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Toxins Apr 2022Cocaine is one of the most consumed stimulants throughout the world, as official sources report. It is a naturally occurring sympathomimetic tropane alkaloid derived... (Review)
Review
Cocaine is one of the most consumed stimulants throughout the world, as official sources report. It is a naturally occurring sympathomimetic tropane alkaloid derived from the leaves of , which has been used by South American locals for millennia. Cocaine can usually be found in two forms, cocaine hydrochloride, a white powder, or 'crack' cocaine, the free base. While the first is commonly administered by insufflation ('snorting') or intravenously, the second is adapted for inhalation (smoking). Cocaine can exert local anaesthetic action by inhibiting voltage-gated sodium channels, thus halting electrical impulse propagation; cocaine also impacts neurotransmission by hindering monoamine reuptake, particularly dopamine, from the synaptic cleft. The excess of available dopamine for postsynaptic activation mediates the pleasurable effects reported by users and contributes to the addictive potential and toxic effects of the drug. Cocaine is metabolised (mostly hepatically) into two main metabolites, ecgonine methyl ester and benzoylecgonine. Other metabolites include, for example, norcocaine and cocaethylene, both displaying pharmacological action, and the last one constituting a biomarker for co-consumption of cocaine with alcohol. This review provides a brief overview of cocaine's prevalence and patterns of use, its physical-chemical properties and methods for analysis, pharmacokinetics, pharmacodynamics, and multi-level toxicity.
Topics: Cocaine; Dopamine; Ethanol
PubMed: 35448887
DOI: 10.3390/toxins14040278 -
ACS Chemical Neuroscience Oct 2018In this Review, we consider the story of cocaine from its humble origins in South America to its status as one of the most abused substances in 21st century society. The... (Review)
Review
In this Review, we consider the story of cocaine from its humble origins in South America to its status as one of the most abused substances in 21st century society. The synthesis and biosynthesis of cocaine are discussed, as well as its pharmacokinetics, metabolism, pharmacology, and importance in modern neuroscience and molecular imaging.
Topics: Cocaine; Crack Cocaine; Dopamine Uptake Inhibitors; History, 19th Century; History, 20th Century; History, 21st Century; Humans
PubMed: 29630337
DOI: 10.1021/acschemneuro.8b00117 -
Molecular Psychiatry Jan 2022Cocaine craving, seeking, and relapse are mediated, in part, by cocaine-induced adaptive changes in the brain reward circuits. The nucleus accumbens (NAc) integrates and... (Review)
Review
Cocaine craving, seeking, and relapse are mediated, in part, by cocaine-induced adaptive changes in the brain reward circuits. The nucleus accumbens (NAc) integrates and prioritizes different emotional and motivational inputs to the reward system by processing convergent glutamatergic projections from the medial prefrontal cortex, basolateral amygdala, ventral hippocampus, and other limbic and paralimbic brain regions. Medium spiny neurons (MSNs) are the principal projection neurons in the NAc, which can be divided into two major subpopulations, namely dopamine receptor D1- versus D2-expressing MSNs, with complementing roles in reward-associated behaviors. After cocaine experience, NAc MSNs exhibit complex and differential adaptations dependent on cocaine regimen, withdrawal time, cell type, location (NAc core versus shell), and related input and output projections, or any combination of these factors. Detailed characterization of these cellular adaptations has been greatly facilitated by the recent development of optogenetic/chemogenetic techniques combined with transgenic tools. In this review, we discuss such cell type- and projection-specific adaptations induced by cocaine experience. Specifically, (1) D1 and D2 NAc MSNs frequently exhibit differential adaptations in spinogenesis, glutamatergic receptor trafficking, and intrinsic membrane excitability, (2) cocaine experience differentially changes the synaptic transmission at different afferent projections onto NAc MSNs, (3) cocaine-induced NAc adaptations exhibit output specificity, e.g., being different at NAc-ventral pallidum versus NAc-ventral tegmental area synapses, and (4) the input, output, subregion, and D1/D2 cell type may together determine cocaine-induced circuit plasticity in the NAc. In light of the projection- and cell-type specificity, we also briefly discuss ensemble and circuit mechanisms contributing to cocaine craving and relapse after drug withdrawal.
Topics: Cocaine; Hippocampus; Neurons; Nucleus Accumbens; Synapses
PubMed: 33963288
DOI: 10.1038/s41380-021-01112-2 -
Postgraduate Medical Journal Sep 2005Cocaine is the second commonest illicit drug used and the most frequent cause of drug related deaths. Its use is associated with both acute and chronic complications... (Review)
Review
Cocaine is the second commonest illicit drug used and the most frequent cause of drug related deaths. Its use is associated with both acute and chronic complications that may involve any system, the most common being the cardiovascular system. Cocaine misuse has a major effect in young adult drug users with resulting loss of productivity and undue morbidity with cocaine related cardiac and cerebrovascular effects. Many cocaine users have little or no idea of the risks associated with its use. Patients, health care professionals, and the public should be educated about the dangers and the considerable risks of cocaine use. This review concentrates on the cardiovascular effects of cocaine and their management.
Topics: Adolescent; Adult; Aortic Dissection; Aortic Aneurysm; Cocaine; Cocaine-Related Disorders; Heart Diseases; Humans; Risk Factors; Stroke
PubMed: 16143686
DOI: 10.1136/pgmj.2004.028571 -
International Journal of Molecular... May 2022The dynamic balance of mitochondrial fission and fusion maintains mitochondrial homeostasis and optimal function. It is indispensable for cells such as neurons, which... (Review)
Review
The dynamic balance of mitochondrial fission and fusion maintains mitochondrial homeostasis and optimal function. It is indispensable for cells such as neurons, which rely on the finely tuned mitochondria to carry out their normal physiological activities. The potent psychostimulant cocaine impairs mitochondria as one way it exerts its neurotoxicity, wherein the disturbances in mitochondrial dynamics have been suggested to play an essential role. In this review, we summarize the neurotoxicity of cocaine and the role of mitochondrial dynamics in cellular physiology. Subsequently, we introduce current findings that link disturbed neuronal mitochondrial dynamics with cocaine exposure. Finally, the possible role and potential therapeutic value of mitochondrial dynamics in cocaine neurotoxicity are discussed.
Topics: Cocaine; Homeostasis; Mitochondria; Mitochondrial Dynamics; Neurons
PubMed: 35628228
DOI: 10.3390/ijms23105418 -
Communications Biology Sep 2022Human and animal studies have reported widespread reductions in cerebral blood flow associated with chronic cocaine exposures. However, the molecular and cellular...
Human and animal studies have reported widespread reductions in cerebral blood flow associated with chronic cocaine exposures. However, the molecular and cellular mechanisms underlying cerebral blood flow reductions are not well understood. Here, by combining a multimodal imaging platform with a genetically encoded calcium indicator, we simultaneously measured the effects of acute cocaine on neuronal and astrocytic activity, tissue oxygenation, hemodynamics and vascular diameter changes in the mouse cerebral cortex. Our results showed that cocaine constricted blood vessels (measured by vessel diameter Φ changes), decreasing cerebral total blood volume (HbT) and temporally reducing tissue oxygenation. Cellular imaging showed that the mean astrocytic Ca dependent fluorescence [Formula: see text] increase in response to cocaine was weaker but longer lasting than the mean neuronal Ca dependent fluorescence [Formula: see text] changes. Interestingly, while cocaine-induced [Formula: see text] increase was temporally correlated with tissue oxygenation change, the [Formula: see text] elevation after cocaine was in temporal correspondence with the long-lasting decrease in arterial blood volumes. To determine whether the temporal association between astrocytic activation and cocaine induced vasoconstriction reflected a causal association we inhibited astrocytic Ca using GFAP-DREADD(Gi). Inhibition of astrocytes attenuated the vasoconstriction resulting from cocaine, providing evidence that astrocytes play a critical role in cocaine's vasoconstrictive effects in the brain. These results indicate that neurons and astrocytes play different roles in mediating neurovascular coupling in response to cocaine. Our findings implicate neuronal activation as the main driver of the short-lasting reduction in tissue oxygenation and astrocyte long-lasting activation as the driver of the persistent vasoconstriction with cocaine. Understanding the cellular and vascular interaction induced by cocaine will be helpful for future putative treatments to reduce cerebrovascular pathology from cocaine use.
Topics: Animals; Astrocytes; Cerebrovascular Circulation; Cocaine; Cocaine-Related Disorders; Humans; Mice; Vasoconstriction
PubMed: 36097038
DOI: 10.1038/s42003-022-03877-w -
Postgraduate Medical Journal Jun 2007Stroke is the third most common cause of death in developed countries. In England and Wales, 1000 people under the age of 30 have a stroke each year. Cocaine is the most... (Review)
Review
Stroke is the third most common cause of death in developed countries. In England and Wales, 1000 people under the age of 30 have a stroke each year. Cocaine is the most commonly used class A drug, and the first report of cocaine-induced stroke was in 1977. Since the development of alkaloidal "crack" cocaine in the 1980s, there has been a significant rise in the number of case reports describing both ischaemic and haemorrhagic stroke associated with cocaine use. Cocaine is a potent central nervous system stimulant, and acts by binding to specific receptors at pre-synaptic sites preventing the reuptake of neurotransmitters. The exact mechanism of cocaine-induced stroke remains unclear and there are likely to be a number of factors involved including vasospasm, cerebral vasculitis, enhanced platelet aggregation, cardioembolism, and hypertensive surges associated with altered cerebral autoregulation. The evidence surrounding each of these factors will be considered here.
Topics: Animals; Cocaine; Cocaine-Related Disorders; Endothelin-1; Humans; Stroke; Vasospasm, Intracranial
PubMed: 17551070
DOI: 10.1136/pgmj.2006.055970 -
Biology of Sex Differences Jun 2023The development and persistence of addiction is mediated in part by drug-induced alterations in nucleus accumbens (NAc) function. AMPA-type glutamate receptors (AMPARs)...
BACKGROUND
The development and persistence of addiction is mediated in part by drug-induced alterations in nucleus accumbens (NAc) function. AMPA-type glutamate receptors (AMPARs) provide the main source of excitatory drive to the NAc and enhancements in transmission of calcium-permeable AMPARs (CP-AMPARs) mediate increased cue-triggered drug-seeking following prolonged withdrawal. Cocaine treatment regimens that result in psychomotor sensitization enhance subsequent drug-seeking and drug-taking behaviors. Furthermore, cocaine-induced locomotor sensitization followed by 14 days of withdrawal results in an increase in glutamatergic synaptic transmission. However, very few studies have examined cocaine-induced alterations in synaptic transmission of females or potential effects of experimenter-administered cocaine on NAc CP-AMPAR-mediated transmission in either sex.
METHODS
Male and female rats were given repeated systemic cocaine injections to induce psychomotor sensitization (15 mg/kg, i.p. 1 injection/day, 8 days). Controls received repeated saline (1 mL/kg, i.p). After 14-16 days of withdrawal brain slices were prepared and whole-cell patch-clamp approaches in the NAc core were used to measure spontaneous excitatory post-synaptic currents (sEPSC), paired pulse ratio, and CP-AMPAR transmission. Additional female rats from this same cohort were also given a challenge injection of cocaine at withdrawal day 14 to assess the expression of sensitization.
RESULTS
Repeated cocaine produced psychomotor sensitization in both sexes. In males this was accompanied by an increase in sEPSC frequency, but not amplitude, and there was no effect on the paired pulse ratio. Males treated with cocaine and saline had similar sensitivity to Naspm. In contrast, in females there were no significant differences between cocaine and saline groups on any measure, despite females showing robust psychomotor sensitization both during the induction and expression phase.
CONCLUSIONS
Overall, these data reveal striking sex differences in cocaine-induced NAc glutamate plasticity that accompany the induction of psychomotor sensitization. This suggests that the neural adaptations that contribute to sensitization vary by sex.
Topics: Female; Rats; Male; Animals; Cocaine; Nucleus Accumbens; Rats, Sprague-Dawley; Glutamic Acid; Synaptic Transmission; Receptors, AMPA
PubMed: 37355656
DOI: 10.1186/s13293-023-00525-8 -
Annals of Palliative Medicine Jun 2021Cocaine abuse is a serious global public health and social problem, and cocaine detoxification remains a challenge. Benzoylecgonine (BE) is the main toxic metabolite... (Review)
Review
Cocaine abuse is a serious global public health and social problem, and cocaine detoxification remains a challenge. Benzoylecgonine (BE) is the main toxic metabolite after cocaine consumption, with a longer retention time in the body and environment than cocaine itself. According to many studies, the toxicity of BE to humans is as significant as cocaine itself. Moreover, BE is recognized as an addictive drug contaminant in the environment, especially the freshwater system, leading to worries of its ecotoxicity. Extensive studies on the adverse effects of BE on both humans and ecology have been conducted, showing a marked sub-lethal toxicity of BE to diverse organisms. To eliminate BE in vivo and in vitro, various elimination methods have been developed and their BE removal capacity were evaluated. In this review, we aimed to summarize information in the literature to understand better BE toxicity and elimination that may facilitate the clinical treatment of cocaine abuse. By studying the critical role of BE in cocaine abuse, we propose that the ideal treatment for cocaine abuse should not only detoxify cocaine itself but also remove or degrade BE. Emphasizing the necessity of developing effective BE elimination methods is significant for the development of potential clinical treatments and environmental protections.
Topics: Cocaine; Humans
PubMed: 34118862
DOI: 10.21037/apm-21-243 -
Neuropsychopharmacology : Official... Aug 2013Cocaine has actions in the peripheral nervous system that reliably precede--and thus predict--its soon-to-follow central rewarding effects. In cocaine-experienced...
Cocaine has actions in the peripheral nervous system that reliably precede--and thus predict--its soon-to-follow central rewarding effects. In cocaine-experienced animals, the peripheral cocaine signal is relayed to the central nervous system, triggering excitatory input to the ventral tegmental origin of the mesocorticolimbic dopamine system, the system that mediates the rewarding effects of the drug. We used cocaine methiodide, a cocaine analog that does not cross the blood-brain barrier, to isolate the peripheral actions of cocaine and determine their central and behavioral effects in animals first trained to lever-press for cocaine hydrochloride (the centrally acting and abused form of the drug). We first confirmed with fast-scan cyclic voltammetry that cocaine methiodide causes rapid dopamine release from dopamine terminals in cocaine hydrochloride-trained rats. We then compared the ability of cocaine hydrochloride and cocaine methiodide to establish conditioned place preferences in rats with self-administration experience. While cocaine hydrochloride established stronger place preferences, cocaine methiodide was also effective and its effectiveness increased (incubated) over weeks of cocaine abstinence. Cocaine self-administration was extinguished when cocaine methiodide or saline was substituted for cocaine hydrochloride in the intravenous self-administration paradigm, but cocaine hydrochloride and cocaine methiodide each reinstated non-rewarded lever-pressing after extinction. Rats extinguished by cocaine methiodide substitution showed weaker cocaine-induced reinstatement than rats extinguished by saline substitution. These findings suggest that the conditioned peripheral effects of cocaine can contribute significantly to cocaine-induced (but not stress-induced) cocaine craving, and also suggest the cocaine cue as an important target for cue-exposure therapies for cocaine addiction.
Topics: Animals; Cocaine; Conditioning, Operant; Conditioning, Psychological; Dopamine; Drug-Seeking Behavior; Extinction, Psychological; Male; Nucleus Accumbens; Rats; Reward; Self Administration
PubMed: 23535778
DOI: 10.1038/npp.2013.75