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PubMed2000

Effects of cocaine context on NAcc dopamine and behavioral activity after repeated intravenous cocaine administration.

In two conditioning experiments, identical procedures (previously shown to produce place preferences for a cocaine-paired environment) were used to assess dopaminergic and behavioral activity correlates of cocaine reward conditioning and sensitization. In these experiments, animals received repeated injections of intravenous cocaine (4.2 mg/kgx6) or saline (0.2 mlx6) on alternating days. One group in each of these experiments ('Cocaine Cues') occupied a consistent distinctive environment during cocaine treatments and testing sessions. For the other conditioned group ('Novel'), all procedures were the same, except that the last cocaine injection was administered while animals were occupying a novel environment. During day 1 and day 6 of the cocaine treatment, behavioral activity was assessed in experiment 1 and in vivo microdialysis procedures were conducted in experiment 2. Over the course of the conditioning sessions, cocaine-induced behavioral activity (locomotion and rearing) increased significantly in the Cocaine Cues group, but not in the Novel group. In addition, cocaine-induced increases in NAcc dopamine levels were significantly greater when cocaine-experienced animals were tested in a cocaine-paired environment compared to equally experienced and cocaine-naive animals tested in a novel environment. Context-dependent behavioral sensitization is a well-documented phenomenon. The observation of a corresponding enhancement of dopamine efflux in lieu of a lengthy withdrawal period is uncommon, but can be attributed to methodological differences across studies. The present study uniquely demonstrates concurrent context-dependent potentiation of behavioral and dopaminergic responses to cocaine occurring in conjunction with cocaine reward.

Animals↗
PubMed1999

Pretreatment with the putative anti-addictive drug, ibogaine, increases the potency of cocaine to elicit locomotor responding: a study with acute and chronic cocaine-treated rats.

RATIONALE: Results of single-dose studies suggest that the effects of pretreatment with the putative anti-addictive compound, ibogaine, on drug-induced locomotor behavior depends on the previous drug history of the animal. OBJECTIVES: To compare the effects of ibogaine pretreatment on the dose-locomotor response function for cocaine in rats treated chronically with either saline or cocaine. METHODS: Rats were chronically treated with either cocaine (15 mg/kg, IP, once daily for 5 days, followed by 2 week withdrawal) or saline. Ibogaine (40 mg/kg, IP) or vehicle was administered and 19 h later, a cocaine dose-locomotor response test was conducted (0, 5, 10, 20 and 40 mg/kg, IP). RESULTS: Chronic cocaine administration augmented the locomotor response to cocaine in chronic cocaine-treated rats, compared to acutely treated controls. Ibogaine pretreatment enhanced the locomotor effects of cocaine in both chronic and acute cocaine groups. Furthermore, due to the shape of the dose-response curve, in chronic cocaine but not in acute cocaine rats, ibogaine pretreatment enhanced the locomotor response to 5 and 10 mg/kg cocaine while decreasing the locomotor response to 40 mg/kg cocaine. CONCLUSIONS: These data demonstrate definitively that ibogaine can enhance sensitivity to the locomotor stimulant effects of cocaine, an effect which depends, in part, on the previous cocaine history of the animal.

Animals↗
PubMed2001

Differential interaction of GBR 12909, a dopamine uptake inhibitor, with cocaine and methamphetamine in rats discriminating cocaine.

RATIONALE: Inhibitors of neuronal dopamine uptake, such as GBR 12909, decrease IV cocaine self-administration by laboratory animals and have been proposed as potential therapeutic agents for abuse of psychomotor stimulant drugs. OBJECTIVES: This study was performed to determine how GBR 12909 alters the discriminative stimulus effects of methamphetamine and cocaine. METHODS: Rats were trained to discriminate between IP injections of 10 mg/kg cocaine and saline and were tested for stimulus generalization to cocaine, GBR 12909, and methamphetamine. Based upon the ED50 of the individual drugs, combinations of GBR 12909 and either cocaine or methamphetamine were tested that comprised a) 1 part GBR 12909 and 2 parts cocaine or methamphetamine, or b) 2 parts GBR 12909 and 1 part cocaine or methamphetamine. RESULTS: GBR 12909 and cocaine were equipotent and 30-fold less potent than methamphetamine in producing cocaine-like discriminative effects. GBR 12909 and cocaine produced cocaine-like discriminative effects synergistically in the ratio of 1 part GBR 12909:2 parts cocaine (0.16+0.32 to 1.92+ 3.87 mg/kg) and nearly synergistically in the ratio of 2 parts GBR 12909:1 part cocaine (0.32+0.16 to 3.92+ 1.91 mg/kg). GBR 12909 and methamphetamine (0.32+0.02 to 3.20+0.22 mg/kg or 0.65+0.01 to 6.53+0.1 mg/kg) were simply additive in both sets of fixed-ratio dose combinations. CONCLUSIONS: The synergy of GBR 12909 and cocaine and the additivity of GBR 12909 and methamphetamine run counter to the presumed mechanisms of action of these drugs at dopamine nerve terminals, which might have implications for the use of GBR 12909 in the treatment of addiction to cocaine or amphetamines.

Animals↗
PubMed1996

Cocaethylene is as cardiotoxic as cocaine but is less toxic than cocaine plus ethanol.

Cocaethylene is a pharmacologically active cocaine metabolite that is produced in the liver by the transesterification of cocaine only in the presence of ethanol. The acute cardiovascular effects of cocaethylene are not known. We compared the acute cardiovascular effects of cocaethylene with cocaine and with cocaine plus ethanol in 18 dogs. We administered cocaethylene 7.5 mg/kg to 6 dogs, cocaine 7.5 mg/kg to 6 dogs, and cocaine 7.5 mg/kg plus ethanol 1 gm/kg to 6 dogs. The dose of each drug was chosen to produce in dogs the concentrations of cocaethylene or cocaine that have been measured in patients who have experienced cardiotoxic reactions to cocaine or cocaine plus ethanol. Arterial, left ventricular (LV), pulmonary artery wedge pressures (PAWP), the maximum rate of LV pressure rise [(dP/dt)max] and fall [(dP/dt)min], and heart rate (HR) were continuously measured. Stroke volume was determined 3 times during the first hour after drug administration then hourly for four hours. The concentrations of cocaethylene and cocaine peaked in the serum at 3717 +/- 651 ng/ml and 4140 +/- 459 ng/ml, respectively, two minutes after each bolus. The median half-life of cocaethylene was 144.3 minutes whereas the median half-life of cocaine was 96.7 minutes (p < 0.01). Cocaethylene maximally decreased (dP/dt)max by 44%, (dP/dt)min by 29%, and stroke volume by 28% (all p < 0.01) and increased the PAWP by 50% (p < 0.02) and the HR by 13% (p = NS) during the first hour. Cocaine maximally decreased (dP/dt)max by 40%, (dP/dt)min by 31%, and the stroke volume by 26% and increased the PAWP by 100% and the HR by 46% (all p < 0.01) during the first hour. Ethanol plus cocaine maximally decreased (dP/dt)max by 68%, (dP/dt)min by 78% and the stroke volume by 49% and increased the PAWP by 118% and the HR by 74% (all p < 0.01) during the first hour. In this last group, (dP/dt)max and stroke volume remained depressed by approximately 20% (p < 0.01) for five hours. We conclude that cocaethylene is as toxic as cocaine to the myocardium but is less toxic than ethanol plus cocaine.

Animals↗
PubMed1994

Saccadic distractibility in cocaine dependent patients: a preliminary laboratory exploration of the cocaine-OCD hypothesis.

Epidemiologic Cachment Area Survey (ECAS) results suggest that cocaine abusing patients are at increased risk for the later development of Obsessive Compulsive Disorder (OCD), and a need for attention in laboratory and clinical research to the 'cocaine-OCD hypothesis' has been described. Analysis of the ECAS data, however, could not rule out the possibility of a 'distinctive OCD-like syndrome' related to cocaine use. Such an OCD-like syndrome in cocaine dependent individuals has been recently described, where some cocaine dependent patients compulsively forage for cocaine, especially after a cocaine binge. To further explore a possible relationship between cocaine dependence and OCD, the performance on an antisaccade task of 32 cocaine dependent individuals was compared to a group of 15 individuals without neuropsychiatric or substance abusing histories. OCD patients have been described as having a greater frequency of reflexive glances (i.e., increased saccadic distractibility) during the antisaccade task than normals. No statistically significant differences in antisaccade performance were observed between the cocaine dependent patients and a normal comparison group. However, when the cocaine using group was divided into those endorsing and those not endorsing significant cocaine-induced compulsive foraging, statistically significant differences emerged. Cocaine-induced compulsive foragers had the poorest antisaccade performance. While the small sample sizes and the lack of an OCD control group limit the conclusions that can be drawn from the present study, the results seem to suggest that a cocaine-OCD link might be particularly relevant for those cocaine addicts endorsing compulsive foraging.

Adult↗
PubMed1997

Distinguishing passive contamination from active cocaine consumption: assessing the occupational exposure of narcotics officers to cocaine.

Hair analysis has been used in probationary and parole populations to monitor for cocaine use, but only in very limited settings or circumstances. Its wider adoption has been limited by questions regarding the ability to distinguish environmental contamination of hair via casual contact from actual ingestion. To evaluate this capability we sought to identify persons routinely exposed to cocaine, who were not cocaine users. Undercover narcotics officers engaged in cocaine-centered enforcement activities and evidence room clerks who have no history of cocaine use were identified as an appropriate example population. Thirty-six active undercover officers and four evidence technicians were asked to voluntarily submit hair samples for analysis. Additionally two cocaine contaminated (aqueous soaked), three negative control samples, and hair from a self-reported crack smoker were also blindly submitted to the testing laboratory. The hair samples were washed and after washing, enzyme digested. The wash solutions and hair digest were each analyzed for the presence of cocaine. The results indicate that nearly every person had trace amounts of cocaine contamination in the wash fraction, and one person had cocaine present in their hair digest That person, when retested, was a negative. The laboratory correctly identified and characterized the contaminated, negative, and positive controls. The study concludes that the findings support the capability of hair analysis to distinguish cocaine use from exposure under normal field conditions. The study results indicate that cocaine-abstinent persons who are in chronic, casual environmental contact with cocaine are not likely to test hair positive for cocaine using the analysis protocols followed in this project. The study also indicates that passive microingestion of cocaine needs to be considered when examining persons who are in cocaine intensive environments.

Cocaine↗
PubMed1999

Cocaine and alcohol interactions in the rat: effect on cocaine pharmacokinetics and pharmacodynamics.

The effect of alcohol coadministration on cocaine pharmacokinetics and pharmacodynamics was investigated in awake, freely moving rats. Cocaine plasma and brain extracellular fluid (ECF) concentration-time profiles were characterized after intraperitoneal (ip) administration of 30 mg/kg cocaine to rats that were pretreated with either normal saline or alcohol at 5 g/kg in a balanced crossover experimental design. The neurochemical response to cocaine administration, measured as the change in dopamine concentration in the nucleus accumbens (N ACC) and the change in the mean arterial blood pressure were monitored simultaneously. Intragastric alcohol administration significantly increased cocaine systemic bioavailability after ip administration from 0.550 +/- 0.044 to 0. 754 +/- 0.071. Also, the absorption rate constant increased from 0. 199 +/- 0.045 to 0.276 +/- 0.059 min-1 due to alcohol coadministration; however, this increase was not significant. Alcohol inhibition of cocaine metabolism caused an increase in cocaine elimination half-life from 26.3 +/- 3.6 to 40.0 +/- 8.1 min. Also, cocaine tissue distribution was enhanced by alcohol, resulting in a significant increase in cocaine volume of distribution. Analysis of the brain cocaine concentration-neurochemical effect relationship by the sigmoid-Emax pharmacodynamic model showed that Emax increased from 850 +/- 200 to 1550 +/- 640% of baseline due to alcohol coadministration, whereas EC50 decreased from 3400 +/- 580 to 2000 +/- 650 ng/mL, indicating higher cocaine potency in the presence of alcohol. The estimates of the indirect inhibitory pharmacodynamic model used to examine the plasma cocaine concentration-change in blood pressure relationship were not significantly different after the two treatments. These results indicate that alcohol significantly alters cocaine absorption, distribution, and elimination, resulting in higher and prolonged cocaine plasma concentration. Alcohol coadministration also potentiates the neurochemical response to cocaine administration.

Algorithms↗
PubMed1996

Cocaine disposition in meconium from newborns of cocaine-abusing mothers and urine of adult drug users.

The analysis of meconium for cocaine and metabolites has proved to be a reliable method for the detection of fetal cocaine exposure. Better sensitivity and a larger gestational window of detection have been demonstrated for meconium testing as compared with neonatal urine testing. Cocaine and cocaine metabolites, including benzoylecgonine, ecgonine methyl ester, cocaethylene, norcocaine, benzoylnorecgonine, and m-hydroxybenzoylecgonine, have been identified in meconium. The origin of these metabolites, whether maternal or fetal, has not been established. This study was conducted to compare the disposition of cocaine and metabolites in meconium from fetuses exposed to cocaine with that of urine from cocaine abusers. Meconium specimens were obtained from six neonates of mothers positive for cocaine use by urinalysis or self-reporting or both during pregnancy. Urine specimens were obtained from 17 adult female and 17 adult male cocaine users enrolled in a treatment program. Specimens were analyzed by gas chromatography-mass spectrometry for cocaine and 12 related analytes. The following analytes were identified and measured in meconium and urine: anhydroecgonine methyl ester; ecgonine methyl ester; ecgonine ethyl ester; cocaine; cocaethylene; benzoylecgonine; norcocaine; norcocaethylene; benzoylnorecgonine; m-and p-hydroxycocaine; and m-and p-hydroxybenzoylecgonine. In addition, both m-and p-hydroxybenzoylecgonine were found to exhibit approximately equal cross-reactivity with benzoylecgonine in the EMIT and TDx assays. The presence of p-hydroxybenzoylecgonine in meconium suggested that this newly identified metabolite, like m-hydroxybenzoylecgonine, might serve as a valuable marker of fetal cocaine exposure during pregnancy. The presence of cocaine and anhydroecgonine methyl ester in meconium was attributed to transfer across the placenta from the mother. However, the origin of the hydrolytic and oxidative metabolites of cocaine could not be established because they were also identified in urine specimens of adult female cocaine users and could have arisen in meconium from either fetal or maternal metabolism.

Adult↗
PubMed2003

The relationship between cocaine craving, psychosocial treatment, and subsequent cocaine use.

OBJECTIVE: Regular measurement of craving during treatment for cocaine dependence can monitor patients' clinical status and potentially assess their risk for drug use in the near future. Effective treatment can reduce the correlation between craving and subsequent drug use by helping patients abstain despite high craving. This study examined the relationship between cocaine craving, psychosocial treatment, and cocaine use in the ensuing week. METHOD: In the National Institute on Drug Abuse Collaborative Cocaine Treatment Study, which compared four psychosocial treatments for cocaine dependence, a three-item craving questionnaire was administered weekly to 449 patients to see whether it predicted cocaine use in the ensuing week. Cocaine use was assessed with self-reports and urine screening. RESULTS: With control for the previous week's cocaine use, a higher composite score on the craving questionnaire was associated with greater likelihood of cocaine use in the subsequent week; each 1-point increase on the composite score of the craving questionnaire increased the likelihood of cocaine use in the ensuing week by 10%. However, among patients who received individual plus group drug counseling, the treatment condition with the best overall cocaine use outcome, increased craving scores were not associated with greater likelihood of cocaine use in the subsequent week. CONCLUSIONS: A three-item cocaine craving questionnaire predicted the relative likelihood of cocaine use during the subsequent week. Moreover, the relationship between craving and subsequent cocaine use varied by treatment condition, suggesting that the most effective treatment in the study might have weakened the link between craving and subsequent use.

Adult↗
PubMed1989

Effects of cocaine and related drugs in nonhuman primates. I. [3H]cocaine binding sites in caudate-putamen.

Specific binding sites for [3H]cocaine were identified in caudate-putamen membranes prepared from nonhuman primate brains (Macaca fascicularis and Saimiri sciureus). Saturation of the sites was determined in competition studies using a fixed concentration of [3H]cocaine (2.7 nM) and increasing concentrations of unlabeled cocaine (1 pM-100 microM). Computer resolution of the shallow displacement curve (nH, 0.58) revealed that a two-component binding model [Kd1, 19.2 nM, maximum binding1 (Bmax1), 28.3 pmol/g of tissue; Kd2, 1120 nM, Bmax2, 431 pmol/g of tissue] was statistically preferred over a one-component model (K.50, 283 nM, Bmax, 471 pmol/g of tissue). Binding of [3H]cocaine was NaCl-dependent, with specific binding reduced by 72% when NaCl (100 mM) was omitted from the incubation medium. [3H]Cocaine was displaced stereoselectively by the enantiomers of cocaine and by the diastereoisomers of cocaine and its phenyltropane analog. Cocaine congeners displaced specifically bound [3H]cocaine with IC50 values ranging from 17 nM to over 100 microM in the following rank order of potency: WIN 35,428 greater than WIN 35,065-2 greater than (-)-cocaine greater than WIN 35,981 greater than (-)-norcocaine greater than WIN 35,140 greater than (+)-cocaine, (+)-pseudococaine greater than 3 alpha-tropanyl-1H-indole-carboxylic acid ester greater than 1 alpha H-3 alpha-5 alpha H-tropan-3-yl-3,5-dichlorobenzoate greater than benzoylecgonine, benzoylnorecgonine and (-)-pseudococaine. Several monoamine uptake inhibitors structurally unrelated to cocaine also displaced [3H]cocaine with IC50 values ranging from 1.6 nM to 50 microM. The rank order of potency was: ( +/- )-trans-3-(3',4'-dichlorophenyl)-N-methyl-1-indanamine greater than mazindol greater than nomifensine greater than methylphenidate 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]- 4-(3-phenylpropyl)piperazine, N-[1-(2- benzo(b)thiophenyl)cyclohexyl]piperidine greater than (-)-cocaine greater than 1-amino-4-phenylbicyclo-[2,2,2]-octane greater than bupropion, nisoxetine greater than desipramine, talsupram greater than citalopram. Other drugs, including the dopamine releasing agent (+)-amphetamine and the dopamine receptor agonists (-)-apomorphine, (+)-4-propyl-9-hydroxy-naphthoxazine, quinpirole and SKF 38393 were weak displacers of [3H]cocaine. Monoamine neurotransmitters also were relatively weak, but dopamine was considerably more potent than either norepinephrine or serotonin.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

Evidence on unusual way of cocaine smuggling: cocaine-polymethyl methacrylate (PMMA) solid solution--study of clandestine laboratory samples.

An abandoned clandestine laboratory was seized in Slovenia. All confiscated exhibits were analysed in a forensic laboratory, where the following analytical methods were applied: capillary gas chromatography coupled with mass spectrometry (GC-MS) combined also by solid-phase micro extraction (SPME) and pyrolysis (Py) technique, Fourier transform infrared spectrometry (FTIR) and scanning electron microscopy with energy dispersive X-ray detector (SEM-EDX). The most interesting analytical findings can be summarised as follows: at the crime scene some plastic pieces, which contained cocaine dissolved (as solid solution) in polymethyl methacrylate-plexiglass (PMMA), were found. The highest cocaine concentration measured in the plastic sample was about 15% by weight. Two larger lumps of material (12 and 3 kg) were composed mainly of PMMA and CaCO3 and contained only 0.4 and 0.5% of cocaine, respectively. As for the low cocaine concentration, we assume that those two lumps of material represent discarded waste product--residue after the isolation of cocaine from plastic. Higher quantities of pure solvents (41 l) and solvent mixtures (87 l) were seized. We identified three types of pure solvents (acetone, gasoline and benzine) and two different types of solvent mixtures (benzine/acetone and gasoline/acetone). The total seized volume (87 l) of solvent mixtures holds approximately 395 g of solid residue formed mainly of PMMA and cocaine. Obviously solvent mixtures were used for isolation of cocaine from the plastic. Small quantities of relatively pure cocaine base were identified on different objects. There were two cotton sheets, most probably used for filtration. One sheet had traces of cocaine base (76% purity) on the surface, while cocaine in hydrochloride form (96%) was identified on the other sheet. GC-MS analyses of micro traces isolated from analytical balances showed the presence of cocaine and some common adulterants: phenacetine, lidocaine and procaine. A cocaine sample compressed in the shape of block was also seized. The above analytical findings inferred us to the conclusion that the illicit laboratory was used for the isolation of cocaine from PMMA resin. Further more, analyses confirm that not only isolation but also further manipulation of cocaine, i.e. adulteration/dilution, as well as the formation of cocaine blocks took place in the house. The information obtained through analyses also allowed us to make some hypotheses about possible multistage isolation procedure.

Journal Article↗
PubMed2006

Investigation of the potential pharmacokinetic and pharmaco-dynamic drug interaction between AHN 1-055, a potent benztropine analog used for cocaine abuse, and cocaine after dosing in rats using intracerebral microdialysis.

PURPOSE: AHN 1-055, a benztropine (BZT) analog, binds with high affinity to the dopamine transporter (DAT), possesses behavioral, pharmacokinetic (PK) and brain microdialysate dopamine (DA) profiles distinct from cocaine. Accordingly, the objectives of this study were to evaluate the pharmacokinetics and dopamine release of AHN 1-055, in the presence of cocaine. METHODS: Male Sprague Dawley rats ( approximately 300 g) were administered 5 mg/kg of AHN 1-055 and cocaine i.v. and blood and brain samples were collected over 36 h. In addition, dialysis probes were stereotaxically implanted into the nucleus accumbens and extracellular fluid (ECF) DA levels were measured. PK and PD models were used to describe the relationship between the AHN 1-055, cocaine and DA levels. RESULTS: No significant (p< 0.05) differences were found in the PK parameters of AHN 1-055 alone (V(dss) = 18.7 l/kg, Cl = 1.8 l/h/kg and t(1/2) = 7.69 h) or AHN 1-055 with cocaine (V(dss)=17.4 l/kg, Cl = 1.9 l/h/kg and t(1/2) = 6.82 h). The brain-to-plasma (B/P) ratios (B/P(AHN 1-055) = 4.8 vs B/P(with cocaine) = 4.4) and half-lives (t(1/2(AHN 1-055)) = 6.2 h vs t(1/2(cocaine) = )5.6 h for AHN 1-055 alone and with cocaine were comparable. AHN 1-055 DA profiles were significantly different after co-administration with cocaine. There were no differences in the IC(50) for AHN 1-055, with cocaine, however, the IC(50) for cocaine was significantly reduced with AHN 1-055. CONCLUSIONS: The PK parameters of AHN 1-055 were not changed, however, the effect on DA levels was affected when cocaine was administered with AHNDA profile is affected when dosed with cocaine. This latter effect is a desirable attribute in the development of a medication as a potential substitute therapeutic medication for the treatment of cocaine abuse.

Animals↗
PubMed2000

Effects of dopamine D(1-like) and D(2-like) agonists on cocaine self-administration in rhesus monkeys: rapid assessment of cocaine dose-effect functions.

RATIONALE: The reinforcing effects of cocaine have been most compellingly related to its action as an indirect dopamine agonist. Although it is generally believed that both D(1-like )and D(2-like )receptor mechanisms may be involved, recent studies suggest that D(1-like )and D(2-like )agonists have differing profiles of cocaine-related actions. OBJECTIVE: To develop a procedure for rapid assessment of complete dose-effect functions for cocaine self-administration in rhesus monkeys and to compare the effects of D(1-like )and D(2-like )agonists on cocaine self-administration using this procedure. METHODS: Responding was maintained by various doses of cocaine or by food under a multiple-component schedule [fixed ratio (FR) 30; time out period (TO) 10 s] in 2-h sessions. After responding stabilized, the effects of pretreatment with D(1-like )and D(2-like )agonists (administered i.m., 10 min or 30 min prior to the session) were assessed. RESULTS: Complete inverted U-shaped dose-effect functions for cocaine self-administration were obtained in all five rhesus monkeys trained with the rapid assessment procedure. Both the position and shape of the cocaine dose- effect function remained stable in repeated assessments, and levels of responding were controlled by the unit dose of cocaine rather than by other variables (e.g., infusion duration and volume) that were used to vary the cocaine dose. Pretreatment with the D(1-like) agonists SKF 82958 (0.32-1.8 mg/kg) and R-6-Br-APB (0.1-1. 0 mg/kg) produced downward shifts in the cocaine dose-effect function at doses that also markedly decreased food-maintained responding. In contrast, pretreatment with the D(2-like) agonists quinelorane (0.001-0.01 mg/kg) and 7-OH-DPAT (0.01-0.10 mg/kg) shifted the cocaine dose-effect function to the left. D(2-like) agonists also increased responding maintained by the cocaine-associated cue lights alone, and moderately decreased food-maintained responding. CONCLUSIONS: The results suggest that D(1-like) and D(2-like) agonists produce qualitatively different effects on cocaine self-administration that may influence their usefulness for the treatment of cocaine abuse and dependence.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2002

Immediate-early gene expression in concurrent prenatal ethanol- and/or cocaine-exposed rat pups: intrauterine differences in cocaine levels and Fos expression.

Concurrent use of cocaine and ethanol is a common mode of abuse. Cocaine and ethanol have distinctive pharmacologies but both have been shown to cause uterine vasoconstriction and fetal hypoxia. We developed a paradigm of chronic ethanol exposure via liquid diet coupled with binge cocaine exposure on the last day of gestation. Lipton et al. demonstrated unequal segregation of cocaine in rat fetuses as a function of proximal-distal location in the uterus, indicating a differential vasoconstriction of the two main arteries supplying the uterus in rats receiving cocaine. By performing C-sections after exposure to cocaine, we were able to measure the cocaine content and immediate-early gene (IEG) induction in the brains of fetuses according to their intrauterine position and assess the potentially vasoconstrictive effect of ethanol. HPLC analysis of fetal brains exposed to cocaine supported the study of Lipton et al.: fetuses from the proximal (lower) end of the uterus had more cocaine than fetuses from the distal (upper) end. Concurrent ethanol decreased the amount of cocaine reaching the fetuses and diminished the proximal-distal gradient. There were increased numbers of Fos-immunoreactive cells in fetuses exposed to both ethanol and cocaine compared to cocaine binge only. Additionally, the gradient of c-fos induction observed as a function of intrauterine position in cocaine-treated rats was in the opposite direction: most distal fetuses generally had the most Fos-immunoreactive cells. These results indicate that IEG induction in fetal brains exposed to cocaine and ethanol may be more related to hypoxic consequences of prenatal drug exposure.

Alcohol-Induced Disorders, Nervous System↗
PubMed2004

Influence of handling or aversive stimulation during rats' neonatal or adolescence periods on oral cocaine self-administration and cocaine withdrawal.

Adverse early life events may influence vulnerability for drug intake. The influence of handling or aversive stimulation during neonatal or adolescent periods on adult cocaine oral self-administration and withdrawal were investigated. Neonatal or adolescent rats were exposed to a modified unpredictable stress paradigm or handling for 10 days. When adults, oral cocaine was offered through the two-bottle choice paradigm for 30 days. Rats were submitted to the forced swimming test after cocaine withdrawal. Overall, there was a significant increase of cocaine choice throughout the days of cocaine consumption and an interaction between interventions and cocaine daily choice. Control rats started cocaine intake at a lower level and increased cocaine choice over time, while animals submitted to neonatal interventions started cocaine intake at higher levels of choice, with less increase in cocaine intake during the period of cocaine exposure. Rats receiving aversive stimulation during adolescence also started taking cocaine solution at higher levels. Significantly higher immobility duration and shorter latency to immobility during the forced swimming were detected in these same adolescents that received unpredictable stress, when compared to the control or handled rats, while there was no difference for rats stimulated neonatally. Therefore, early life events increase initial preference for cocaine and promote changes in its abuse pattern, according to the intensity of the event and the age of the individual at the time of the event. Moreover, adverse experiences during adolescence, but not in neonatal phases, increase the vulnerability to depressive-like behaviors during cocaine withdrawal of adult rats.

Adolescent↗
PubMed2005

Modafinil influences the pharmacokinetics of intravenous cocaine in healthy cocaine-dependent volunteers.

OBJECTIVE: To determine if modafinil, a putative treatment for cocaine dependence, influences the pharmacokinetics of intravenous cocaine in otherwise healthy cocaine-dependent volunteers. METHODS: Cocaine 20 or 40 mg was administered intravenously on consecutive days over 1 minute at baseline and after modafinil administration at each of two dosages of 400 and 800 mg/day for 7 days. RESULTS: Twelve subjects completed the clinical protocol. Compared with baseline, the cocaine peak plasma concentration was decreased after both the 20 and 40 mg cocaine infusions, but the reduction was only statistically significant after the 40 mg cocaine infusion (p < 0.01 after modafinil 400 mg/day; p < 0.05 after modafinil 800 mg/day). The area under the cocaine plasma concentration-time curve from 0 to 180 minutes (AUC180) was significantly decreased by modafinil administration (p < 0.01 and p < 0.001 for modafinil 400 and 800 mg/day, respectively, for the cocaine 20mg dose; p < 0.001 for the cocaine 40 mg dose at both modafinil levels). There were no significant changes in total AUC, clearance or elimination half-life of cocaine. CONCLUSION: This study did not find evidence for a harmful pharmacokinetic interaction between modafinil and cocaine. In contrast, long-term administration of modafinil significantly decreased systemic exposure to cocaine during the first 180 minutes following intravenous cocaine administration.

Administration, Oral↗
PubMed2001

Enadoline and butorphanol: evaluation of kappa-agonists on cocaine pharmacodynamics and cocaine self-administration in humans.

Preclinical studies have demonstrated that kappa-opioid agonists can attenuate the neurochemical and behavioral effects of cocaine that are related to its reinforcing efficacy, suggesting that kappa-agonists may serve as pharmacotherapies for cocaine dependence. This 8-week inpatient study examined the ability of enadoline, a selective and high-efficacy kappa-agonist, and butorphanol, a mixed agonist with intermediate efficacy at both mu- and kappa-receptors, to reduce the direct pharmacodynamic effects and self-administration of intravenous cocaine in humans (n = 8). Acute doses of intramuscular enadoline (20, 40, and 80 microg/kg), butorphanol (1.5, 3, and 6 mg/70 kg) and placebo were examined separately as pretreatments during each of three test sessions with cocaine in a constrained random order. A cocaine dose-effect session (0, 20, and 40 mg cocaine i.v., 1 h apart) examined direct pharmacodynamic interactions on subjective and physiological indices; self-administration sessions examined choice behavior for cocaine (40 mg i.v. for six trials) versus money 1) in the presence of a sample cocaine dose with money choices presented in ascending value, and 2) in the absence of a sample dose with money choices presented in descending values. Enadoline (80 microg/70 kg) significantly (p < 0.05) reduced some of the positive subjective effects of cocaine (e.g., ratings of "high"), while butorphanol failed to modify subjective responses. Both agents were safely tolerated in combination with cocaine without adverse physiological responses. Cocaine self-administration was significantly greater across all pretreatment conditions when the sample dose was given and ascending money choices were used. Enadoline and butorphanol failed to modify cocaine self-administration. These data suggest that these kappa-agonists may be safely administered in the presence of cocaine but do not produce significant attenuation of cocaine's direct effects or self-administration under these acute dosing conditions.

Adult↗
PubMed2002

Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats.

dopamine D3 receptor is preferentially localized to the mesocorticolimbic dopaminergic system and has been hypothesized to play a role in cocaine addiction. To study the involvement of the D3 receptor in brain mechanisms and behaviors commonly assumed to be involved in the addicting properties of cocaine, the potent and selective D3 receptor antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide (SB-277011-A) was administered to laboratory rats, and the following measures were assessed: (1) cocaine-enhanced electrical brain-stimulation reward, (2) cocaine-induced conditioned place preference, and (3) cocaine-triggered reinstatement of cocaine seeking behavior. Systemic injections of SB-277011-A were found to (1) block enhancement of electrical brain stimulation reward by cocaine, (2) dose-dependently attenuate cocaine-induced conditioned place preference, and (3) dose-dependently attenuate cocaine-triggered reinstatement of cocaine seeking behavior. Thus, D3 receptor blockade attenuates both the rewarding effects of cocaine and cocaine-induced drug-seeking behavior. These data suggest an important role for D3 receptors in mediating the addictive properties of cocaine and suggest that blockade of dopamine D3 receptors may constitute a new and useful target for prospective pharmacotherapies for cocaine addiction.

Animals↗