Plasma Cocaine Metabolite and Liver CYP450 3A4 Isoenzyme Levels as Indicators of Cocaine Dependence in Rats Treated with Nutritional Supplements (original) (raw)
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Strategic Applications of Measurement Technologies and Instrumentation, 2019
The effects of Salako nutritional supplements on cocaine-dependent Sprague Dawley rats was investigated. Rats were made cocaine-dependent using conditioned place preference (CPP) where craving was analyzed regularly. Cocaine metabolite levels were determined from blood samples. CYP450 3A4 isoenzyme activities were obtained using liver homogenate. Statistical analysis was done using SPSS one-way ANOVA and Duncans multiple range test. Results show that when cocaine use was discontinued, the supplements reduced craving of cocaine significantly. Blood plasma results showed higher benzoylecgonine equilibrium possibly indicating that the supplements aided the removal of stored cocaine metabolites which may have contributed to better management of craving in the rats. CYP450 3A4 isoenzyme activity was further enhanced by the supplements and is indicative of increased cocaine metabolism. The results indicate that the Salako nutritional supplements reduce craving caused by chronic cocaine ad...
Modification of hepatic cytochrome P450 profile by cocaine-induced hepatotoxicity in DBA/2 mouse
European Journal of Pharmacology: Environmental Toxicology and Pharmacology, 1994
Previous studics in our laboratory have shown that a hepatotoxic dose of cocaine increases coumarin 7-hydroxylase activity in male DBA/2 mouse liver. In the present study, the dose-and time-dependent responses of the hepatic CYP2A4/5 complex to cocaine-induced liver damage were studicd. Cocaine increased CYP2A4/5 levels in a dose-dependent manner. The maximal increases in coumarin 7-hydroxylasc activity (4-fold), microsomal CYP2A4/5 content (3-fold) and steady-state mRNA levels (10-fold) were observed at 24 h after administration of a single dose of 60 mg/kg cocaine coinciding with morphologically detectable diffuse liver damage, while the total P450 content was not changed. 3 and 5 days after the daily administration of cocaine severe, mainly pericentral (zone III of Rappaport), liver damage was apparent in parallel with a clear decline in CYP2A4/5 mRNA, protein content and coumarin 7-hydroxylase activity. After 5 days of treatment, CYP2A5 still remained at a very low level but an induction in CYP2B10 protein and related pentoxyresorufin O-dealkylase activity was observed. No marked changes in microsomal CYP2Cx and CYP1A1/2 contents or associated activities were observed. Dimethylnitrosamine N-demethylase activity, a marker for CYP2E1, decreased in parallel with increased cocaine dose and time and the severity of liver damage. Our results demonstrate that (i) administration of cocaine causes a clear but transient increase in the expression of Cyp2a-4/5 gene complex prior to overt liver damage and (ii) microsomal CYP2B10 and related 7-pentoxyresorufin O-dealkylase activity is markedly increased in animals treated for 5 days with cocaine concomitantly with the decrease in other monooxygenases indicating an'association of coumarin 7-hydroxylase activity with liver injury and different roles for coumarin 7-hydroxylase and 7-pentoxyresorufin O-dealkylase activities in cocaine hepatotoxicity.
European Journal of Pharmacology: Environmental Toxicology and Pharmacology, 1994
Cocaine is eliminated and detoxified principally through the metabolism of nonspecific plasma and tissue esterases. Microsomal oxidative metabolism is of importance in cocaine N-demethylation, this being a principal pathway of cocaine bioactivation and hepatotoxicity. The contribution of different cytochrome P450 (CYP) enzymes to cocaine N-demethylase activity was studied in vitro with DBA/2 mouse and human liver microsomes, and cocaine hepatotoxicity was examined in vivo in DBA/2 male mice. Species dependent enzyme kinetics was observed. Cocaine N-demethylase displayed two K m values in murine liver (40-60 #M and 2-3 raM), whereas only one K m value was observed in human liver microsomes (2.3-2.7 raM). We suggest that CYP3A plays a prominent role in the N-demethylation of cocaine for the following reasons: (i) pregnenolone-16acarbonitrile, an inducer of CYP3As increases cocaine N-demethylase in parallel with testosterone 6/3-hydroxylase activity and immunoreactive 3A protein in mouse liver; (ii) human and mouse cocaine N-demethylase and testosterone 6/3-hydroxylase activities can be inhibited by triacetyloleandomycin, cannabidiol, or gestodene, all selective inhibitors of CYP3A P450s; (iii) antibodies directed against P450s within subfamilies 1A, 2A, 2B, 2C, or 2E inhibited cocaine N-demethylase activity only marginally, and fnally, (iv) treatment of mice with triacetyloleandomycin or cannabidiol in vivo significantly attenuated the cocaine-elicited hepatotoxicity as assessed by the serum alanine aminotransferase activity and liver histology in parallel with decreased cocaine N-demethylase activity. The present results demonstrate that the first step of cocaine bioactivation is catalyzed by the CYP3A enzyme(s) in both murine and human liver microsomes and cocaine-induced liver injury in mice may be prevented by the administration of the CYP3A inhibitors.
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Addiction is a chronic relapsing disorder hypothesized to be produced by drug-induced plasticity that renders individuals vulnerable to craving-inducing stimuli such as re-exposure to the drug of abuse. Drug-induced plasticity that may result in the addiction phenotype includes increased excitatory signaling within corticostriatal pathways that correlates with craving in humans and is necessary for reinstatement in rodents. Reduced cystine-glutamate exchange by system x c -appears to contribute to heightened excitatory signaling within the striatum, thereby posing this as a novel target in the treatment of addiction. In the present report, we examined the impact of repeated N-acetyl cysteine, which is commonly used to activate cystine-glutamate exchange, on reinstatement in rodents in a preclinical study and on craving in cocaine-dependent humans in a preliminary, proof-of-concept clinical experiment. Interestingly, repeated administration (7 days) of N-acetyl cysteine (60 mg/kg, IP) produced a significant reduction in cocaine (10 mg/kg, IP)-induced reinstatement, even though rats (N ¼ 10-12/group) were tested 24 h after the last administration of N-acetyl cysteine. The reduction in behavior despite the absence of the N-acetyl cysteine indicates that repeated N-acetyl cysteine may have altered drug-induced plasticity that underlies drug-seeking behavior. In parallel, our preliminary clinical data indicate that repeated administration (4 days) of N-acetyl cysteine (1200-2400 mg/day) to cocaine-dependent human subjects (N ¼ 4 per group) produced a significant reduction in craving following an experimenter-delivered IV injection of cocaine (20 mg/70 kg/60 s). Collectively, these data demonstrate that N-acetyl cysteine diminishes the motivational qualities of a cocaine challenge injection possibly by altering pathogenic drug-induced plasticity.
Hepatology, 1996
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Journal of physiology and pharmacology: an official journal of the Polish Physiological Society
Some empirical evidence suggests that the endocannabinoids (eCB) (e.g. anandamide) may play an important role in cocaine addiction. The eCB act as a retrograde messengers activating CB receptors at the presynaptic membrane and are degraded by enzymatic actions of fatty acid amide hydrolase (FAAH). The present study aimed to examine the effect of the FAAH inhibitors, phenylmethylsulphonyl fluoride (PMSF; i.p.) or cyclohexylcarbamic acid 3-carbamoyl biphenyl-3-yl ester (URB597; i.p.) on the cocaine- or food-maintained self-administration as well as on the cocaine-seeking or food-taking behaviors in rats. Male Wistar rats were implanted with a catheter (iv.) and trained to self-administer cocaine (0.5 mg/kg/infusion) on a fixed ratio 5 schedule of reinforcement with a conditioned stimulus (tone+light). After self-administration stabilized, extinction/reinstatement procedures were carried out during which the rats were tested for the response reinstatement induced by cocaine (10 mg/kg, ...
Alcoholism: Clinical and Experimental Research, 1991
Chronic ethanol consumption potentiates cocaine-induced liver injury in rodents. Since cocaine has to be bioactivated by a cytochrome P-450-dependent N-oxidative pathway to exert its hepatotoxic effects, we studied the role of the ethanol-inducible P-45011E1 for cocaine metabolism. Male Sprague-Dawley rats were pretreated with either a liquid diet containing ethanol (30% of calories) for 4 weeks or injected with pyrazole (200 mg/kg/day, ip, for 3 days). Both agents induced microsomal p-nitrophenol hydroxylation which is a probe for the catalytic activity of P-45011El. However, only ethanol, but not pyrazole, increased both microsomal cocaine N-demethylase activity (by 47%) and the extent of irreversible binding of [3H]-cocaine to microeomal proteins (by lOO%), which was taken as a quantitative endpoint for the formation of a reactive metabolite. Cocaine Ndemethylation and irreversible protein binding of cocaine were not inhibited by P-45011E1 isozyme-selective substrates, nor was the rate of cocaine metabolism and binding decreased by functionally active polyclonal anti-rat P-45011E1 antibodies. Furthermore, pyrazole pretreatment sensitized cultured hepatocytes to the glutathione-dependent cytotoxic effects of nontoxic concentrations of cocaine. These results indicate that (a) cocaine is not a major substrate for the ethanol-inducible P-45011E1, (b) the enhancing effects of ethanol on cocaine bioactivation may be due to induction of other P-450 isoforms, and (c) induction of P-45011E1 may potentiate cocaineinduced hepatocellular toxicity in vitro independently of cocaine metabolism, e.g., by P-45011E 1-dependent oxidative stress.
Current Treatment Options in Psychiatry, 2015
Opinion statement strong concordance between preclinical effectiveness of candidate medications to modify cocaine choice in nonhuman primates and rodents and clinical effectiveness of these medications to modify either cocaine choice in human laboratory studies or metrics of cocaine abuse in patients with cocaine use disorder. The strongest evidence for medication effectiveness in preclinical choice studies has been obtained with maintenance on the monoamine releaser d-amphetamine, a candidate agonist medication for cocaine use analogous to use of methadone to treat opioid abuse or nicotine formulations to treat tobacco dependence.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002
Because most human studies of the neurobiological substrates of the effects of cocaine have been performed with drug-dependent subjects, little information is available about the effects of cocaine in the initial phases of drug use before neuroadaptations to chronic exposure have developed. The purpose of the present study, therefore, was to define the substrates that mediate the initial effects of cocaine in a nonhuman primate model of cocaine self-administration using the 2-[14C]deoxyglucose method. Rhesus monkeys were trained to self-administer 0.03 mg/kg per injection (N = 4) or 0.3 mg/kg per injection (N = 4) cocaine and compared with monkeys trained to respond under an identical schedule of food reinforcement (N = 4). Monkeys received 30 reinforcers per session, and metabolic mapping was conducted at the end of the fifth self-administration session. Cocaine self-administration reduced glucose utilization in the mesolimbic system, including the ventral tegmental area, ventral s...
Craving for Cocaine in Addicted Users: Role of Serotonergic Mechanisms
American Journal on Addictions, 1997
Very few studies have examined the role of serotonin (5-HTJ in the modulation of craving f o r cocaine in cocaine-addicted persons. The authors evaluated whether the acute increase in serotonergic neurotransmission after the administration of a challenging dose of the 5-HTpartiaI agonist meta-chlorophenylpiperazine (m-CPP) bad an effect on spontaneous cocaine craving. Male inpatients (N = 31) who met DSM-III-R criteria for cocaine dependence completed 2 days of testing (separated by 48 hours) that involved the oral administration of m-CPP (0.5 mg/kg of body weight) orplacebo in random order and under double-blind conditions. Patients' craving for cocaine was found to decrease significantly after the administration of m-CPP. These data could provide evidence for a moduIation of cocaine craving by 5-HT systems.