Butyrylcholinesterase is a serine hydrolase that catalyzes the hydrolysis of esters in the body. Unlike its sister enzyme acetylcholinesterase, butyrylcholinesterase has a broad substrate scope and ...lower acetylcholine catalytic efficiency. The difference in tissue distribution and inhibitor sensitivity also points to its involvement external to cholinergic neurotransmission. Initial studies on butyrylcholinesterase showed that the inhibition of the enzyme led to the increment of brain acetylcholine levels. Further gene knockout studies suggested its involvement in the regulation of amyloid-beta, a brain pathogenic protein. Thus, it is an interesting target for neurological disorders such as Alzheimer's disease. The substrate scope of butyrylcholinesterase was recently found to include cocaine, as well as ghrelin, the "hunger hormone". These findings led to the development of recombinant butyrylcholinesterase mutants and viral gene therapy to combat cocaine addiction, along with in-depth studies on the significance of butyrylcholinesterase in obesity. It is observed that the pharmacological impact of butyrylcholinesterase increased in tandem with each reported finding. Not only is the enzyme now considered an important pharmacological target, it is also becoming an important tool to study the biological pathways in various diseases. Here, we review and summarize the biochemical properties of butyrylcholinesterase and its roles, as a cholinergic neurotransmitter, in various diseases, particularly neurodegenerative disorders.
We did a global review to synthesise data on the prevalence, harms, and interventions for stimulant use, focusing specifically on the use of cocaine and amphetamines. Modelling estimated the effect ...of cocaine and amphetamine use on mortality, suicidality, and blood borne virus incidence. The estimated global prevalence of cocaine use was 0·4% and amphetamine use was 0·7%, with dependence affecting 16% of people who used cocaine and 11% of those who used amphetamine. Stimulant use was associated with elevated mortality, increased incidence of HIV and hepatitis C infection, poor mental health (suicidality, psychosis, depression, and violence), and increased risk of cardiovascular events. No effective pharmacotherapies are available that reduce stimulant use, and the available psychosocial interventions (except for contingency management) had a weak overall effect. Generic approaches can address mental health and blood borne virus infection risk if better tailored to mitigate the harms associated with stimulant use. Substantial and sustained investment is needed to develop more effective interventions to reduce stimulant use.
Cocaine users consistently display cognitive impairments. However, it is still unknown whether these impairments are cocaine-induced and if they are reversible. Therefore, we examined the relation ...between changing intensity of cocaine use and the development of cognitive functioning within 1 year. The present data were collected as part of the longitudinal Zurich Cocaine Cognition Study (ZuCo(2)St). Forty-eight psychostimulant-naive controls and 57 cocaine users (19 with increased, 19 with decreased, and 19 with unchanged cocaine use) were eligible for analysis. At baseline and after a 1-year follow-up, cognitive performance was measured by a global cognitive index and four neuropsychological domains (attention, working memory, declarative memory, and executive functions), calculated from 13 parameters of a broad neuropsychological test battery. Intensity of cocaine use was objectively determined by quantitative 6-month hair toxicology at both test sessions. Substantially increased cocaine use within 1 year (mean +297%) was associated with reduced cognitive performance primarily in working memory. By contrast, decreased cocaine use (-72%) was linked to small cognitive improvements in all four domains. Importantly, users who ceased taking cocaine seemed to recover completely, attaining a cognitive performance level similar to that of the control group. However, recovery of working memory was correlated with age of onset of cocaine use-early-onset users showed hampered recovery. These longitudinal data suggest that cognitive impairment might be partially cocaine-induced but also reversible within 1 year, at least after moderate exposure. The reversibility indicates that neuroplastic adaptations underlie cognitive changes in cocaine users, which are potentially modifiable in psychotherapeutical or pharmacological interventions.
•Norcocaethylene and norcocaine are the most toxic metabolites of cocaine.•Therapeutic treatment of cocaine toxicity must account for these toxic metabolites.•The times to the occurrence of ...prostration/seizure/death correlate with the LD50.•Unlike cocaine, norcocaethylene and norcocaine do not induce hyperactivity in mice.
Majority of cocaine users also consume alcohol, and concurrent use of cocaine and alcohol produces cocaethylene, norcocaine, norcocaethylene, and other non-toxic metabolites. It is essential to know their relative toxicity for development of a truly effective therapeutics for cocaine toxicity treatment.
Drug (norcocaethylene or norcocaine)-induced acute toxicity was characterized by the occurrence (and the timing) of prostration, seizure, and death after intraperitoneal administration of the drug (n = 15) using the same strain (Swiss Webster) of male mice reported in previous study by Hearn et al. to determine LD50 of cocaine and cocaethylene. In addition, drug (cocaine, cocaethylene, norcocaine, or norcocaethylene)-induced hyperactivity was determined by locomotor activity testing (n = 8).
According to the animal data, norcocaethylene (LD50=∼39.4 mg/kg) and norcocaine (LD50=∼49.7 mg/kg) are the most toxic metabolites, but they do not induce significant hyperactivity. In addition, the relative toxicity of drugs correlates with the time to the occurrence of prostration/seizure/death after the drug administration.
The relative toxicity of these toxic drugs can be ranked in this order: norcocaethylene > norcocaine > cocaethylene > cocaine. The data suggest that norcocaethylene, norcocaine, and cocaethylene are all significant contributors to acute toxicity of cocaine in concurrent use of cocaine and alcohol. Hence, future therapeutic development for cocaine toxicity treatment must account for detoxification of these more toxic metabolites. In addition, the relative toxicity of different drugs correlates with the average time to the occurrence of death, seizure, or prostration after the drug administration with a same dose close to their LD50 values.
Reduced empathic abilities are frequently observed in drug abusers. These deficits may compromise interpersonal interactions and contribute to diminished social functioning. However, previous ...evidence regarding empathy and addiction is behaviorally unspecific and virtually null in terms of their brain structural or functional correlates. Moreover, no previous study has investigated how empathy is affected by drugs whose consumption is particularly characterized by counter-empathic behaviors. Here, we conducted the first assessment of neurocognitive correlates of empathy for pain in dependent users (predominantly men) of smoked cocaine (SC, coca paste, n = 37). We compared their performance in the empathy task with that of two groups matched in relevant demographic variables: 24 dependent users of insufflated cocaine hydrochloride (CC) and 21 healthy controls. In addition, we explored the structural anatomy and functional connectivity (FC) correlates of empathic impairments across groups. Our results showed that, compared to CC and controls, SC users exhibited a selective reduction of empathic concern for intentional harms. These impairments were associated with lower gray matter volumes in regions subserving social cognition (i.e., right inferior parietal lobule, supramarginal and angular gyri). Furthermore, reduced empathic concern correlated with FC within affective empathy and social cognition networks, which are also linked to cognitive changes reported in addiction (i.e., inferior frontal and orbital gyri, posterior insula, supplementary motor area, cingulate cortex). Our findings suggest that chronic consumption of SC may involve reduced empathic concern and relevant neuroanatomical and FC abnormalities, which, in turn, may result in social interaction dysfunction. These results can inform theoretical and applied developments in neuropsychopharmacology.
•This is the first study to investigate correlates of empathy in smoked cocaine dependent (SCD) users.•SCD users show selective reduction of empathic concern.•Empathic concern in SCD is associated with lower gray matter volumes in social cognition regions.•Empathic concern in SCD correlates with functional connectivity within social cognition networks.•SCD exhibit lower empathic skills than insufflated cocaine hydrochloride dependent users.
Rationale and objectives The 5-HT.sub.2A and 5-HT.sub.2C receptors have been shown to be differentially involved in modulating cocaine-induced behaviors. In this study we investigated the effects of ...the 5-HT.sub.2A antagonist MDL100907 (0.3 mg/kg, i.p.) and the 5-HT.sub.2C antagonist SB242084 (0.5 mg/kg, i.p.) on development, expression, and recall of cocaine-induced conditioned place preference (CPP) in high- (HR) and low-responder (LR) rats to novelty. Results First, we examined the effects of MDL100907 and SB242084 on development of cocaine-induced CPP. Our results indicated that LR, but not HR, animals conditioned with SB242084 + cocaine showed a significantly higher CPP response than controls. This effect was long lasting, as it was still present 30 days after the last conditioning session. Second, we investigated the acute effects of MDL100907 and SB242084 on CPP expression 24 h after cocaine conditioning. Again, our data showed that SB242084 significantly enhanced the expression of cocaine CPP in LR, but not HR animals. Finally, we studied the acute effects of MDL100907 and SB242084 on CPP recall 30 days after cocaine conditioning. Neither MDL100907 nor SB242084 significantly affected the CPP response regardless of the rats' behavioral phenotype. Conclusions This is the first study investigating the contribution of 5-HT.sub.2A and 5-HT.sub.2C receptors on development, expression, and recall of cocaine-induced CPP in the HR-LR model of individual vulnerability to drug abuse. Our results show that SB242084 differentially modulates development and expression of CPP in HR vs. LR rats and suggest that 5-HT.sub.2C receptors play a key role in individual differences on cocaine reward-related learning/memory processes. Keywords Phenotype * Conditioning * Cocaine * Serotonin receptor * Learning and memory
Rationale We previously showed that muscarinic agonists with M.sub.1 and/or M.sub.4 receptor affinities attenuated cocaine discrimination and self-administration in wild-type mice but not in ...M.sub.1/M.sub.4 double-knockout mice. Objective This study aims to elucidate the respective contributions of M.sub.1 and M.sub.4 receptors to this effect. Methods Knockout mice lacking either the M.sub.1 subtype (M.sub.1.sup.-/-) or the M.sub.4 subtype (M.sub.1.sup.-/-) and wild-type mice were trained to discriminate 10 mg kg cocaine from saline. Muscarinic ligands were tested for modulation of cocaine discrimination: xanomeline (M.sub.1/M.sub.4-preferring agonist), VU0357017 (M.sub.1-selective partial agonist), 77-LH-28-1 (M.sub.1 agonist), and BQCA (M.sub.1-selective positive allosteric modulator). Results Xanomeline produced rightward shifts in the cocaine dose-effect curve in all three genotypes, but most robustly in wild-type mice. VU0357017 produced rightward shifts in the cocaine dose-effect curve in wild-type and M.sub.4.sup.-/- mice, but not in M.sub.1.sup.-/- mice. Response rates were suppressed by xanomeline in wild-type and M.sub.1.sup.-/- but not in M.sub.4.sup.-/- mice and were unaltered by VU0357017. 77-LH-28-1 and BQCA also showed evidence of attenuating cocaine's discriminative stimulus, but at doses that suppressed responding or had other undesirable effects. Intriguingly, both VU0357017 and 77-LH-28-1 exhibited U-shaped dose-effect functions in attenuating cocaine discrimination. None of the drugs substituted for the cocaine stimulus. Conclusions Attenuation of the cocaine stimulus by VU0357017 depended upon M.sub.1 receptors, and full effects of xanomeline depended upon both M.sub.1 and M.sub.4 receptors. Therefore M.sub.1-selective agonists and mixed M.sub.1/M.sub.4 agonists may be promising leads for developing medications that block cocaine's effects. Keywords Acetylcholine receptor * Muscarinic * Cocaine * Addiction * Knockout * Drug discrimination
It is a grand challenge to develop a truly effective treatment of substance use disorder (SUD), particularly for cocaine and other drugs without an FDA-approved treatment available, because a truly ...effective therapy must effectively block the drug's physiological and reinforcing effects during the entire period of treatment in order to achieve the long-time abstinence required by the FDA. Whether a biologic, such as monoclonal antibody, vaccine, or therapeutic enzyme, can be truly effective for SUD treatment or not has been the subject of extensive debate. The main debate question is whether a biologic, particularly an exogenous enzyme, can effectively block the drug's reinforcing effect. In this report, we demonstrate that a modest dose of a recently redesigned long-acting cocaine hydrolase, CocH3-Fc(M6), can be used to effectively block the psychostimulant, discriminative stimulus, and reinforcing effects of cocaine for a sufficiently long period of time. For example, a dose of 3 mg/kg CocH3-Fc(M6) completely blocked the discriminative stimulus and reinforcing effects for 24/25 days and continued to significantly attenuate/decrease the cocaine effects for at least 29 days in rats. All the animal data consistently suggest that the long-acting cocaine hydrolase is a truly promising candidate of enzyme therapy for treatment of cocaine use disorder.
•There is no FDA-approved medication specific for cocaine overdose or dependence.•It is challenging to block effects of cocaine without affecting normal function of brain.•Accelerating cocaine hydrolysis is recognized as a promising therapeutic strategy.•An enzyme is capable of long-lasting blocking of cocaine discrimination in rats.•The enzyme is capable of long-lasting blocking of cocaine self-administration in rats.
Cocaine Gootenberg, Paul
1999., 1999, 20020104, 2002, 2002-01-01, 2002-01-04
eBook
Cocaine examines the rise and fall of this notorious substance from its legitimate use by scientists and medics in the nineteenth century to the international prohibitionist regimes and drug gangs of ...today. Themes explored include: * Amsterdam's complex cocaine culture * the manufacture, sale and control of cocaine in the United States * Japan and the Southeast Asian cocaine industry * export of cocaine prohibitions to Peru * sex, drugs and race in early modern London Cocaine unveils new primary sources and covert social, cultural and political transformations to shed light on cocaine's hidden history.
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