbR]) and in intracellular calcium concentrations ([Ca2+]i), which we measured in the somatosensory cortex and that were associated with behavioral manifestations of temporal paralysis [14, 15]. Acute cocaine triggered vasoconstriction and ischemia in naive rats but these effects were shorter lasting than in the chronically exposed rats suggesting sensitization with repeated exposure. Cocaine’s vascular effects and its ability to increase neuronal [Ca2+]i is likely to contribute to its neurotoxicity
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