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.

Memantine Attenuates Cocaine and neuroHIV Neurotoxicity in the Medial Prefrontal Cortex

“…Consistent with our previous findings, when drug-naïve rats were exposed to cocaine, there was a rapid increase in calcium concentration in neurons in PFC ( Allen et al, 2019 ; Du et al, 2021 ), especially in glutamatergic pyramidal neurons ( Nasif et al, 2005a ; Nasif et al, 2005b ; Ford et al, 2009 ; Napier et al, 2014 ; Wayman et al, 2015 ; Wayman et al, 2016 ). Excessive calcium influx could be one of the triggers for excitotoxicity that contributes to dysregulation, injury, and ultimately loss of cortical neurons in mice and rats treated chronically with cocaine ( Olney et al, 1991 ; George et al, 2008 ; Clare et al, 2021 ).…”

“…Pretreatment of both non-Tg and HIV-1 Tg rats with memantine significantly reduced the differences in cocaine response between them, suggesting that NMDAR blockade may blunt neuroHIV-associated PFC neuronal hyper-reactivity that is enhanced further by cocaine. Importantly, this result is similar to findings in our earlier studies, showing that the blockade of voltage-gated L-type calcium channels (L-channels) significantly reduces cocaine- and/or neuroHIV-induced PFC neuronal calcium and hemodynamic dysregulation ( Nasif et al, 2005b ; Ford et al, 2009 ; Khodr et al, 2016 ; Wayman et al, 2016 ; Du et al, 2021 ).…”

“…To compare cocaine’s effect on PFC with and without NMDA blockade by memantine in the same animal, we administered cocaine twice, first following the vehicle and then after MEM pretreatment (expt 2, Table 1 ). To minimize the effects of remaining cocaine from the first injection on the response of the second cocaine injection, we waited 2 h between infusions ( Du et al, 2021 ).…”

“…From full-field images, we selected the hemisphere in which GCaMP6f was injected and expressed ( Supplementary Figures S2, S3 ). ROIs were then positioned in regions along the periphery of the GCaMP6f expression and were placed to avoid vasculature, as described in our previous publications ( Allen et al, 2019 ; Du et al, 2020 ; Du et al, 2021 ; Park et al, 2022 ). This ROI positioning criterion was used to minimize the risk of GCaMP6f overexposure following cocaine administration as well as to prevent confounding effects of hemodynamic changes on the measured [Ca 2+ ] i fluorescent signal.…”

“…Like HAND, preclinical models of cocaine use disorders (CUDs) showed that cocaine alone led to neuronal calcium dysregulation in brain tissues as well as hypoxemia in the PFC ( Allen et al, 2019 ; Du et al, 2021 ). In combination with the dysregulation of voltage-gated L-type Ca 2+ channels ( Nasif et al, 2005a ; Nasif et al, 2005b ; Ford et al, 2009 ; Napier et al, 2014 ; Wayman et al, 2015 ; Wayman et al, 2016 ), NMDA receptors are also pivotal in the development of addictive behaviors and neural adaptations that are mediated by neuronal Ca 2+ dysregulation.…”