Cocaine-induced ischemia in prefrontal cortex is associated with escalation of cocaine intake in rodents

Du, Congwu; Volkow, Nora D.; You, Jiang; Park, Kicheon; Allen, Craig P.; Koob, George F.

doi:10.1038/s41380-018-0261-8

Cited by 24 publications

(23 citation statements)

References 52 publications

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“…This is consistent with our prior reports of cocaine-induced vasoconstriction and CBFv reduction in the anesthetized mouse brain (Ren et al, 2012, which occurred promptly post cocaine injection in this study and sustained for at least 30 min (Liu et al, 1993). Similarly, cocaine-induced ΔHbO 2 decreases in the anesthetized state are consistent in magnitude and dynamics with those we reported previously in anesthetized animals (Du et al, 2018). In contrast, in the awake state, cocaine did not change vessel diameter or hemodynamics until 15 min post cocaine at which time it increased ΔCBFv and ΔHbO 2 .…”

Section: Conclusion and Discussionsupporting

confidence: 93%

Hemodynamic and neuronal responses to cocaine differ in awake versus anesthetized animals: Optical brain imaging study

et al. 2019

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Cocaine is a highly addictive drug with complex pharmacological effects. Most preclinical imaging studies investigating the effects of cocaine in the brain have been performed under anesthesia, which confounds findings. To tackle this problem, we used optical imaging to compare the effects of cocaine in the awake versus the anesthetized state. For this purpose, we customized an air floating mobile cage to fit the multi-wavelength spectral and laser speckle optical imaging system and implanted a multi-layer cranial window over the mouse somatosensory cortex. Results showed significant differences in neuronal activity and hemodynamics at baseline and in response to cocaine between the awake and the anesthetized state (isoflurane anesthesia). Specifically, 1) at baseline isoflurane dilated cerebral vessels, increased cerebral blood flow and depressed neuronal Ca 2+ activity compared to the awake state; 2) acute cocaine (1 mg/kg iv) vasoconstricted blood vessels (arteries and veins) and decreased cerebral blood flow and oxygenated hemoglobin in the anesthetized state but not in the awake condition; 3) cocaine increased the accumulation of mean intracellular Ca 2+ in neurons in the anesthetized state but not in the awake condition; and 4) in the awake state acute cocaine increased neuronal activities (increased the frequency of Ca 2+ transients) and increased neuronal synchronization. We also corroborated that in the wake state cocaine also disrupted neurovascular coupling. These findings indicate that both vascular and neuronal responses to cocaine are influenced by isoflurane anesthesia, which highlights the importance of imaging awake animals when studying the effects of cocaine or other drugs in the brain.

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Section: Conclusion and Discussionsupporting

confidence: 93%

Hemodynamic and neuronal responses to cocaine differ in awake versus anesthetized animals: Optical brain imaging study

et al. 2019

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“…To investigate the molecular mechanisms that underlie interactions between HIV and METH, we performed gene expression profiling of the mPFC, which has been consistently implicated in craving and the escalation of drug taking (Du et al, 2018;George et al, 2008;Goldstein and Volkow, 2011). Here, we show that the increase in METH self-administration in HIV Tg rats under LgA conditions was associated with an increase in inflammation.…”

Section: Discussionmentioning

confidence: 83%

Increases in compulsivity, inflammation, and neural injury in HIV transgenic rats with escalated methamphetamine self-administration under extended-access conditions

Guglielmo

Chen

et al. 2020

Brain Research

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The abuse of stimulants, such as methamphetamine (METH), is associated with treatment noncompliance, a greater risk of viral transmission, and the more rapid clinical progression of immunological and central nervous system human immunodeficiency virus (HIV) disease. The behavioral effects of METH in the setting of HIV remain largely uncharacterized. We used a stateof-the-art paradigm of the escalation of voluntary intravenous drug self-administration in HIV transgenic (Tg) and wildtype rats. The rats were first allowed to self-administer METH under short-access (ShA) conditions, which is characterized by a nondependent and more "recreational" pattern of METH use, and then allowed to self-administer METH under long-access (LgA) conditions, which leads to compulsive (dependent) METH intake. HIV Tg and wildtype rats selfadministered equal amounts of METH under ShA conditions. HIV Tg rats under LgA METH selfadministration following a 4-week enforced abstinence period to model the intermittent pattern of stimulant abuse in humans, developed greater motivation to self-administer METH and selfadministered larger amounts of METH. Impairments in function of the medial prefrontal cortex (mPFC) contribute to compulsive drug and alcohol intake. Gene expression profiling of the mPFC

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“…Cocaine is one of the most addictive drugs and its use, which has expanded markedly in the past decade, is a major contributor of overdose fatalities in the United States [ 28 ]. 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 PFC contribute to impairments in executive function that facilitate compulsive drug taking [ 8 ]. In humans, chronic use of cocaine causes damages to the PFC disrupting CBF [ 5 ], metabolic activity [ 31 , 32 ], structure [ 33 , 34 ], function [ 35 , 36 ], and neurotransmission [ 37 – 39 ].…”

Section: Conclusion and Discussionmentioning

confidence: 99%

“…We had previously shown using a rodent model of chronic cocaine self-administration that animals that consumed high doses of cocaine showed sensitized responses to cocaine-induced vasoconstriction in PFC and the concomitant hypoxemia was associated with escalation of cocaine intake [ 8 ]. In this chronic model of cocaine administration that emulates human cocaine consumption, NIF pretreatment prevented cocaine’s vasoconstriction and neuronal [Ca 2+ ] i increases while decreasing cocaine intake and blocking reinstatement [ 8 ]. Here we expand these finding to show that NIF prevents cocaine-induced vasoconstriction and neuronal [Ca 2+ ] i accumulation, even in naive animals.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

“…The elevated intracellular [Ca 2+ ] i accumulation resulting from cocaine exposures is associated with its actions on L-type Ca 2+ channels (L-channels) [ 16 ]. Studies have shown that Ca 2+ antagonists can modify cocaine-induced behavioral effects including motor activity and reinforcement [ 8 , 17 ]. Acute cocaine abnormally increases Ca 2+ influx in cortical neurons [ 18 ], most likely via L-channels, whereas chronic cocaine up-regulates L-channels in pyramidal cortical neurons [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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

Park

Allen

et al. 2021

Transl Psychiatry

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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.

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Cocaine-induced ischemia in prefrontal cortex is associated with escalation of cocaine intake in rodents

Cited by 24 publications

References 52 publications

Hemodynamic and neuronal responses to cocaine differ in awake versus anesthetized animals: Optical brain imaging study

Hemodynamic and neuronal responses to cocaine differ in awake versus anesthetized animals: Optical brain imaging study

Increases in compulsivity, inflammation, and neural injury in HIV transgenic rats with escalated methamphetamine self-administration under extended-access conditions

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

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