Effect of cocaine metabolites on behavior: Possible neuroendocrine mechanisms

doi:10.1016/0361-9230(95)02040-3

Brain Research Bulletin

Volume 39, Issue 1, 1996, Pages 43-48

https://doi.org/10.1016/0361-9230(95)02040-3 Get rights and content

Abstract

The predominant cocaine metabolites were tested for central nervous system effects by intracerebroventricular (ICV) administration in rats. We found two types of responses: cocaine, norcocaine (NC), benzoylecgonine (BE), and benzoylnorecgonine (Nor BE) produced stimulatory effects, whereas ecgonine methyl ester (EME) and ecgonine (EC) resulted in no specific effect or sedation. A novel metabolite interaction was revealed when rats were pretreated with EME, which inhibited both analgesia and seizures by subsequently administered cocaine. Pretreatment with EC inhibited both cocaine and BE seizures and seizure-associated death. Direct injection of EME into the nucleus accumbens significantly suppressed systemic cocaine potentiation of intracranial electrical self-stimulation of the ventral tegmental area, whereas corticotropin releasing hormone injected ICV selectively potentiated BE-induced seizures and death. These results confirm multiple, metabolite-mediated activities in the central nervous system. Pharmacological interactions of the metabolites with each other and/or with neurohormones may help explain some of the pathophysiological effects seen in human chronic cocaine abuse.

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LC/MS/MS evaluation of cocaine and its metabolites in different brain areas, peripheral organs and plasma in cocaine self-administering rats
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Citation Excerpt :
BE is formed by nonenzymatic hydrolysis, while EME formation is catalyzed by esterases localized in the liver and serum [42]. Both BE and EME are bioactive metabolites of cocaine [30, 41], less toxic than the parent drug [46] and having an approximately five times longer half-life (t1/2) in biological matrices than cocaine [7, 29, 45, 46]. Ten percent of cocaine administered to the body is catalyzed by the liver microsomal reactions via CYP2B1 enzymes in rats [2], and by CYP3A enzymes in mice and humans [34–36] leading to the formation of a pharmacologically active N-demethylated metabolite, norcocaine (NC).
We employed a cocaine intravenous self-administration model based on positive reinforcement of animals' instrumental reactions (i.e., lever pressing) rewarded by a dose of the drug. We also carried out simultaneous characterization of the phar-macokinetics of cocaine and its metabolites in rats during withdrawal; in this part of the experiments, we investigated the cocaine (2 mg/kg, iv)-induced changes in the distribution, rate constant, clearance and t_1/2 of the parent drug and its metabolites in different structures of the brain and in peripheral tissues.
By using liquid chromatography-tandem mass spectrometry (LC/MS/MS) we measured the levels of cocaine and its major metabolites.
Our results demonstrate differences in the levels of cocaine after cocaine self-administration in the rat, with the highest concentration seen in the striatum and the lowest in the cerebellum. Cocaine metabolites determined in the rat brain remained at very low levels (benzoylecgonine), irrespectively of the brain area, whereas the norcocaine concentration varied from 1.56 μg/g (the nucleus accumbens) to 2.73 μg/g (the striatum).
Atandem LC/MS/MS is a valid method for evaluation of brain and peripheral levels ofcocaine and its metabolites. Our results demonstrate brain area-dependent differences in the levels of cocaine after its self-administration in the rat. There were also differences in pharmacokinetic parameters among the brain areas and peripheral tissues following a bolus iv injection of cocaine to rats withdrawn from cocaine; among brain structures the slowest metabolic rate was detected for the striatum.
Positional linker effects in haptens for cocaine immunopharmacotherapy
2007, Bioorganic and Medicinal Chemistry Letters
Cocaine use remains a serious problem, despite intensive efforts to curb abuse. Given the lack of effective pharmacotherapeutics for the treatment of cocaine addiction, research groups have targeted immunopharmacotherapy in which the drug user’s immune system is trained to recognize and remove cocaine prior to entry into the central nervous system. Antibody cocaine esterases and simple binders have been procured, however, rates and/or affinities still need improvement before clinical trials are warranted. Herein, we report the synthesis and testing of two new haptens for the procurement of cocaine binding antibodies and cocaine esterase catalytic antibodies. Central in the design of these haptens was the placement of the linker functionality distal from the anticipated cocaine epitopes in an attempt to bury the hapten deep within an antibody combining site to gain possible entropic and enthalpic advantages.
Estrogen and progesterone affect cocaine pharmacokinetics in female rats
2006, Brain Research Bulletin
Several studies have reported sex differences in behavioral responses to cocaine whereby females display a greater degree of locomotor activity. Fluctuations in estrogen and progesterone during the estrous cycle have been postulated to underlie these behavioral differences. In this study, we tested the hypothesis that hormonal replacement (estrogen or progesterone) in ovariectomized rats affects cocaine pharmacokinetics. We found that estrogen replacement did not affect cocaine-induced locomotor activity, but progesterone attenuated locomotor counts in comparison with control groups receiving only sesame oil. Estrogen, however, decreased brain levels of cocaine and norcocaine 30 min after cocaine administration in comparison to the group-receiving vehicle at that time point. In addition, in progesterone-treated rats, levels of benzoylecgonine and ecgonine methylester were higher at 30 min post-administration than at 15 min. No changes were found in blood levels of the metabolites. These findings suggest that while progesterone has an impact on locomotor behavior, pharmacokinetic effects may have a limited role in mediating behavioral responses to cocaine.
Plasma cocaine levels, metabolites, and locomotor activity after subcutaneous cocaine injection are stable across the postpartum period in rats
2005, Pharmacology Biochemistry and Behavior
Plasma levels of cocaine (COC) and two of its principle metabolites, benzoylecgonine (BE) and ecgonine methyl ester (EME) were determined by liquid chromatography–tandem mass spectrometry (LC/MS/MS) in samples collected up to 3 h after a subcutaneous injection of cocaine (10 mg/kg) on six different days between days 4 and 24 postpartum, a period of dramatic change in the endocrine state of the female rat. Locomotor activity was measured in the same animals during this period using automated animal activity monitors. Additional measures in males provide a link to existing literature. We found that plasma levels of cocaine and its metabolites, as well as their respective time courses, are remarkably uniform across the postpartum period in female rats, as are the effects of cocaine on locomotor activity. Data from males show accord with prior published values. COC and BE, but not EME levels, were higher in males, and the time courses of COC and BE levels after injection varied somewhat between postpartum females and males; however, neither baseline nor cocaine-induced locomotor activity differed between postpartum females and males. We conclude that in the postpartum rat, there are no significant differences in the peripheral processing or general accessibility of cocaine to the brain to activate motor systems across the postpartum period. These data are critical to our understanding of differences in the reward salience of cocaine across the postpartum period and in other adult rat models [Mattson BJ, Williams S, Rosenblatt JS, Morrell JI. Comparison of two positive reinforcing stimuli: pups and cocaine throughout the postpartum period. Behav Neurosci 2001;115:683–94, Mattson BJ, Williams SE, Rosenblatt JS, Morrell JI. Preferences for cocaine- or pup-associated chambers differentiate otherwise behaviorally identical postpartum maternal rats. Psychopharmacology (Berl) 2003;167:1–8].
Intravenous butyrylcholinesterase administration and plasma and brain levels of cocaine and metabolites in rats
2005, European Journal of Pharmacology
Butyrylcholinesterase is a major cocaine-metabolizing enzyme in humans and other primates, catalyzing hydrolysis to ecgonine methylester. Increasing butyrylcholinesterase activity may be a treatment for cocaine addiction. We evaluated the effect of 30-min pretreatment with horse-derived butyrylcholinesterase (5–15,000 U i.v.) or with the selective butyrylcholinesterase inhibitor cymserine (10 mg/kg i.v.) on the metabolism of cocaine (17 mg/kg i.p.) in anesthetized rats. Venous blood samples were collected for two hours after cocaine administration and later assayed for cocaine and metabolites by gas chromatography/mass spectroscopy. Whole brains were collected after the last blood sample and similarly assayed. Butyrylcholinesterase significantly increased plasma and brain ecgonine methylester levels and decreased cocaine plasma half-life from 26.2 min (saline) to 16.4 min (15,000 U). Butyrylcholinesterase had no significant effect on plasma or brain cocaine or benzoylecgonine levels. Cymserine had no effect on any variable. These findings suggest that butyrylcholinesterase treatment may have benefits in enhancing cocaine metabolism and in increasing levels of ecgonine methylester, which may have a protective action against cocaine.
Sex differences in cocaine-induced behavioral responses, pharmacokinetics, and monoamine levels
2004, Neuropharmacology
Female rats display a more robust behavioral response to acute cocaine administration than do male rats. However, a clear understanding of the biological mechanisms underlying these differences remains elusive. The present study investigated whether sexual dimorphisms in cocaine-induced motor behavior might be based on monoaminergic levels and/or cocaine pharmacokinetics. An acute injection of cocaine (5, 15, 20 or 30 mg/kg) or saline was administered to male and female rats, and behavioral activity was monitored for 3 h. Following acute cocaine or saline administration motor behavior varied according to dose and sex; overall, female rats displayed greater rearing counts and stereotypic scores, greater total locomotor counts at 15, 20, and 30 mg/kg of cocaine, and greater ambulatory counts at 20 and 30 mg/kg of cocaine than did male rats. Neurochemical determinations in post-mortem tissue showed that both male and female rats had increases in total dopamine (DA) in the caudate putamen (CPu) 15 min following cocaine administration. Additionally, male rats had a decrease in dihydroxyphenylacetic acid (DOPAC)/DA turnover. Female rats showed significant reductions in total levels of DA, DOPAC, HVA, serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA), and DOPAC/DA turnover in the nucleus accumbens (NAc). Male rats displayed a reduction only in DOPAC/DA turnover and increases in 5-HT in the NAc following cocaine administration. Furthermore, sex differences in cocaine metabolism were observed where females had greater brain/blood levels of norcocaine and ecgonine methyl ester while male rats had higher blood levels of benzoylecgonine. These results suggest that sex differences in the behavioral responses to cocaine administration could be explained in part by intrinsic differences in both monoaminergic levels and metabolic processes.

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ArticleEffect of cocaine metabolites on behavior: Possible neuroendocrine mechanisms

Abstract

Developmental Brain Res.

Eur. J. Pharm.

Am. J. Emerg. Med.

Psychoneuroendocrinology

Brain Res.

Life Sciences

Life Sciences

J. Chromatography

J. Pediatrics

Forensic Science International

Life Sci.

Pharmacol. Biochem. Behav.

Am. J. Med.

Pharmacological Res. Commun.

A potential vaccine for cocaine abuse prophylaxis

Immunopharmacology

Passive freebase cocaine (‘crack’) inhalation by infants and toddlers

Am. J. Dis. Child.

Detection of cocaine, norcocaine, and cocaethylene in the meconium of premature neonates

J. Forensic Sciences

Detection of cocaine, norcocaine, and cocaethylene

J. Forensic Sciences

Sajous's Analytic Cyclopedia of Practical Medicine

Detection and determination of pseudo-cocaine in coca leaves and illicit cocaine samples

J. Forensic Sciences

Article
Effect of cocaine metabolites on behavior: Possible neuroendocrine mechanisms