Cocaine in high concentrations inhibits platelet aggregation in vitro

Cagienard, F; Schulzki, T.; Reinhart, Walter H.

doi:10.3233/ch-131795

Cited by 4 publications

(1 citation statement)

References 30 publications

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“…In humans, neuropsychiatric complications are evident in approximately 60% of cocaine users including depression, suicidal ideation, paranoia, kleptomania, and catatonia. Cocaine use disorder also leads to a series of neurological disorders such as seizures, optic neuropathy, cerebral infarction, subarachnoid and intracerebral hemorrhage, multifocal cerebral ischemia, and cerebral atrophy, as well as cardiac dysfunction including myocardial infarction triggering global brain ischemia and edema (Moorman et al., 2013; Bodmer et al., 2014; Cagienard et al., 2014; Sharma et al., 2014; Sordo et al., 2014). Despite this broad foundation of clinical knowledge, the detailed mechanisms underlying cocaine-induced effects in the brain remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Cocaine Directly Inhibits α6-Containing Nicotinic Acetylcholine Receptors in Human SH-EP1 Cells and Mouse VTA DA Neurons

Chen

Gao

et al. 2019

Front. Pharmacol.

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Alpha6-containing nicotinic acetylcholine receptors are primarily found in neurons of the midbrain dopaminergic (DA) system, suggesting these receptors are potentially involved in drug reward and dependence. Here, we report a novel effect that cocaine directly inhibits α6N/α3Cβ2β3-nAChR (α6*-nAChRs) function. Human α6*-nAChRs were heterologously expressed within cells of the SH-EP1 cell line for functional characterization. Mechanically dissociated DA neurons from mouse ventral tegmental area (VTA) were used as a model of presynaptic α6*-nAChR activation since this method preserves terminal boutons. Patch-clamp recordings in whole-cell configuration were used to measure α6*-nAChR function as well as evaluate the effects of cocaine. In SH-EP1 cells containing heterologously expressed human α6*-nAChRs, cocaine inhibits nicotine-induced inward currents in a concentration-dependent manner with an IC 50 value of 30 μM. Interestingly, in the presence of 30 μM cocaine, the maximal current response of the nicotine concentration-response curve is reduced without changing nicotine’s EC 50 value, suggesting a noncompetitive mechanism. Furthermore, analysis of whole-cell current kinetics demonstrated that cocaine slows nAChR channel activation but accelerates whole-cell current decay time. Our findings demonstrate that cocaine-induced inhibition occurs solely with bath application, but not during intracellular administration, and this inhibition is not use-dependent. Additionally, in Xenopus oocytes, cocaine inhibits both α6N/α3Cβ2β3-nAChRs and α6M211L/α3ICβ2β3-nCAhRs similarly, suggesting that cocaine may not act on the α3 transmembrane domain of chimeric α6N/α3Cβ2β3-nAChR. In mechanically isolated VTA DA neurons, cocaine abolishes α6*-nAChR-mediated enhancement of spontaneous inhibitory postsynaptic currents (sIPSCs). Collectively, these studies provide the first evidence that cocaine directly inhibits the function of both heterologously and naturally expressed α6*-nAChRs. These findings suggest that α6*-nAChRs may provide a novel pharmacological target mediating the effects of cocaine and may underlie a novel mechanism of cocaine reward and dependence.

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Section: Introductionmentioning

confidence: 99%

Cocaine Directly Inhibits α6-Containing Nicotinic Acetylcholine Receptors in Human SH-EP1 Cells and Mouse VTA DA Neurons

Chen

Gao

et al. 2019

Front. Pharmacol.

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A Comprehensive View of the Neurotoxicity Mechanisms of Cocaine and Ethanol

2015

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Substance use disorder is an emerging problem concerning to human health, causing severe side effects, including neurotoxicity. The use of illegal drugs and the misuse of prescription or over-the-counter drugs are growing in this century, being one of the major public health problems. Ethanol and cocaine are one of the most frequently used drugs and, according to the National Institute on Drug Abuse, their concurrent consumption is one of the major causes for emergency hospital room visits. These molecules act in the brain through different mechanisms, altering the nervous system function. Researchers have focused the attention not just in the mechanism of action of these drugs, but also in the mechanism by which they damage the nervous tissue (neurotoxicity). Therefore, the goal of the present review is to provide a global perspective about the mechanisms of the neurotoxicity of cocaine and ethanol.

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Toxicity/Substance Abuse

Sweis

Biller

2017

Primer on Cerebrovascular Diseases

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Cocaine in high concentrations inhibits platelet aggregation in vitro

Cited by 4 publications

References 30 publications

Cocaine Directly Inhibits α6-Containing Nicotinic Acetylcholine Receptors in Human SH-EP1 Cells and Mouse VTA DA Neurons

Cocaine Directly Inhibits α6-Containing Nicotinic Acetylcholine Receptors in Human SH-EP1 Cells and Mouse VTA DA Neurons

A Comprehensive View of the Neurotoxicity Mechanisms of Cocaine and Ethanol

Toxicity/Substance Abuse

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