The Experts below are selected from a list of 585 Experts worldwide ranked by ideXlab platform

Karine M. Clauwaert - One of the best experts on this subject based on the ideXlab platform.

  • the determination of cocaine benzoylecgonine and Cocaethylene in small volume oral fluid samples by liquid chromatography quadrupole time of flight mass spectrometry
    Journal of Analytical Toxicology, 2004
    Co-Authors: Karine M. Clauwaert, Tineke N Decaestecker, Kjell A Mortier, Willy E Lambert, Dieter Deforce, C Van Peteghem, Jan Van Bocxlaer
    Abstract:

    A quantitative analysis was developed for the determination of cocaine, benzoylecgonine, and Cocaethylene in oral fluid using liquid chromatography-tandem mass spectrometry. After internal standardization and solid-phase extraction, chromatographic separation was achieved on a reversed-phase column by gradient elution. The reconstructed mass chromatograms of the collision-induced dissociation transitions of m/z 290 --> m/z 168 (benzoylecgonine), m/z 304 --> m/z 168+119 (2'-methylbenzoylecgonine), m/z 304 --> m/z 182 (cocaine), m/z 318 --> m/z 196 (Cocaethylene), and m/z 318 --> m/z 182+119 (2'-methylcocaine) were used for quantitation. The developed method was adequately validated. Good linearity was obtained from 10 to 1000 microg/L. Extraction recoveries exceeded 85% for all compounds. Excellent total and within-run reproducibilities (CV% /= 3) was 1 microg/L for all three compounds. As such, a method for drug abuse confirmation analysis in oral fluid, compatible with the present day saliva collecting devices, is obtained. The method was applied to real samples (n = 15) obtained from suspected drug users, of which seven proved positive. The concentrations found in the positive samples were between 10.2 and 200.6 microg/L for cocaine, < limit of quantification (LOQ) and 10.5 microg/L for Cocaethylene, and < LOQ and 59.2 microg/L for benzoylecgonine.

  • the determination of cocaine benzoylecgonine and Cocaethylene in small volume oral fluid samples by liquid chromatography quadrupole time of flight mass spectrometry
    Journal of Analytical Toxicology, 2004
    Co-Authors: Karine M. Clauwaert, Tineke N Decaestecker, Kjell A Mortier, Willy E Lambert, Dieter Deforce, C Van Peteghem, J. Van Bocxlaer
    Abstract:

    A quantitative analysis was developed for the determination of cocaine, benzoylecgonine, and Cocaethylene in oral fluid using liquid chromatography-tandem mass spectrometry. After internal standardization and solid-phase extraction, chromatographic separation was achieved on a reversed-phase column by gradient elution. The reconstructed mass chromatograms of the collision-induced dissociation transitions of m/z 290 -~ m/z 168 (benzoylecgonine), m/z 304 ~ m/z 168+ 119 (2'-methylbenzoylecgonine), m/z 304 ~ m/z 182 (cocaine), m/z 318 ~ m/z 196 (Cocaethylene), and m/z 318 -~ m/z 182+119 (2'-methylcocaine) used for quantitation. The developed method was adequately validated. Good linearity was obtained from 10 to 1000 pg/L. Extraction recoveries exceeded 85 % for all compounds. Excellent total and within-run reproducibilities (CV% 3) was 1 pg/L for all three compounds. As such, a method for drug abuse confirmation analysis in oral fluid, compatible with the present day saliva collecting devices, is obtained. The method was applied to real samples (n = 15) obtained from suspected drug users, of which seven proved positive. The concentrations found in the positive

  • liquid chromatographic determination of cocaine benzoylecgonine and Cocaethylene in whole blood and serum samples with diode array detection
    Journal of Chromatographic Science, 1997
    Co-Authors: Karine M. Clauwaert, Jan Van Bocxlaer, Willy E Lambert, André P. De Leenheer
    Abstract:

    An extraction with Bond Elut Certify solid-phase extraction (SPE) columns is developed for the isolation of cocaine, benzoylecgonine, and Cocaethylene from whole blood and serum followed by reversed-phase liquid chromatography with diode-array detection. Two internal standards (2'-methylbenzoylecgonine and 2'-methylcocaine) with close structural resemblance to benzoylecgonine (a carboxylic acid) and to the two esters, cocaine and Cocaethylene, are used in the analytical procedure. A thorough evaluation of this SPE and a comparison with different liquid-liquid extractions clearly show the superiority of the SPE. A linear response (correlation coefficient greater than 0.998) over a broad concentration range (0.025-5.0 micrograms/mL) is obtained. The sensitivity, specificity, precision (coefficients of variation less than 4.9% for within-day reproducibility and less than 5.3% for total reproducibility), and accuracy of the method are excellent for each analyte. Forensic blood samples from people suspected of cocaine abuse are analyzed and show the usefulness of the method, even for degraded postmortem samples.

  • Analysis of cocaine, benzoylecgonine, and Cocaethylene in urine by HPLC with diode array detection.
    Analytical Chemistry, 1996
    Co-Authors: Karine M. Clauwaert, Jan Van Bocxlaer, And Willy E. Lambert, André P. De Leenheer
    Abstract:

    A solid phase extraction method was developed for the isolation of cocaine, benzoylecgonine, and Cocaethylene from urine followed by high-performance liquid chromatography/diode array detection. The application of a new solid hybrid phase extraction technology produced much cleaner extracts than conventional extraction procedures and made the selective extraction of substances with different polarities possible. Two internal standards with great structural resemblance to benzoylecgonine (a carboxylic acid) and to the two esters, cocaine and Cocaethylene, respectively, were synthesized. A linear response over a broad concentration range was obtained. The sensitivity, specificity, and accuracy were satisfactory for each analyte. Hydrolysis of cocaine and Cocaethylene to benzoylecgonine during extraction and analysis was less than 0.5%. The method described can be used to corroborate cocaine use, to establish cocaine overdoses, and to study pharmacological effects of cocaine and its metabolites.

German Torres - One of the best experts on this subject based on the ideXlab platform.

  • Differential Behavioral Responses to Cocaethylene of Long-Evans and Sprague-Dawley Rats: Role of Serotonin
    2016
    Co-Authors: Judith M Horowitz, Mark B Kristal, German Torres
    Abstract:

    rat; strain differences; striatum; ventral tegmental area ABSTRACT Cocaethylene is a neuroactive metabolite derived from the concurrent consumption of cocaine and ethanol. The effects of Cocaethylene on locomotor activity, stereotypy, and rearing in Long-Evans and Sprague-Dawley rats were compared.Asingle cocaine injection (molar equivalent of 60 µmol/kg Cocaethylene, intraperitoneal) elicited a robust series of motor output behaviors, including locomotion, stereotypy, and rearing over a 30-minute testing period in Long-Evans rats. In contrast, Cocaethylene administra-tion, under comparable testing conditions, produced no significant changes in locomotor and investigatory behaviors. Because Cocaethylene has relatively little impact on serotonin (5-HT) reuptake as opposed to reuptake of dopamine, we pretreated Long-Evans rats with fluoxetine (10mg/kg; IP), a selective 5-HT reuptake inhibitor. Fluoxetine profoundly augmented Cocaethylene-stimulated behaviors in this rat phenotype. To examine whether other rat strains exhibit a similar response to Cocaethylene, Sprague-Dawley rats were injected (IP) with Cocaethylene and their behavior patterns monitored over a 30-minute testing period. Cocaethylene produced marked locomotor and explor-atory behaviors in this strain, suggesting therefore that Long-Evans and Sprague-Dawley rats differ in their response to Cocaethylene. To relate these behavioral differences to possible structural differences in the neuronal density of dopaminergic or serotonergic neurons, Long-Evans and Sprague-Dawley brains were evaluated for tyrosine hydroxylase and 5-HT immunocytochemistry. No gross morphological differ-ences in neuronal architecture or density were found in the ventral tegmental area or dorsal raphe nucleus of the two rat phenotypes. These results indicate that two commonly used rat strains show a differential response to Cocaethylene and the neurochemical basis for this behavioral difference may be related to synaptic 5-H

  • Cocaethylene effects on brain systems and behavior
    Addiction Biology, 1999
    Co-Authors: Judith M Horowitz, German Torres
    Abstract:

    Cocaethylene is a psychoactive metabolite formed during the combined consumption of cocaine and ethanol. In this brief review, we discuss several well-characterized effects of this metabolite with an emphasis on the neurobiological and behavioral correlates of polydrug addiction. Included herein are the descriptions of some of the changes in trans-synaptic transmission and their relationship to pathological behaviors associated with a chronic, drug-dependent state that may be altered by the spatial or temporal dynamics of Cocaethylene.

  • Cocaethylene synthesis in drosophila
    Neuroscience Letters, 1999
    Co-Authors: German Torres, Judith M Horowitz
    Abstract:

    Cocaethylene is an active cocaine metabolite that targets mammalian neural reward pathways and thus contributes to the reinforcing and addictive properties of ethanol and cocaine. Using gas chromatography-mass spectrometry, we find that fruit flies (Drosophila melanogaster) possess a cellular mechanism through which cocaine can be converted to Cocaethylene, presumably via ethanol-sensitive enzymes. These findings illustrate the striking similarity of gene products in humans and flies, which might reflect a homologous role in the metabolic inactivation of cocaine. Further, this conservation of metabolic steps suggests that Drosophila can be used to study cellular, molecular and biochemical processes leading to polydrug abuse and addiction.

  • activating properties of cocaine and Cocaethylene in a behavioral preparation of drosophila melanogaster
    Synapse, 1998
    Co-Authors: German Torres, Judith M Horowitz
    Abstract:

    The use of Drosophila as a model to study the behavioral consequences of stimulant drugs was analyzed in an active preparation of decapitated Drosophila. Application of cocaine and Cocaethylene to discrete nerve cord cells regulating motor programs of behavior produced striking patterns of behavioral activity in a concentration-related manner. In general, intense circling behavior and significant wing buzzing activity were distinguishable behavioral markers in flies treated with mM concentrations of cocaine or Cocaethylene. The significant changes in motor behavior induced by stimulant drugs in decapitated flies were not reproduced by the application of apomorphine, a direct dopamine (DA) agonist, or octopamine, a naturally occurring transmitter in arthropods. Because both cocaine and Cocaethylene interfere with DA reuptake in mammals, we characterized the role of DA receptors mediating increased stereotypy and motor behavior in flies. Coadministration of SCH-23390, a specific D1 receptor antagonist, significantly attenuated the behavior-activating properties of cocaine and Cocaethylene in this active experimental preparation. Therefore, the receptor protein mediating the behavioral responses to stimulant drugs in Drosophila is pharmacologically similar to the mammalian D1 subtype. In rats, cocaine- and Cocaethylene-induced behavioral activity is complex, with increasing evidence that the D1 receptor interacts significantly with N-methyl-D-aspartate (NMDA) receptor pathways to produce an altered behavioral phenotype. To further characterize additional receptor subtypes targeted by the actions of cocaine and Cocaethylene, we pretreated flies with MK-801 and dextromethorphan. Both of these drugs are potent, selective noncompetitive NMDA receptor antagonists. Interestingly, MK-801 and dextromethorphan profoundly reduced the behavior-activating properties of cocaine and Cocaethylene in Drosophila. Therefore, as in rats, the NMDA (and D1) receptor pathways in this arthropod represent obligatory targets for the behavioral effects of stimulant drugs.

  • differential behavioral responses to Cocaethylene of long evans and sprague dawley rats role of serotonin
    Synapse, 1997
    Co-Authors: Judith M Horowitz, Mark B Kristal, German Torres
    Abstract:

    Cocaethylene is a neuroactive metabolite derived from the concurrent consumption of cocaine and ethanol. The effects of Cocaethylene on locomotor activity, stereotypy, and rearing in Long-Evans and Sprague-Dawley rats were compared.A single cocaine injection (molar equivalent of 60 μmol/kg Cocaethylene, intraperitoneal) elicited a robust series of motor output behaviors, including locomotion, stereotypy, and rearing over a 30-minute testing period in Long-Evans rats. In contrast, Cocaethylene administration, under comparable testing conditions, produced no significant changes in locomotor and investigatory behaviors. Because Cocaethylene has relatively little impact on serotonin (5-HT) reuptake as opposed to reuptake of dopamine, we pretreated Long-Evans rats with fluoxetine (10 mg/kg; IP), a selective 5-HT reuptake inhibitor. Fluoxetine profoundly augmented Cocaethylene-stimulated behaviors in this rat phenotype. To examine whether other rat strains exhibit a similar response to Cocaethylene, Sprague-Dawley rats were injected (IP) with Cocaethylene and their behavior patterns monitored over a 30-minute testing period. Cocaethylene produced marked locomotor and exploratory behaviors in this strain, suggesting therefore that Long-Evans and Sprague- Dawley rats differ in their response to Cocaethylene. To relate these behavioral differences to possible structural differences in the neuronal density of dopaminergic or serotonergic neurons, Long-Evans and Sprague-Dawley brains were evaluated for tyrosine hydroxylase and 5-HT immunocytochemistry. No gross morphological differences in neuronal architecture or density were found in the ventral tegmental area or dorsal raphe nucleus of the two rat phenotypes. These results indicate that two commonly used rat strains show a differential response to Cocaethylene and the neurochemical basis for this behavioral difference may be related to synaptic 5-HT bioavailability.

Robert B Parker - One of the best experts on this subject based on the ideXlab platform.

  • Cocaethylene metabolism and interaction with cocaine and ethanol role of carboxylesterases
    Drug Metabolism and Disposition, 2003
    Co-Authors: Casey S Laizure, Timothy D Mandrell, Naomi M Gades, Robert B Parker
    Abstract:

    Carboxylesterases are important in the metabolism of cocaine, catalyzing the hydrolysis of cocaine to its two major metabolites, benzoylecgonine and ecgonine methyl ester. In the presence of ethanol, some cocaine undergoes transesterification with ethanol instead of hydrolysis with water producing the active metabolite, Cocaethylene. The metabolic fate of Cocaethylene is unknown, but given its structural similarity to cocaine, it was hypothesized that Cocaethylene would also be metabolized by carboxylesterases and its elimination decreased in the presence of ethanol, as is cocaine's. Dogs were given cocaine alone, Cocaethylene alone, cocaine and ethanol, Cocaethylene and ethanol, and cocaine and Cocaethylene on separate study days and sequential blood samples drawn. Plasma concentrations of cocaine, benzoylecgonine, and Cocaethylene were determined by high-performance liquid chromatography. The pharmacokinetic dispositions of cocaine and Cocaethylene were similar with clearance values of 0.91 ± 0.22 and 0.79 ± 0.16 l/min, and volumes of distribution of 2.6 ± 0.82 and 2.7 ± 0.47 l/kg, respectively. Both cocaine and Cocaethylene clearances were decreased about 20% when given with ethanol. Following administration of Cocaethylene alone, benzoylecgonine achieved similar plasma concentrations as those attained following cocaine alone, which indicates that benzoylecgonine is a major metabolite of Cocaethylene. Carboxylesterases play an important role in the elimination of both cocaine and Cocaethylene.

  • Cocaethylene formation in rat dog and human hepatic microsomes
    Life Sciences, 1999
    Co-Authors: Ning Song, Robert B Parker, Casey S Laizure
    Abstract:

    Abstract The dog and rat are important animal models for studying the role of Cocaethylene in the pharmacodynamic interaction between cocaine and ethanol. In a previous study in our laboratory it was found that a cocaine dose of 3 mg/kg IV and ethanol 1 g/kg IV failed to produce detectable concentrations of Cocaethylene in the plasma of dogs. In follow up to this result, the pharmacokinetic disposition of cocaine and Cocaethylene in the dog were determined to be similar. These results suggested significant differences between animal and human Cocaethylene formation may occur. To test this possibility the in vitro formation of Cocaethylene was determined in rat, dog and human hepatic microsomal preparations containing cocaine (0–7 mM) and ethanol (50 mM). Nonlinear least-squares regression was used to estimate Km and Vmax and the results were compared statistically. The mean ± standard deviation for Km and Vmax in the rat, dog and human were 0.53 ± 0.04, 0.97 ± 0.07, and 0.56 ± 0.08 mM, and 390 ± 9, 233 ± 6, and 60 ± 3 pmol/minute/mg protein, respectively. The Km in the dog was significantly greater (p dog > human; p in vivo studies that appear to show that humans produce more Cocaethylene than dogs. It is suggested by the authors that route of cocaine administration may be an important factor in the formation of Cocaethylene when cocaine and ethanol are co-administered.

  • evaluation of dose dependent pharmacokinetics of Cocaethylene and cocaine in conscious dogs
    Life Sciences, 1997
    Co-Authors: Robert B Parker, Timothy D Mandrell, Cheri L Williams, Steven Laizure, John J Lima
    Abstract:

    Abstract Cocaine use continues to be widespread in the United States. Most cocaine users co-ingest ethanol resulting in decreased elimination of cocaine and formation of the active cocaine metabolite, Cocaethylene, by hepatic carboxylesterases. In a recentt study from our laboratory in dogs to evaluate the cocaine-ethanol interaction, we demonstrated a similar ethanol-induced reduction in cocaine metabolism, although we were unable to detect Cocaethylene when the two drugs were given together. This unexpected finding could be explained by ethanol-induced inhibition of cocaine metabolism via a pathway that does not involve hepatic carboxylesterases or formation of Cocaethylene that inhibits cocaine metabolism and is then rapidly cleared. The purpose of the present study is to determine which of these mechanisms best explain our data by characterizing the pharmacokinetics of cocaine and Cocaethylene over a range of doses in conscious dogs. Seven adult mongrel dogs received 1, 3, and 5 mg/kg cocaine and Cocaethylene HCl base with each drug dose administered iv on a separate study day. Arterial blood samples were collected at various times after each dose and analyzed for cocaine and Cocaethylene by HPLC. Cocaine clearance was dose-dependent with clearance decreasing from 1.53 ± 0.31 to 1.09 ± 0.11 l/min as the dose was increased from 1 to 5 mg/kg (p

  • effects of ethanol and Cocaethylene on cocaine pharmacokinetics in conscious dogs
    Drug Metabolism and Disposition, 1996
    Co-Authors: Robert B Parker, Timothy D Mandrell, Cheri L Williams, Steven Laizure, Gregory S Labranche, John J Lima
    Abstract:

    Coingestion of cocaine and ethanol is common among cocaine users, and this combination is reported to enhance the euphoric effects of cocaine. The cardiovascular effects of cocaine are increased in the presence of ethanol, although the mechanism(s) involved in this interaction are poorly understood. Recent studies suggest the enhanced cardiac effects may be caused by ethanol-mediated inhibition of cocaine metabolism leading to higher cocaine plasma concentrations. However, these studies were all performed in animals or humans that form Cocaethylene when ethanol and cocaine are coadministered. Thus, it is also possible that Cocaethylene could inhibit cocaine's metabolism. Preliminary studies in our laboratory indicate the dog does not form detectable quantities of Cocaethylene after coadministration of cocaine and intravenous ethanol. Thus, the dog may be a useful model for isolating the individual contributions of ethanol and Cocaethylene to this interaction. The purpose of the present study was to confirm this observation, and to determine the effects of ethanol and Cocaethylene on cocaine pharmacokinetics in the conscious dog. Six dogs received cocaine (3 mg/kg i.v.) alone, ethanol (1 g/kg i.v.) followed by cocaine (3 mg/kg i.v.), and cocaine (3 mg/kg i.v.) + Cocaethylene (3 mg/kg i.v.). Cocaethylene was not detected in any of the plasma samples from the six dogs after administration of cocaine and ethanol. Ethanol and Cocaethylene reduced mean cocaine clearance by 47% and 26%, respectively. Inhibition of cocaine's metabolism by both ethanol and Cocaethylene may play an important role in mediating the enhanced effects of cocaine in the presence of ethanol.

  • quantitation of cocaine and Cocaethylene in canine serum by high performance liquid chromatography
    Journal of Chromatography B: Biomedical Sciences and Applications, 1996
    Co-Authors: Cheri L Williams, Robert B Parker, Steven Laizure, John J Lima
    Abstract:

    A reversed-phase high-performance liquid chromatographic procedure for the determination of cocaine and Cocaethylene in canine serum has been developed. The compounds were extracted from 1 ml of alkalinized canine serum with hexane. Chromatographic separation was achieved with a cyanopropyl column (250 x 4.6 mm I.D., 5 microns) using a mobile phase of acetonitrile and phosphate buffer, pH 7.40 (38:62, v/v) flowing at 1 ml/min. Eluate was monitored by a variable-wavelength UV detector set to 230 nm. The extraction procedure yields an average recovery of 99 and 96% for cocaine and Cocaethylene, respectively. The between-day coefficients of variation, at 2400 ng/ml, for cocaine and Cocaethylene were both 8.6% and the within-day coefficients of variation, at 400 ng/ml, for cocaine and Cocaethylene were 7.3 and 8.0%, respectively. A concentration-time profile resulting from administration of 3 mg/kg cocaine and Cocaethylene to the dog revealed a similar disposition between cocaine and Cocaethylene, with a clearance and volume of distribution at steady-state values of 72.8 and 61.0 ml/min/kg and 2.6 and 2.7 1/kg, respectively.

Judith M Horowitz - One of the best experts on this subject based on the ideXlab platform.

  • Differential Behavioral Responses to Cocaethylene of Long-Evans and Sprague-Dawley Rats: Role of Serotonin
    2016
    Co-Authors: Judith M Horowitz, Mark B Kristal, German Torres
    Abstract:

    rat; strain differences; striatum; ventral tegmental area ABSTRACT Cocaethylene is a neuroactive metabolite derived from the concurrent consumption of cocaine and ethanol. The effects of Cocaethylene on locomotor activity, stereotypy, and rearing in Long-Evans and Sprague-Dawley rats were compared.Asingle cocaine injection (molar equivalent of 60 µmol/kg Cocaethylene, intraperitoneal) elicited a robust series of motor output behaviors, including locomotion, stereotypy, and rearing over a 30-minute testing period in Long-Evans rats. In contrast, Cocaethylene administra-tion, under comparable testing conditions, produced no significant changes in locomotor and investigatory behaviors. Because Cocaethylene has relatively little impact on serotonin (5-HT) reuptake as opposed to reuptake of dopamine, we pretreated Long-Evans rats with fluoxetine (10mg/kg; IP), a selective 5-HT reuptake inhibitor. Fluoxetine profoundly augmented Cocaethylene-stimulated behaviors in this rat phenotype. To examine whether other rat strains exhibit a similar response to Cocaethylene, Sprague-Dawley rats were injected (IP) with Cocaethylene and their behavior patterns monitored over a 30-minute testing period. Cocaethylene produced marked locomotor and explor-atory behaviors in this strain, suggesting therefore that Long-Evans and Sprague-Dawley rats differ in their response to Cocaethylene. To relate these behavioral differences to possible structural differences in the neuronal density of dopaminergic or serotonergic neurons, Long-Evans and Sprague-Dawley brains were evaluated for tyrosine hydroxylase and 5-HT immunocytochemistry. No gross morphological differ-ences in neuronal architecture or density were found in the ventral tegmental area or dorsal raphe nucleus of the two rat phenotypes. These results indicate that two commonly used rat strains show a differential response to Cocaethylene and the neurochemical basis for this behavioral difference may be related to synaptic 5-H

  • Cocaethylene effects on brain systems and behavior
    Addiction Biology, 1999
    Co-Authors: Judith M Horowitz, German Torres
    Abstract:

    Cocaethylene is a psychoactive metabolite formed during the combined consumption of cocaine and ethanol. In this brief review, we discuss several well-characterized effects of this metabolite with an emphasis on the neurobiological and behavioral correlates of polydrug addiction. Included herein are the descriptions of some of the changes in trans-synaptic transmission and their relationship to pathological behaviors associated with a chronic, drug-dependent state that may be altered by the spatial or temporal dynamics of Cocaethylene.

  • Cocaethylene synthesis in drosophila
    Neuroscience Letters, 1999
    Co-Authors: German Torres, Judith M Horowitz
    Abstract:

    Cocaethylene is an active cocaine metabolite that targets mammalian neural reward pathways and thus contributes to the reinforcing and addictive properties of ethanol and cocaine. Using gas chromatography-mass spectrometry, we find that fruit flies (Drosophila melanogaster) possess a cellular mechanism through which cocaine can be converted to Cocaethylene, presumably via ethanol-sensitive enzymes. These findings illustrate the striking similarity of gene products in humans and flies, which might reflect a homologous role in the metabolic inactivation of cocaine. Further, this conservation of metabolic steps suggests that Drosophila can be used to study cellular, molecular and biochemical processes leading to polydrug abuse and addiction.

  • activating properties of cocaine and Cocaethylene in a behavioral preparation of drosophila melanogaster
    Synapse, 1998
    Co-Authors: German Torres, Judith M Horowitz
    Abstract:

    The use of Drosophila as a model to study the behavioral consequences of stimulant drugs was analyzed in an active preparation of decapitated Drosophila. Application of cocaine and Cocaethylene to discrete nerve cord cells regulating motor programs of behavior produced striking patterns of behavioral activity in a concentration-related manner. In general, intense circling behavior and significant wing buzzing activity were distinguishable behavioral markers in flies treated with mM concentrations of cocaine or Cocaethylene. The significant changes in motor behavior induced by stimulant drugs in decapitated flies were not reproduced by the application of apomorphine, a direct dopamine (DA) agonist, or octopamine, a naturally occurring transmitter in arthropods. Because both cocaine and Cocaethylene interfere with DA reuptake in mammals, we characterized the role of DA receptors mediating increased stereotypy and motor behavior in flies. Coadministration of SCH-23390, a specific D1 receptor antagonist, significantly attenuated the behavior-activating properties of cocaine and Cocaethylene in this active experimental preparation. Therefore, the receptor protein mediating the behavioral responses to stimulant drugs in Drosophila is pharmacologically similar to the mammalian D1 subtype. In rats, cocaine- and Cocaethylene-induced behavioral activity is complex, with increasing evidence that the D1 receptor interacts significantly with N-methyl-D-aspartate (NMDA) receptor pathways to produce an altered behavioral phenotype. To further characterize additional receptor subtypes targeted by the actions of cocaine and Cocaethylene, we pretreated flies with MK-801 and dextromethorphan. Both of these drugs are potent, selective noncompetitive NMDA receptor antagonists. Interestingly, MK-801 and dextromethorphan profoundly reduced the behavior-activating properties of cocaine and Cocaethylene in Drosophila. Therefore, as in rats, the NMDA (and D1) receptor pathways in this arthropod represent obligatory targets for the behavioral effects of stimulant drugs.

  • differential behavioral responses to Cocaethylene of long evans and sprague dawley rats role of serotonin
    Synapse, 1997
    Co-Authors: Judith M Horowitz, Mark B Kristal, German Torres
    Abstract:

    Cocaethylene is a neuroactive metabolite derived from the concurrent consumption of cocaine and ethanol. The effects of Cocaethylene on locomotor activity, stereotypy, and rearing in Long-Evans and Sprague-Dawley rats were compared.A single cocaine injection (molar equivalent of 60 μmol/kg Cocaethylene, intraperitoneal) elicited a robust series of motor output behaviors, including locomotion, stereotypy, and rearing over a 30-minute testing period in Long-Evans rats. In contrast, Cocaethylene administration, under comparable testing conditions, produced no significant changes in locomotor and investigatory behaviors. Because Cocaethylene has relatively little impact on serotonin (5-HT) reuptake as opposed to reuptake of dopamine, we pretreated Long-Evans rats with fluoxetine (10 mg/kg; IP), a selective 5-HT reuptake inhibitor. Fluoxetine profoundly augmented Cocaethylene-stimulated behaviors in this rat phenotype. To examine whether other rat strains exhibit a similar response to Cocaethylene, Sprague-Dawley rats were injected (IP) with Cocaethylene and their behavior patterns monitored over a 30-minute testing period. Cocaethylene produced marked locomotor and exploratory behaviors in this strain, suggesting therefore that Long-Evans and Sprague- Dawley rats differ in their response to Cocaethylene. To relate these behavioral differences to possible structural differences in the neuronal density of dopaminergic or serotonergic neurons, Long-Evans and Sprague-Dawley brains were evaluated for tyrosine hydroxylase and 5-HT immunocytochemistry. No gross morphological differences in neuronal architecture or density were found in the ventral tegmental area or dorsal raphe nucleus of the two rat phenotypes. These results indicate that two commonly used rat strains show a differential response to Cocaethylene and the neurochemical basis for this behavioral difference may be related to synaptic 5-HT bioavailability.

David N Bailey - One of the best experts on this subject based on the ideXlab platform.

  • cocaine and Cocaethylene binding to normal human brain and alzheimer disease brain
    Therapeutic Drug Monitoring, 2000
    Co-Authors: David N Bailey
    Abstract:

    The binding of cocaine and Cocaethylene to homogenates of both normal whole brain and whole brain with Alzheimer disease patients (Alzheimer brain) was investigated in vitro using equilibrium dialysis of the unlabelled drugs at 4°C. Two binders of cocaine were characterized in normal brain (binder 1: K a , 5.73 x 10 3 L/mol; B o , 7.44 x 10 -5 mol/L) (binder 2: K a , 1.54 x 10 3 L/mol; B o , 2.50 x 10 -4 mol/L) and in Alzheimer brain (binder 1: K a , 3.08 x 10 2 L/mol; B o , 6.66 x 10 -4 mol/L) (binder 2: K a , 8.74 x 10 1 L/mol; B o , 4.30 x 10 -3 mol/L). For Cocaethylene three binders were noted in normal brain (binder 1: K a , 3.23 x 10 3 L/mol; B o , 1.22 x 10 -4 mol/L) (binder 2: K a , 3.10 x 10 3 L/mol; B o , 2.01 x 10 -4 mol/L) (binder 3: K a , 1.63 x 10 3 L/mol; B o , 3.59 x 10 -4 mol/L) and two binders in Alzheimer brain (binder 1: K a , 5.18 x 10 3 L/mol; B o , 3.06 × 10 -5 mol/L) (binder 2: K a , 3.36 × 10 3 L/mol; B o , 7.75 × 10 -5 mol/L). The binding of cocaine to normal brain was much stronger than to Alzheimer brain (ten- to 100-fold), whereas the binding of Cocaethylene was similar in normal and Alzheimer brain. Cocaine and Cocaethylene binding to human brain was compared with cocaine and Cocaethylene binding to other human tissues previously studied by this laboratory.

  • procainamide inhibition of human hepatic degradation of cocaine and Cocaethylene in vitro
    Journal of Analytical Toxicology, 1999
    Co-Authors: David N Bailey
    Abstract:

    I Procainamide (PA), a cardioactive drug, inhibited the degradation of both cocaine (COC) and Cocaethylene (CE) when either was incubated in human liver homogenates for 3 h at 37~ PA appeared to enhance the formation of CE when COC and ethanol (ETOH) were incubated together in liver

  • cocaine and Cocaethylene binding to human milk
    American Journal of Clinical Pathology, 1998
    Co-Authors: David N Bailey
    Abstract:

    Abstract The binding of cocaine and its ethyl analog, Cocaethylene, to human milk was studied using equilibrium dialysis at 4°C. For cocaine, a low-affinity, high-capacity binder was noted (equilibrium constant of association, K a , 3.12 × 10 3 L/mol; concentration of binding sites, B 0 3.85 × 10 -4 mol/L), as well as a very low affinity, high-capacity binder (K a , 7.54 × 10 2 L/mol; B 0 , 1.42 × 10 -3 mol/L). For Cocaethylene, 2 low-affinity, high-capacity binders were suggested. a stronger (K a , 3.79 × 10 3 L/mol; B 0 , 3.27 × 10 -4 mol/L) and a weaker (K a , 1.84 × 10 3 L/mol; B 0 , 8.91 × 10 -4 mol/L) binder The low-affinity, high-capacity binder for cocaine and Cocaethylene seems to be albumin, while the weaker nonspecific binding may be due to lipids. Up to 55% of cocaine and up to 61% of Cocaethylene were bound to milk; such binding, coupled with the lower pH of milk (6.9) relative to that of serum (7.4), may enhance the mammary secretion of these 2 basic drugs, having important consequences for the nursing infant.

  • cocaine and Cocaethylene binding to human placenta in vitro
    American Journal of Obstetrics and Gynecology, 1997
    Co-Authors: David N Bailey
    Abstract:

    Abstract Objective: The aim of the study was to determine the binding profiles of cocaine and its ethyl homolog, Cocaethylene, in human placenta. Study design: Pooled whole human placental homogenates supplemented with either nonlabeled cocaine or Cocaethylene over the concentration range 10 to 5000 × 10 –7 mol/L were submitted for equilibrium dialysis. Drug concentrations were measured by high-pressure liquid chromatography. Scatchard analysis of the data was performed. Results: A high-affinity, low-capacity binder was identified for cocaine (equilibrium constant of association, 3.68 × 10 5 L/mol; concentration of binding sites, 4.36 × 10 –6 mol/L) and for Cocaethylene (equilibrium constant of association, 2.42 × 10 4 L/mol; concentration of binding sites, 2.65 × 10 –5 mol/L). Also, a low-affinity, high-capacity binder was noted for cocaine (equilibrium constant of association, 1.93 × 10 3 L/mol; concentration of binding sites, 5.28 × 10 –4 mol/L) and for Cocaethylene (equilibrium constant of association, 2.15 × 10 2 L/mol; concentration of binding sites, 2.65 × 10 –3 mol/L). The concentration of binding sites expressed as moles per gram of placenta was as follows: high-affinity binder (cocaine, 4.36 × 10 –8 ; Cocaethylene, 2.65 × 10 –7 ) and low-affinity binder (cocaine, 5.28 × 10 –6 ; Cocaethylene, 2.65 × 10 –5 ). Up to 59% of cocaine and up to 42% of Cocaethylene was bound. Conclusion: Human placenta may serve as a depot for cocaine and Cocaethylene.

  • cocaine and Cocaethylene binding in human serum
    American Journal of Clinical Pathology, 1995
    Co-Authors: David N Bailey
    Abstract:

    The binding of cocaine (COC) and Cocaethylene (CE) in human serum was studied by equilibrium dialysis. Scatchard analysis suggested a high-affinity binder (K a , 2.56 X 10 4 L/mol ; B 0 , 7.38 X 10 -5 mol/L) and a low-affinity binder (K a , 4.47 X 10 3 L/mol ; B a , 2.77 X 10 -4 mol/L) for COC. Two high-affinity binders (K a , 5.21 X 10 4 L/mol ; B o , 2.54 X 10 -5 mol/L ; and K a , 4.32 X 10 4 L/mol ; B o , 2.43 X 10 -5 mol/L) were discernible for CE. For both compounds additional, very-low-affinity, high-capacity (nonspecific) binding was also seen. Supplementation of serum with specific proteins suggested that the high-affinity binding was due to alpha-1-acid glycoprotein, whereas the low-affinity binding was due to albumin, inasmuch as such supplementation increased the ratio of bound to free drug for both COC and CE.(Key words : Albumin ; Alpha-1-acid glycoprotein ; Binding sites ; Cocaethylene ; Cocaine ; Equilibrium constant of association ; Equilibrium dialysis ; Proteins ; Scatchard analysis; Serum) Am J Clin Pathol 1995 ;104 :180-186.