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PubMed2004

A fatal overdose of cocaine associated with coingestion of marijuana, buprenorphine, and fluoxetine. Body fluid and tissue distribution of cocaine and its metabolites determined by hydrophilic interaction chromatography-mass spectrometry(HILIC-MS).

Chromatographic separation of highly polar basic drugs with ideal ionspray mass spectrometry volatile mobile phases is a difficult challenge. A new quantification procedure was developed using hydrophilic interaction chromatography-mass spectrometry with turbo-ionspray ionization in the positive mode. After addition of deuterated internal standards and simple clean-up liquid extraction, the dried extracts were reconstituted in 500 microL pure acetonitrile and 5 microL was directly injected onto a Waters Atlantis HILIC 150- x 2.1-mm, 3-microm column. Chromatographic separations of cocaine, seven metabolites, and anhydroecgonine were obtained by linear gradient-elution with decreasing high concentrations of acetonitrile (80-56% in 18 min). This high proportion of organic solvent makes it easier to be coupled with MS. The eluent was buffered with 2 mM ammonium acetate at pH 4.5. Except for m-hydroxy-benzoylecgonine, the within-day and between-day precisions at 20, 100, and 500 ng/mL were below 7 and 19.1%, respectively. Accuracy was also below +/- 13.5% at all tested concentrations. The limit of quantification was 5 ng/mL (%Diff < 16.1, %RSD < 4.3) and the limit of detection below 0.5 ng/mL. This method was successfully applied to a fatal overdose. In Switzerland, cocaine abuse has dramatically increased in the last few years. A 45-year-old man, a known HIV-positive drug user, was found dead at home. According to relatives, cocaine was self-injected about 10 times during the evening before death. A low amount of cocaine (0.45 mg) was detected in the bloody fluid taken from a syringe discovered near the corpse. Besides injection marks, no significant lesions were detected during the forensic autopsy. Toxicological investigations showed high cocaine concentrations in all body fluids and tissues. The peripheral blood concentrations of cocaine, benzoylecgonine, and methylecgonine were 5.0, 10.4, and 4.1 mg/L, respectively. The brain concentrations of cocaine, benzoylecgonine, and methylecgonine were 21.2, 3.8, and 3.3 mg/kg, respectively. The highest concentrations of norcocaine (about 1 mg/L) were measured in bile and urine. Very high levels of cocaine were determined in hair (160 ng/mg), indicating chronic cocaine use. A low concentration of anhydroecgonine methylester was also found in urine (0.65 mg/L) suggesting recent cocaine inhalation. Therapeutic blood concentrations of fluoxetine (0.15 mg/L) and buprenorphine (0.1 microg/L) were also discovered. A relatively high concentration of Delta(9)-THC was measured both in peripheral blood (8.2 microg/L) and brain cortex (13.5 microg/kg), suggesting that the victim was under the influence of cannabis at the time of death. In addition, fluoxetine might have enhanced the toxic effects of cocaine because of its weak pro-arrhythmogenic properties. Likewise, combination of cannabinoids and cocaine might have increase detrimental cardiovascular effects. Altogether, these results indicate a lethal cocaine overdose with a minor contribution of fluoxetine and cannabinoids.

Analgesics, Opioid↗
PubMed2003

Mixed cocaine agonist/antagonist properties of (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylate, a piperidine-based analog of cocaine.

The present study investigated the pharmacological properties of a piperidine-based novel cocaine analog, namely, (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylic acid [(+)-CPCA]. Like cocaine, (+)-CPCA inhibited rat synaptosomal dopamine and norepinephrine uptake with high affinity, but was 33-fold less potent than cocaine in inhibiting serotonin uptake. Like cocaine, (+)-CPCA is a locomotor stimulant, although it was less potent and efficacious than cocaine. Importantly, pretreatment with (+)-CPCA dose dependently blocked the locomotor stimulant effects of cocaine in rats. (+)-CPCA completely substituted for cocaine in drug discrimination tests, although it was about 3 times less potent than cocaine. It was also self-administered by rats. Unexpectedly, (+)-CPCA did not enhance cocaine-induced convulsions in mice. As expected from rodent studies, rhesus monkeys readily self-administered (+)-CPCA. However, compared with cocaine, (+)-CPCA showed limited reinforcing properties in rats as assessed by both fixed and progressive ratio intravenous drug self-administration tests. These results collectively suggest that (+)-CPCA has an atypical pharmacological profile having both cocaine-like "agonist" and some cocaine "antagonist" properties. These properties of (+)-CPCA suggest that it may have utility in the treatment of cocaine craving and dependence.

Animals↗
PubMed1991

Nifedipine protects the heart from the acute deleterious effects of cocaine if administered before but not after cocaine.

BACKGROUND: We tested the hypothesis that nifedipine, a calcium channel blocker, could ameliorate the toxic effects of cocaine on the myocardium. METHODS AND RESULTS: In an initial protocol, anesthetized dogs were pretreated with nifedipine or saline and then administered cocaine (10 mg/kg, i.v. bolus). Coronary blood flow, heart rate, mean arterial pressure, and the first derivation of left ventricular pressure (dP/dt) were measured at baseline, 2 minutes, and 15 minutes after cocaine administration. Nifedipine pretreatment prevented the early cocaine-induced decrease in coronary blood flow and improved left ventricular dP/dt compared with untreated control animals. After cocaine, ejection fraction fell in the saline group to 37 +/- 3% but increased in the nifedipine group to 59 +/- 4% (p less than 0.05). In a second protocol, vehicle or intravenous nifedipine was administered after an infusion of cocaine (10 mg/kg). In contrast to pretreatment, there was no significant improvement in left ventricular function or coronary blood flow in nifedipine-treated versus control animals. Data from the study also suggested that cocaine acts directly on the myocardium. Within seconds of cocaine bolus administration, coronary blood flow in control animals increased to a peak level 59 +/- 14% higher than before cocaine and left ventricular dP/dt decreased by 23 +/- 5%, providing evidence that cocaine causes direct depression of myocardial function independent of a decrease in myocardial blood flow. CONCLUSIONS: We conclude that nifedipine administered as a pretreatment protects against the depression of myocardial function and decrease in coronary blood flow caused by acute cocaine administration. However, when nifedipine is given after cocaine, no improvement is seen. Cocaine has a direct negative inotropic effect on the heart that is independent of a decrease in coronary blood flow.

Animals↗
PubMed1992

Early afterdepolarizations and triggered activity induced by cocaine. A possible mechanism of cocaine arrhythmogenesis.

BACKGROUND: Cocaine may produce life-threatening cardiac arrhythmias, but it is not clear whether this is an indirect effect of coronary vasoconstriction and ischemia or a direct myocardial effect of the substance. Except for its effects on the Na+ current as a local anesthetic, little is known about the direct electrophysiological actions on cardiac cells. Therefore, we studied the effects of cocaine on action potentials and membrane currents in isolated feline ventricular myocytes to test the hypothesis that cocaine-induced arrhythmogenesis may be based on cellular and ionic mechanisms. METHODS AND RESULTS: Action potentials and membrane currents were recorded using the patch clamp technique. Single cells were isolated from feline left ventricles by enzymatic digestion. Exposure to cocaine (10 or 50 microM) depressed the plateau phase of the action potential and prolonged action potential duration. Action potential duration measured at 90% repolarization (APD90) was increased from 280 +/- 12 msec to 325 +/- 17 msec (p less than 0.01) by 5-minute exposure to 10 mumol cocaine, when the cells were stimulated at 1 Hz. During exposure to 50 mumol cocaine, APD90 was markedly increased from 298 +/- 13 msec to 437 +/- 35 msec (p less than 0.01) in seven of 16 cells, and early afterdepolarizations (EADs) developed in these cells. The take-off potential and the amplitude of EADs were -28.3 +/- 2.3 mV and 16.8 +/- 1.2 mV, respectively. Triggered activity arising from EADs was induced in four of the seven cells. Addition of 1 nmol isoproterenol augmented EADs and induced sustained triggered activity, whereas they were suppressed by exposure to 2 microM verapamil. Whole-cell voltage clamp experiments revealed that cocaine (50 microM) reduced the peak L-type Ca2+ current from 1.03 +/- 0.13 nA to 0.79 +/- 0.11 nA (23% reduction, p less than 0.05). Cocaine also reduced the peak delayed rectifier K+ current from 362 +/- 51 pA to 113 +/- 32 pA (69% reduction, p less than 0.01). However, cocaine did not affect activation and inactivation kinetics of these channels. Cocaine had no effect on the inward rectifier K+ current. CONCLUSIONS: We conclude that cocaine can prolong action potential duration and induce EADs and triggered activity by blocking the delayed rectifier K+ current, and that cocaine-induced abnormalities of repolarization, modulated by its inhibitory effects on catecholamine reuptake, may play a role in the potential of cocaine for induction of acute fatal arrhythmias.

Action Potentials↗
PubMed1995

Cocaine and exercise: physiological responses of cocaine-conditioned rats.

To compare the physiological response to a cocaine-exercise challenge in cocaine-conditioned animals with that of acute-cocaine animals, rats were injected i.p. with either cocaine (20 mg.kg-1) or saline, twice daily for 14 consecutive days. On the 15th day (test day) cocaine-conditioned rats received an i.v. injection of cocaine (5 mg.kg-1) (chronic group). One-half of the chronic saline rats also received the cocaine injection (acute group), while the other half received saline (saline group). Immediately after injection, all rats were either rested or exercised (22 m.min-1, 10% grade) for 30 min. For most parameters there was no difference between the responses of the chronic and acute cocaine groups at rest or to the cocaine-exercise challenge. During exercise, both cocaine groups had similarly higher lactate values than the saline animals (P < 0.05). Both groups had similarly greater reductions in glycogen content of the white and red vastus muscles than occurred in the saline group; and both groups had similar increases in corticosterone. In contrast, cocaine-conditioned animals had a greater rise in norepinephrine (P < 0.059) and epinephrine (P < 0.001) in response to cocaine-exercise than did the acute group. The mechanism responsible for the exaggerated catecholamine response in the chronic cocaine animals is unknown.

Adaptation, Physiological↗
PubMed2006

Is there epidemiological evidence to support the idea that a cocaine dependence syndrome emerges soon after onset of cocaine use?

The present study uses latent class methods and multiple regression to shed light on hypothesized cocaine dependence syndromes experienced by community residents, who initiated cocaine use within 24 months of survey assessment, and explores possible variation in risk. Identified within public use data files from the United States National Household Surveys on Drug Abuse (NHSDA), and with assessments completed between 1995 and 1998, the study sample consists of 927 recent-onset cocaine users, defined as having initiated cocaine use no more than 24 months prior to assessment (approximate median elapsed time since onset of use approximately 12-13 months). The NHSDA included items to assess seven clinical features often associated with cocaine dependence, which were used in latent class modeling. Empirically derived latent classes, in conjunction with prior theory, tend to support a three-class solution, according to which 4% of recent-onset users are members of a class that resembles the DSM-IV cocaine dependence syndrome (mean: 5.4 clinical features (CF)); 16% might be in a cocaine dependence prodrome (mean: 2.4 CF); 80% of recent-onset cocaine users had few or no clinical features (mean<1 CF). Results from latent class regressions indicate that susceptibility to rapid transition from first cocaine use to onset of the LCA-assigned cocaine dependence syndrome might depend upon whether the user starts smoking crack-cocaine and, independently, age at first cocaine use.

Adolescent↗
PubMed1994

Opioid modulation of the discriminative stimulus effects of cocaine: comparison of µ, kappa and delta agonists in squirrel monkeys discriminating low doses of cocaine.

Modulation of the discriminative stimulus effects of cocaine by the µ agonist morphine, the kappa agonist U 50, 488, and the delta agonist BW 373U86 was investigated in squirrel monkeys using a two-lever drug discrimination procedure. Monkeys initially were trained to discriminate intramuscular injections of 0.3 or 0.56mg/kg cocaine from vehicle and subsequently retrained to discriminate a 3- to 5.6-fold lower dose of cocaine (0.1 or 0.18mg/kg). After retraining, dose-response functions for the discriminative stimulus effects of cocaine were shifted to the left and ED(50) values were reduced 2- to 6-fold compared to values obtained with the higher training doses. In drug substitution experiments, morphine (0.03-1.0mg/kg), U 50,488 (0.1-3.0mg/kg) and BW 373U86 (0.001-0.1mg/kg) did not reproduce the discriminative stimulus effects of the low training doses of cocaine, although U 50,488 engendered a majority of responses on the cocaine-associated lever in two of three monkeys. In drug interaction experiments, pretreatment with morphine (0.3mg/kg) potentiated the discriminative stimulus effects of the low training doses of cocaine such that the cocaine dose-response functions were shifted to the left and ED(50) values were reduced 3- to 7-fold. Pretreatment with U 50,488 (0.3mg/kg), on the other hand, attenuated the discriminative stimulus effects of the low training doses of cocaine such that the cocaine dose-response functions were shifted to the right and ED(50) values were increased approximately 4-fold. The cocaine-modulating effects of morphine and U 50,488 in these experiments were qualitatively similar to those observed previously when the monkeys were trained to discriminate higher doses of cocaine. In contrast to the effects of the µ and kappa agonists, pretreatment with BW 373U86 (0.01 or 0.03mg/kg) did not systematically alter the discriminative stimulus effects of cocaine regardless of training dose.

Journal Article↗
PubMed2005

Effects of intra-nucleus accumbens shell administration of dopamine agonists and antagonists on cocaine-taking and cocaine-seeking behaviors in the rat.

RATIONALE: Dopamine signaling in the nucleus accumbens (NAc) plays an important role in regulating drug-taking and drug-seeking behaviors, but the role of D(1)- and D(2)-like receptors in this regulation remains unclear. OBJECTIVES: Our objective was to study the role of NAc D(1)- and D(2)-like receptors in the reinstatement of cocaine-seeking behavior and the regulation of stabilized cocaine intake in rats. METHODS: Using a within-session reinstatement procedure, whereby animals self-administer cocaine (90 min) and extinguish responding (150 min) in a single session, we assessed the ability of NAc microinfusions of the D(1) agonist SKF 81297 and the D(2) agonist 7-OH-DPAT to reinstate extinguished cocaine seeking. The effects of the D(1) antagonist SCH 23390 and the D(2) antagonist eticlopride pretreatment on agonist- and cocaine-primed reinstatement were also measured. Similar agonist and antagonist treatments were tested for their ability to modulate stabilized cocaine and sucrose self-administration. RESULTS: Intra-NAc infusions of either SKF 81297 (0.3-3.0 microg) or 7-OH-DPAT (1.0-10.0 microg) dose-dependently reinstated cocaine seeking with greater efficacy in the medial core than in the shell subregion and at doses that also stimulated locomotor behavior. Intra-NAc shell infusions of SCH 23390 (1.0 microg) and eticlopride (3.0-10.0 microg) blocked cocaine-primed reinstatement (2.0 mg/kg, i.v.) and indiscriminately blocked reinstatement induced by either intra-NAc D(1) or D(2) agonists. Doses of agonists that triggered reinstatement failed to alter stabilized cocaine intake, whereas doses of antagonists that blocked reinstatement increased cocaine intake in the shell. CONCLUSIONS: Both D(1) and D(2) receptors in the NAc play a prominent, and perhaps cooperative, role in regulating cocaine-taking and cocaine-seeking behaviors.

Animals↗
PubMed2005

The role of cocaine in heroin-related deaths. Hypothesis on the interaction between heroin and cocaine.

In recent years, there has been an increase in cocaine-related deaths at the Department of Legal Medicine and Public Health of Pavia, probably reflecting the rising trend in cocaine use in Western Europe. Deaths from cocaine alone have increased from 6 cases in 1979-1991 (1.5% of drug-of-abuse deaths) to 13 in 1992-2002 (3.2%) and comparing the same periods, heroin-related deaths (HRDs) involving cocaine more than doubled from 8 (1.9%) to 22 (5.4%). In an attempt to investigate the role of cocaine in HRDs, acute narcotic death cases testing positive for cocaine use (blood cocaine or metabolite concentration >0.01 mg/l, COC+) were examined. Only cases from 1997 to 2001 were considered as in this period all data were obtained using the same analytical procedures (free morphine and total morphine by DPC Coat-A-Count radioimmunoassay before and after enzymatic hydrolysis, cocaine and metabolites in blood by SPE, TMS derivatization and gas chromatography-mass spectrometry (GC-MS)). The median, minimum and maximum concentrations of free morphine in blood (FM) and total morphine in blood (TM), urine (UM) and bile (BM) in the COC+ group (n = 9) were compared with those calculated in the group of "pure" HRDs (no other drugs detected in blood, COC-, n = 30). Differences among the medians in the two groups were statistically evaluated using the two-tailed Mann-Whitney U-Test. Statistical analysis was also carried out including in both groups cases with a blood alcohol concentration (BAC) > 20 mg/L (COC+, n = 19; COC-, n = 76). For the COC+ group, median TM was lower (0.32 mg/l versus 0.90 mg/l, P = 0.0214), median FM was lower, but not statistically significant (0.08 mg/l versus 0.28 mg/l, P = 0.1064), FM/TM ratio was similar (0.33 and 0.35), UM was also similar (21.0 mg/l and 18.0 mg/l), and BM was higher (90.0 mg/l versus 49.0 mg/l, P = 0.0268). Similar comparison results were obtained by repeating statistical analyses after including in the two groups cases with positive BAC. The picture observed for HRD cases involving cocaine is very different from what was previously observed for HRD cases involving ethanol [A. Polettini, A. Groppi, M. Montagna, The role of alcohol abuse in the etiology of heroin related deaths: evidence for pharmacokinetic interactions between heroin and alcohol, J. Anal. Toxicol. 23 (1999) 570-576], and updated with more recent data; in the high-ethanol (HE, BAC > 1000 mg/l) group, TM was lower than in the low-ethanol (LE, BAC <or= 1000 mg/l) group (0.59 mg/l versus 0.90 mg/l, P = 0.0180), FM/TM ratio was higher (0.66 versus 0.43, P = 0.0038), FM was equal, UM was lower (0.21 mg/l versus 13.0 mg/l, P = 0.0001), as was BM (10.0 mg/l versus 26.5 mg/l, P = 0.0156). The observed lower TM in the COC+ group supports the hypothesis of an interaction of cocaine with heroin in the cause of death, as previously observed for the heroin-ethanol interaction. However, ethanol results suggested that a pharmacokinetic interaction is prevalent (inhibition of heroin metabolism, as suggested by the increased FM/TM ratio, resulting in reduced urinary and biliary excretion). In the case of cocaine, a pharmacodynamic interaction seems to prevail, as the FM/TM ratio remains unchanged and UM and BM are not lower in the COC+ group. The hypothesis of a pharmacodynamic interaction of cocaine with heroin could not be confirmed owing to the paucity of data and the many uncontrolled variables involved.

Adolescent↗
PubMed2005

Dopamine D1 or D2 receptor antagonism within the basolateral amygdala differentially alters the acquisition of cocaine-cue associations necessary for cue-induced reinstatement of cocaine-seeking.

The basolateral amygdala complex has been implicated in the formation and utilization of cocaine-cue associations in rat models of cue-induced reinstatement to cocaine-seeking behavior. We have previously demonstrated the importance of dopamine inputs to the basolateral amygdala complex in the reinstatement of cocaine-seeking behavior following chronic cocaine self-administration. Here we show that selective blockade of amygdalar dopamine D1 and D2 receptors during acquisition of cocaine-cue associations has distinctive effects on subsequent conditioned-cued cocaine-seeking behavior. Male, Sprague-Dawley rats were first trained to self-administer i.v. cocaine on a fixed ratio 1 schedule for 5 days. Subjects then received bilateral, intra-basolateral amygdala complex infusions of a dopamine D1 receptor antagonist (SCH23390, 0.25-2.0 microg/side; experiment 1), a dopamine D2 receptor antagonist (raclopride, 0.625-5.0 microg/side; experiment 2), or vehicle just prior to a single classical conditioning session, during which a light+tone cue was discretely paired with passive infusions of cocaine in the absence of lever responding. Following five additional days of cocaine self-administration and 7-10 days of extinction training, animals underwent multiple tests for cue-induced reinstatement. SCH23390 (2.0 microg/side), administered at the time of cocaine-cue association only, produced an attenuation of reinstatement to cue-induced cocaine-seeking behavior. In contrast, low doses of raclopride potentiated, while a higher dose of raclopride attenuated cue-induced reinstatement. These results demonstrate unique contributions of D1 vs. D2 receptors in mediating dopamine inputs within the basolateral amygdala complex during the formation of cocaine-stimulus associations that are critical for cue-induced reinstatement.

Amygdala↗
PubMed2004

Effects of progesterone treatment on cocaine responses in male and female cocaine users.

We recently reported that progesterone treatment attenuated some of the subjective effects of smoked cocaine in female cocaine users. In this study, we further examined the interaction between progesterone and cocaine in both male and female cocaine users using subjective, physiological and behavioral outcomes. A total of 10 subjects, 6 male and 4 female cocaine users, had two experimental sessions. Before each session, participants received either two oral doses of 200 mg of progesterone or placebo. Two hours after the second dose of medication treatment, the participants received a 0.3 mg/kg dose of cocaine intravenously and started the self-administration period, in which five optional doses of cocaine were available. Progesterone treatment attenuated the cocaine-induced diastolic blood pressure increases without affecting the systolic blood pressure and heart rate increases. Progesterone treatment also attenuated the subjective ratings of high and feel the effect of last dose in response to cocaine but did not affect cocaine self-administration behavior. These results suggest that progesterone attenuates some of the physiological and subjective effects of cocaine in both male and female participants. The effects of progesterone treatment on cocaine dependence need to be further studied in controlled trials.

Adult↗
PubMed1999

Effects of contingent and non-contingent cocaine on drug-seeking behavior measured using a second-order schedule of cocaine reinforcement in rats.

Rats were trained to respond with intravenous cocaine as the reinforcer under a fixed interval 15-min schedule, during which conditioned stimuli paired with cocaine were presented contingent on completion of a fixed ratio of 10 responses (i.e., second-order schedule of reinforcement). The effects of contingent and noncontingent cocaine were investigated. The results show that pretreatment with noncontingent (i.e., experimenter-administered) cocaine led to a satiation-like effect that was reflected in decreased numbers of responses and a tendency for an increased latency to initiate responding when the doses of cocaine administered were similar to or higher than the training/maintenance dose of cocaine. By contrast, noncontingent administration of cocaine doses lower than the training/maintenance dose, and response-contingent cocaine administration, led to increased drug-seeking behavior, as reflected in increased numbers of responses. The present data indicate that at least two factors determine whether administration of cocaine would lead to drug-seeking behavior: whether the cocaine administration is contingent or noncontingent, and the relative magnitude of the cocaine dose administered in relation to the training/maintenance dose of cocaine.

Analysis of Variance↗
PubMed2005

Effects of isradipine on cocaine-induced changes in cognitive performance in recently abstinent cocaine-dependent individuals.

Recently abstinent cocaine-dependent individuals, compared with healthy controls, appear more likely to exhibit deficits in cognitive performance and attention. Individuals with such cognitive deficits might be less able to avail themselves of rehabilitative or relapse-prevention efforts. Pharmacotherapy that reduces the impairment in cognitive performance among cocaine-dependent individuals would be a useful clinical tool. Preclinical and human studies suggest that the dihydropyridine-class calcium-channel antagonist, isradipine, can enhance neurocognitive function in some neuropsychiatric disorders. Isradipine, presumably by increasing cerebral blood flow and its actions at various neurotransmitter systems, might, therefore, ameliorate the impairment in cognitive performance and attention seen in cocaine addicts and enhance the expected modest improvement in performance during acute cocaine-taking in these same individuals. Among 12 male and female cocaine-dependent individuals, we examined the effects of low and high doses of intravenous cocaine (0, 0.325, and 0.650 mg/kg) on cognitive performance and attention in both the presence and absence of isradipine (0 or 30 mg sustained release each evening prior to testing, plus 0 or 15 mg immediate release each morning 2 h before the cocaine or placebo cocaine infusion and on the day of testing). Intravenous cocaine produced a modest increase in cognitive performance and attention. Isradipine, both with and without cocaine, had no effect on these same parameters. Hence, cocaine-taking by cocaine-dependent individuals produces little improvement in cognitive performance and attention in either the presence or absence of isradipine.

Adult↗
PubMed2005

Acute intravenous low- and high-dose cocaine reduces quantitative global and regional cerebral blood flow in recently abstinent subjects with cocaine use disorder.

Cocaine-induced hypoperfusion, a risk factor for ischemic stroke, has not been fully characterized during experimental drug-taking among individuals with cocaine use disorder. We sought to examine cocaine's dose-dependent, time-related effects on cerebral blood flow. In a double-blind, randomized human laboratory study with a counterbalanced order of drug administration, 31 male and female subjects with cocaine use disorder were divided into two groups receiving either (a) low-dose cocaine (0.325 mg/kg intravenously) or placebo (N=15) or (b) high-dose cocaine (0.650 mg/kg intravenously) or placebo (N=16). The different dose conditions were administered on test days separated by a rest period of >or=48 h. Cerebral blood flow was assessed quantitatively using H(2)O(15) positron emission tomography. Experimentally administered low- and high-dose cocaine conditions versus their corresponding placebo conditions were associated with global and regional hypoperfusion. The trend for high- versus low-dose cocaine to be associated with greater hypoperfusion achieved statistical significance only for the dopamine-rich sublobar and midbrain regions. Cocaine's hypoperfusion effects were maximal at 8 mins after infusion (i.e., at about the expected peak of intravenous cocaine levels) and had mostly dissipated by 32 mins after infusion. Although hypoperfusion occurred throughout the brain, the left hemispheric dopamine-rich sublobar region was the most severely affected. Cocaine-induced cerebral hypoperfusion is associated with the time course of its pharmacological effects, and dopamine-rich areas, particularly in the left hemisphere, may be most vulnerable. Increasingly larger doses of cocaine may be associated with greater risk for ischemic stroke.

Adolescent↗
PubMed2006

Estrogen receptor beta, but not alpha, mediates estrogen's effect on cocaine-induced reinstatement of extinguished cocaine-seeking behavior in ovariectomized female rats.

Preclinical and clinical studies indicate that females are more vulnerable to relapse than males, and the neurobiological effects of estrogen are thought to mediate, in part, the sex differences in cocaine-taking behavior. The goal of the present study was to investigate the involvement of estrogen receptor alpha (ERalpha) and beta (ERbeta) in estrogen-mediated increases in cocaine-induced reinstatement of extinguished cocaine-seeking behavior in ovariectomized (OVX) female rats. Rats were initially trained to self-administer cocaine (0.4 mg/kg/inf, i.v.) under a fixed-ratio 1 (FR 1) schedule of reinforcement during daily 2-h sessions. After a 10-day maintenance period, cocaine solutions were replaced with saline, and self-administration was extinguished over a 14-day period. OVX rats were then treated with either the mixed ERalpha/beta agonist estradiol benzoate (EB), the ERalpha-selective agonist, propyl-pyrazole-triol (PPT), the ERbeta-selective agonist, diarylpropionitrile (DPN), or a vehicle control (dimethyl sulfoxide, DMSO). Treatment lasted a total of 9 days, and during this time, rats were assessed for nonreinforced reinstatement of extinguished cocaine-seeking behavior after priming injections of saline or cocaine (5, 10, or 15 mg/kg, i.p.). OVX rats showed no differences in self-administration during maintenance or extinction. OVX rats treated with EB exhibited greater responding for cocaine during reinstatement compared to OVX+DMSO controls. Selective activation of ERbeta with DPN also increased cocaine-induced reinstatement responding, whereas selective activation of ERalpha with PPT did not affect cocaine-seeking behavior. These results indicate that estrogen influences the propensity for reinstatement of extinguished cocaine-seeking behavior, and that estrogen-mediated enhancement of cocaine-induced reinstatement responding involves the activation of ERbeta.

Animals↗
PubMed2002

Cocaine treatment increases extracellular cholecystokinin (CCK) in the nucleus accumbens shell of awake, freely moving rats, an effect that is enhanced in rats that are behaviorally sensitized to cocaine.

Cholecystokinin (CCK) is co-localized with dopamine, is known to modulate dopamine neurotransmission and is involved in behavioral sensitization to psychostimulants. To better understand its role, CCK was measured by microdialysis in the nucleus accumbens (NAC) shell in response to cocaine in drug-naive rats and in rats that are behaviorally sensitized to cocaine. Basal extracellular levels of CCK in drug-naive rats were 0.17 pg/20 min fraction, while in cocaine-sensitized rats, they were significantly higher (0.56 pg). Treating drug-naive rats with cocaine caused a significant increase in CCK to 0.58 pg. Cocaine treatment of cocaine-sensitized rats increased CCK to 0.98. When analyzed as a function of time after cocaine treatment, these increases were sustained and were significantly different from CCK levels of saline-treated rats. In cocaine-sensitized rats, CCK levels following cocaine treatment were also significantly higher than levels in drug-naive animals receiving a single injection of cocaine. These results provide evidence for an activation of the mesolimbic and/or cerebral cortical CCK system in response to repeated cocaine administration. These results provide a neurochemical basis for an important role of CCK (via modulation of dopamine neurotransmission) in expression of cocaine sensitization.

Animals↗
PubMed2003

Escalation of cocaine self-administration does not depend on altered cocaine-induced nucleus accumbens dopamine levels.

Previous studies showed that prolonged access to cocaine or heroin self-administration (long access, or LgA) produces an escalation in drug intake not observed with limited access to the drug (short access, or ShA). The present experiment employed in vivo microdialysis to test the role of alterations in drug pharmacokinetics and/or efficacy in increasing dopamine (DA) levels in the nucleus accumbens (NAcc) during cocaine intake escalation. In experiment 1, both ShA and LgA rats were challenged with passive intravenous administration of cocaine (0.125-1 mg/injection). Regardless of the doses tested, there was no difference between groups in the ability of cocaine to increase NAcc DA levels and no group differences in the temporal profile of dialysate cocaine levels. In experiment 2, cocaine and DA concentrations were measured during cocaine self-administration. Self-administration produced sustained increases of DA in the NAcc with LgA rats maintaining greater steady levels of DA (750% of baseline) than ShA rats (400% of baseline). The difference in the LgA versus ShA rats was not due to differences in the efficacy of cocaine to elevate DA levels, or in the rate of cocaine metabolism, but was directly related to the amount of self-administered cocaine. These findings show that changes in cocaine efficacy or pharmacokinetics do not play a critical role in cocaine intake escalation.

Animals↗
PubMed2001

Molecular mechanisms of cocaine reward: combined dopamine and serotonin transporter knockouts eliminate cocaine place preference.

Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET). Cocaine reward/reinforcement has been linked to actions at DAT or to blockade of SERT. However, knockouts of neither DAT, SERT, or NET reduce cocaine reward/reinforcement, leaving substantial uncertainty about cocaine's molecular mechanisms for reward. Conceivably, the molecular bases of cocaine reward might display sufficient redundancy that either DAT or SERT might be able to mediate cocaine reward in the other's absence. To test this hypothesis, we examined double knockout mice with deletions of one or both copies of both the DAT and SERT genes. These mice display viability, weight gain, histologic features, neurochemical parameters, and baseline behavioral features that allow tests of cocaine influences. Mice with even a single wild-type DAT gene copy and no SERT copies retain cocaine reward/reinforcement, as measured by conditioned place-preference testing. However, mice with no DAT and either no or one SERT gene copy display no preference for places where they have previously received cocaine. The serotonin dependence of cocaine reward in DAT knockout mice is thus confirmed by the elimination of cocaine place preference in DAT/SERT double knockout mice. These results provide insights into the brain molecular targets necessary for cocaine reward in knockout mice that develop in their absence and suggest novel strategies for anticocaine medication development.

Animals↗