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PubMed2005

Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost-variable-payoff fixed-ratio cocaine self-administration in rats.

In rats, acute administration of SB-277011A, a highly selective dopamine (DA) D(3) receptor antagonist, blocks cocaine-enhanced brain stimulation reward, cocaine-seeking behaviour and reinstatement of cocaine-seeking behaviour. Here, we investigated whether SB-277011A attenuates cocaine reinforcement as assessed by cocaine self-administration under variable-cost-variable-payoff fixed-ratio (FR) and progressive-ratio (PR) reinforcement schedules. Acute i.p. administration of SB-277011A (3-24 mg/kg) did not significantly alter cocaine (0.75 mg/kg/infusion) self-administration reinforced under FR1 (one lever press for one cocaine infusion) conditions. However, acute administration of SB-277011A (24 mg/kg, i.p.) progressively attenuated cocaine self-administration when: (a) the unit dose of self-administered cocaine was lowered from 0.75 to 0.125-0.5 mg/kg, and (b) the work demand for cocaine reinforcement was increased from FR1 to FR10. Under PR (increasing number of lever presses for each successive cocaine infusion) cocaine reinforcement, acute administration of SB-277011A (6-24 mg/kg i.p.) lowered the PR break point for cocaine self-administration in a dose-dependent manner. The reduction in the cocaine (0.25-1.0 mg/kg) dose-response break-point curve produced by 24 mg/kg SB-277011A is consistent with a reduction in cocaine's reinforcing efficacy. When substituted for cocaine, SB-277011A alone did not sustain self-administration behaviour. In contrast with the mixed DA D(2)/D(3) receptor antagonist haloperidol (1 mg/kg), SB-277011A (3, 12 or 24 mg/kg) failed to impede locomotor activity, failed to impair rearing behaviour, failed to produce catalepsy and failed to impair rotarod performance. These results show that SB-277011A significantly inhibits acute cocaine-induced reinforcement except at high cocaine doses and low work requirement for cocaine. If these results extrapolate to humans, SB-277011A or similar selective DA D(3) receptor antagonists may be useful in the treatment of cocaine addiction.

Animals↗
PubMed2002

Effects of SCH 23390 and eticlopride on cocaine-seeking produced by cocaine and WIN 35,428 in rats.

RATIONALE: Exposure to a small amount of cocaine can trigger relapse, and so an understanding of the mechanisms underlying cocaine-seeking are important for the development of effective anti-relapse treatments. OBJECTIVES: The present study sought to compare the contributions of dopamine D(1)- and D(2)-like receptors in drug-seeking produced by cocaine and WIN 35,428. METHODS: Reinstatement of extinguished cocaine self-administration was measured for rats that received injections of cocaine (5.0-20.0 mg/kg) or WIN 35,428 (0.1-1.0 mg/kg) following extinction. Prior to the injection of cocaine or WIN 35,428, rats received an injection of the D(1)-like antagonist, SCH 23390 (0.001-0.010 mg/kg) or the D(2)-like antagonist, eticlopride (0.01-0.30 mg/kg). Effects of SCH 23390 (0.01 mg/kg) on cocaine-produced locomotor activation were also measured in separate groups of rats. RESULTS: The ability of both cocaine and WIN 35,428 to produce cocaine-seeking was dose-dependent. Within the range of doses tested, SCH 23390 failed significantly to attenuate the ability of either cocaine or WIN 35,428 to reinstate extinguished cocaine self-administration, although cocaine-produced locomotor activation was significantly attenuated by pretreatment with the highest dose of SCH 23390. Eticlopride attenuated both cocaine and WIN 35,428 produced cocaine-seeking but lower doses were required to decrease WIN 35,428-produced cocaine-seeking. CONCLUSIONS: These results suggest that dopamine D(2) mechanisms are involved in cocaine-seeking produced by both cocaine and WIN 35,428. The lower potency of eticlopride in attenuating cocaine-produced cocaine-seeking suggest that cocaine's effects at sites other than the dopamine transporter contribute to its ability to elicit drug-seeking.

Animals↗
PubMed1990

Extracellular concentrations of cocaine and dopamine are enhanced during chronic cocaine administration.

Chronic cocaine administration produces significant increases in cocaine-induced locomotor activity and stereotypy. In vivo microdialysis procedures were used to monitor extracellular dopamine (DA) and cocaine concentrations in the nucleus accumbens (N ACC) and cocaine concentrations in plasma of animals that received chronic or acute cocaine treatments. Following a cocaine challenge injection, concentrations of both cocaine and DA increased to significantly higher levels over time in animals that had received daily cocaine injections for 10 or 30 days than in control animals that received daily injections of saline. Concentrations of cocaine and DA in the N ACC reached maximum levels in the first 30 min following a challenge injection of cocaine. The maximum cocaine concentrations of 10- and 30-day chronic animals were, respectively, 186% and 156%, whereas the maximum DA concentrations were 264% and 216% above the maximum values observed in acute control animals. The results indicate that reverse tolerance effects observed following chronic cocaine administration may in part be accounted for by increased cocaine concentrations. Furthermore, chronic cocaine administration (over a 10- or 30-day period) increased the concentration of cocaine detected in plasma above control levels following a challenge injection. The increase in brain concentrations of cocaine in chronic animals is apparently due to increased concentrations of cocaine in plasma. A physiological change occurs in the periphery as a result of chronic cocaine administration that increases cocaine concentrations in plasma, increases extracellular cocaine levels in the brain, and increases the extracellular concentration of DA in the N ACC.

Animals↗
PubMed1998

Cocaine enhances monocyte migration across the blood-brain barrier. Cocaine's connection to AIDS dementia and vasculitis?

Cocaine has wide-ranging effects on the immune and neuroendocrine systems (Fiala et al., 1996) resembling an inflammatory "stress" response with upregulation of pro-inflammatory cytokines and stimulation of the HPA axis (Gan et al., 1997). Cocaine abuse has also been associated with vascular pathology, including vasculitis, vasospasm and hemorrhage. These effects suggest that cocaine could perturb the function of endothelial cells, including the blood-brain barrier, and influence the progression to AIDS in HIV-infected individuals (Shapshak et al., 1997; Goodkin et al., 1997). In order to understand clinical consequences of cocaine abuse, it is important to gain insight into molecular and cellular basis of cocaine's effects on immune and endothelial cells. Cocaine's in vitro effects on (a) permeability, (b) immune cell migration, (c) adhesion molecules, and (d) cytokine expression were investigated in a blood-brain barrier model constructed with brain microvascular endothelial cells and fetal astrocytes with the following results: (a) cocaine and tumor necrosis factor-alpha (TNF-alpha) increased the model's permeability to inulin similarly in a dose-responsive fashion; (b) cocaine (10(-4) to 10(-8_ M) enhanced monocyte migration across the barrier with the maximum increase, approximately 100%, by 10(-5) M cocaine; (c) cocaine treatment also increased the expression of endothelial adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecules-1 (VCAM-1) and platelet/endothelial cell adhesion molecule-1 (PECAM-1); (d) although the cocaine in vitro effects on cytokine production by mononuclear cells have been difficult to assess due to a heterogeneity in the degree of responsiveness between individuals, the data suggest that mononuclear cells from cocaine addicts are sensitized to in vitro cocaine challenge with hypersecretion of inflammatory cytokines. Cocaine's in vivo manifestations are compatible with these in vitro effects: (A) chronic cocaine treatment of rats significantly increased rolling white blood cell flux, leukocyte-endothelium adhesion, and ICAM-1 expression in the mesentery (House et al., 1996); (B) cocaine injection to cocaine-dependent subjects tipped the balance of cytokine secretion by mononuclear cells to Th1-type (Gan et al., 1997), and (C) cocaine injection stimulated the hypothalamic-pituitary axis (HPA) to increase both anti- and pro-inflammatory hormonal secretion. Collectively, these results suggest that the immune effects of cocaine on endothelial, immune and neuroendocrine cells impair the function of the blood-brain, barrier, increase cell emigration from the blood vessels, in particular into the brain, and may cause vasculitis. These effects could also increase importation of HIV-1 into the brain.

AIDS Dementia Complex↗
PubMed2002

Effects of excitotoxic lesions of the basolateral amygdala on cocaine-seeking behavior and cocaine conditioned place preference in rats.

Incentive motivation for cocaine, elicited by cocaine-associated stimuli, is thought to be involved in craving and relapse. To examine the role of the basolateral amygdala complex (BLC) in this phenomenon, we assessed the effects of post-training BLC lesions on extinction of cocaine-seeking behavior and cocaine-conditioned place preference (CPP) and the effects of pre-training BLC lesions on acquisition of cocaine-CPP. In Experiment 1, rats were first trained to self-administer cocaine and then received bilateral infusions of the excitotoxin, N-methyl-D-aspartic acid (NMDA, 0.12 M; 0.3 microl/side), or vehicle into the BLC. They were then tested repeatedly for extinction of cocaine-seeking behavior (i.e. nonreinforced responses in the presence of cocaine-paired stimuli). Subsequently, they were trained and tested for acquisition of cocaine-CPP (i.e. increased time spent in a previously cocaine-paired, relative to a saline-paired, environment). Locomotion and compartment entries were also measured. In Experiment 2, rats were first trained and tested for cocaine-CPP, and then received NMDA or vehicle infusions into the BLC. Subsequently, they were tested repeatedly for extinction of cocaine-CPP. Post-training BLC lesions retarded extinction of cocaine-seeking behavior and cocaine-CPP, whereas pre-training lesions disrupted acquisition of cocaine-CPP. These effects did not appear to be related to changes in general activity. We suggest that pre-training BLC lesions disrupted acquisition of cocaine-CPP by impairing assignment of incentive value to cocaine-paired stimuli, whereas post-training BLC lesions disrupted extinction of cocaine-conditioned behaviors by impairing the assessment of the current incentive value of cocaine-paired stimuli.

Amygdala↗
PubMed1998

Cocaine and metabolite concentrations in plasma during repeated oral administration: development of a human laboratory model of chronic cocaine use.

Long-term use of cocaine may produce neurophysiological and metabolic alterations that differ from acute drug use. A laboratory model that was capable of evaluating the effects of chronic cocaine administration in human subjects was needed. Chronic oral administration of cocaine was considered a feasible route because of the ease of administration, control of dosing patterns, and possible reduction in medical risks compared with the intravenous and smoked routes. This clinical study was conducted to evaluate chronically administered oral cocaine as a means of studying cocaine addiction and withdrawal in humans. Cocaine-abusing volunteers were given multiple doses of oral cocaine each day in up to 16 daily sessions (including three placebo sessions). In each daily session, volunteers received five equal doses separated by hourly intervals. Across sessions, the dose was increased from an initial dose of 100 mg (500 mg/day) to 400 mg (2000 mg/day) in the last session. The dose for each consecutive cocaine session was increased by 25 mg/dose/session (125-mg total increase per session). Twelve subjects were enrolled in the study; however, three subjects dropped out prior to completion of at least three sessions. Two subjects completed all 13 cocaine sessions. The remaining seven subjects completed from 3 to 11 sessions; their participation was terminated early for safety and behavioral reasons. Plasma was collected during all sessions and analyzed for cocaine and metabolites by solid-phase extraction followed by gas chromatography-mass spectrometry. Oral cocaine administration resulted in peak plasma concentrations of cocaine approximately 1 h after administration. Accumulation of cocaine was evident between hourly doses and there was evidence of dose-proportional increases in area under the curve (AUC) measures across sessions. A variety of cocaine metabolites was measured in plasma including benzoylecgonine, ecgonine methyl ester, norcocaine, benzoylnorecgonine, and p and m-hydroxy metabolites of cocaine and benzoylecgonine. During chronic oral dosing, there appeared to be a trend for AUC ratios (AUCmetabolite/AUCcocaine) of benzoylecgonine and ecgonine methyl ester to decrease and norcocaine to increase, indicating the possibility of dose-, time-, or route-dependent changes in the absorption and/or metabolism of cocaine. Overall, this study demonstrated that chronic oral dosing of cocaine produced dose-related increases in plasma cocaine concentration, and this model could be useful for studying the effects of chronic cocaine use in human subjects.

Administration, Oral↗
PubMed2002

Effects of GBR 12909, WIN 35,428 and indatraline on cocaine self-administration and cocaine seeking in rats.

RATIONALE: It has been proposed that drugs that decrease cocaine self-administration or cocaine seeking by laboratory animals might be effective pharmacotherapies in the treatment of cocaine addiction. Previous studies have suggested that the dopamine uptake inhibitor, GBR 12909, might be such a candidate drug because it decreases cocaine self-administration. Other studies have shown that GBR 12909 elicits cocaine seeking, which might limit its utility as an anti-cocaine pharmacotherapy. OBJECTIVES: The present study sought to compare the potency of GBR 12909 in decreasing cocaine self-administration and in eliciting cocaine seeking. These findings were compared to effects produced by the cocaine analog, WIN 35,428 and the non-specific monoamine uptake inhibitor, indatraline. METHODS: A within-session protocol was used to obtain the dose-effect relationship for cocaine self-administration in a single 5-6 h daily test session. Rats were pretreated with GBR 12909 (3.0-30.0 mg/kg), WIN 35,428 (0.1-1.0 mg/kg) or indatraline (0.03-1.00 mg/kg) 30 min prior to the test session. RESULTS: GBR 12909 and WIN 35,428 decreased responding maintained by intermediate and high doses of cocaine but indatraline failed to alter the cocaine dose-effect curve. Other groups of rats demonstrated that pretreatment with all three drugs reinstated extinguished cocaine-taking behavior, although indatraline was less efficacious than either GBR 12909 or WIN 35,428. Cocaine-produced drug seeking was enhanced by pretreatment with the highest doses of GBR 12909 and WIN 35,428 but was unaffected by pretreatment with indatraline. A low dose of GBR 12909 that decreased cocaine self-administration failed to produce drug seeking but equal doses of WIN 35,428 were required to decrease cocaine self-administration and to elicit drug seeking. CONCLUSIONS: These data suggest a preferred profile of effects of GBR 12909 as an anti-cocaine pharmacotherapy. It is noted, however, that this drug might be expected to potentiate the ability of cocaine to elicit cocaine seeking following abstinence.

Animals↗
PubMed2001

Dopamine transporter binding without cocaine-like behavioral effects: synthesis and evaluation of benztropine analogs alone and in combination with cocaine in rodents.

RATIONALE: Previous SAR studies demonstrated that small halogen substitutions on the diphenylether system of benztropine (BZT), such as a para-Cl group, retained high affinity at the cocaine binding site on the dopamine transporter. Despite this high affinity, the compounds generally had behavioral effects different from those of cocaine. However, compounds with meta-Cl substitutions had effects more similar to those of cocaine. OBJECTIVES: A series of phenyl-ring analogs of benztropine (BZT) substituted with 3'-, 4'-, 3',4"- and 4',4"-position Cl-groups were synthesized and their pharmacology was evaluated in order to assess more fully the contributions to pharmacological activity of substituents in these positions. METHODS: Compounds were synthesized and their pharmacological activity was assessed by examining radioligand binding and behavioral techniques. RESULTS: All of the compounds displaced [3H]WIN 35,428 binding with affinities ranging from 20 to 32.5 nM. Affinities at norepinephrine ([3H]nisoxetine) and serotonin ([3H]citalopram) transporters, respectively, ranged from 259 to 5120 and 451 to 2980 nM. Each of the compounds also inhibited [3H]pirenzepine binding to muscarinic M1 receptors, with affinities ranging from 0.98 to 47.9 nM. Cocaine and the BZT analogs produced dose-related increases in locomotor activity in mice. However, maximal effects of the BZT analogs were uniformly less than those produced by cocaine, and were obtained 2-3 h after injection compared to the relatively rapid onset (within 30 min) of cocaine effects. In rats trained to discriminate i.p. saline from 29 mumol/kg cocaine (10 mg/kg), cocaine produced a dose-related increase in responding on the cocaine lever, reaching 100% at the training dose; however, none of the BZT analogs fully substituted for cocaine, with maximum cocaine responding from 20 to 69%. Despite their reduced efficacy compared to cocaine in cocaine discrimination, none of the analogs antagonized the effects of cocaine. As has been reported previously for 4'-Cl-BZT, the cocaine discriminative-stimulus effects were shifted left-ward by co-administration of the present BZT analogs. CONCLUSIONS: The present results indicate that although the BZT analogs bind with relatively high affinity and selectivity at the dopamine transporter, their behavioral profile is distinct from that of cocaine. The present results suggest that analogs of BZT may be useful as treatments for cocaine abuse in situations in which an agonist treatment is indicated. These compounds possess features such as reduced efficacy compared to cocaine and a long duration of action that may render them particularly useful leads for the development of therapeutics for cocaine abusers.

Animals↗
PubMed1992

The accumulation and disappearance of cocaine and benzoylecgonine in rat hair following prolonged administration of cocaine.

Hair samples were obtained at various time periods from male Sprague-Dawley rats following the injection of cocaine hydrochloride in doses of 5, 10, and 20 mg/kg, ip, for 28 days. Hair samples were also taken continually after the dosing was stopped until the presence of cocaine and benzoylecgonine were no longer detected in hair. Cocaine and benzoylecgonine in hair and plasma were analyzed by gas chromatography/mass spectrometry. Both cocaine and benzoylecgonine were found in hair samples 4 days after the initiation of cocaine administration. When cocaine dosing was stopped after 28 days, approximately 25 to 30 days were required for cocaine and benzoylecgonine to disappear from rat hair in the group of animals that received the highest dose of cocaine. The disappearance of cocaine and benzoylecgonine followed first-order kinetics. The mean rate constant and mean half-life for cocaine disappearance from hair were 0.212 +/- 0.005 day-1 and 3.31 +/- 0.09 days, respectively, and the mean rate constant and mean half-life for benzoylecgonine disappearance from hair were 0.098 +/- 0.006 day-1 and 6.90 +/- 0.28 days, respectively. The mean plasma concentrations of cocaine on Day 25 for the 5, 10, and 20 mg/kg doses of cocaine were 508 +/- 42, 852 +/- 95, and 2027 +/- 75 ng/mL, respectively, and the mean plasma benzoylecgonine levels for the 5, 10, and 20 mg/kg doses of cocaine were 49.9 +/- 7.0, 103.3 +/- 9.3, and 191.0 +/- 16.0 ng/mL, respectively. There was a positive correlation between the doses of cocaine hydrochloride administered and the plasma levels of both cocaine and benzoylecgonine. This study showed that cocaine and benzoylecgonine can be measured in rat hair following the administration of cocaine and that it was possible to correlate the concentrations of cocaine and benzoylecgonine found in hair with the doses of cocaine that were administered.

Animals↗
PubMed1997

Behavioral sensitization to cocaine in the absence of altered brain cocaine levels.

We conducted experiments investigating the role of altered cocaine distribution in behavioral sensitization. The first was designed to determine whether carry-over from one injection to the next occurs after acute cocaine administration. Female, Sprague-Dawley rats were administered 5 mg/kg 3H-cocaine and 24 h later were challenged with either 5 mg/kg unlabeled cocaine or saline. Animals were sacrificed 15 min after drug administration. There was no difference between groups in cocaine levels in brain, liver, or plasma, thus indicating that carry-over did not occur following acute cocaine administration. The second experiment was designed to determine whether bound cocaine could be released following acute or multiple dose cocaine administration. In the acute dose study, animals were administered either 20 mg/kg cocaine or saline, challenged 24 h later with 5 mg/kg 3H-cocaine, and sacrificed 5 min after drug administration. Animals with previous cocaine experience exhibited a significant increase in the number of rearings. The groups did not differ in brain or plasma cocaine levels. In the multiple dose study, animals were injected daily for 4 days with 20 mg/kg cocaine or saline, challenged with 5 mg/kg 3H-cocaine on day 5, and sacrificed 10 min after drug administration. Animals with previous cocaine experience exhibited significantly greater locomotor activity and number of rearings. There was no difference between groups in cocaine levels in various brain regions, plasma, or liver. Brain cocaine content in various regions was significantly correlated, though heterogeneously distributed within the various regions. The highest cocaine levels were found in hippocampus, striatum, thalamus/hypothalamus, and cortex. These results provide further evidence that behavioral sensitization is not the result of cocaine redistribution following repeated administration.

Animals↗
PubMed1998

Modification of cataleptic responses to dopamine receptor antagonists after withdrawal from chronic cocaine or cocaine plus dopamine antagonist administration.

1. In mice pretreated chronically with cocaine (indirect dopamine agonist: 10 mg/kg, s.c. on alternating days for 15 days), haloperidol (dopamine D2 antagonist: 0.3 mg/kg i.p.) exerted an enhanced cataleptic response, but SCH23390 (dopamine D1 antagonist: 0.3 mg/kg i.p.) produced an attenuated response at 24 h, which converted to a supernormal response, when it was administered 15-60 days after withdrawal from cocaine. 2. A challenge dose of SCH23390 exhibited enhanced catalepsy when given 15 days, but not at 24 h, after the last pretreatment dose of SCH23390 (0.1-1.0 mg/kg s.c.). In contrast, haloperidol catalepsy was not affected by the SCH23390 pretreatment. 3. However, in animals chronically pretreated with haloperidol (0.1-1.0 mg/kg s.c.), a challenge dose of SCH23390 as well as haloperidol exhibited attenuated cataleptic effects at 24 h and normal cataleptic responses at 15 days after the last dose of the pretreatment regimen. 4. Challenge doses of haloperidol or SCH23390 given to mice 24 h after chronic cocaine pretreatment produced enhanced and attenuated cataleptic responses, respectively; however, these responses were no longer produced when haloperidol or SCH23390 was given to mice pretreated chronically with a combination of cocaine and either haloperidol or SCH23390. 5. The enhanced catalepsy produced by a challenge dose of SCH23390 (15-60 days after chronic cocaine) was further potentiated when it was administered to animals that had been pretreated chronically with a combination of SCH23390 and cocaine, but was antagonized in animals pretreated chronically with haloperidol and cocaine. In contrast, the degree of enhanced cataleptic responses produced by a challenge dose of haloperidol 30-60 days after pretreatment chronically with a combination of cocaine + SCH23390 was similar to that seen after chronic cocaine alone. However, this enhanced response was antagonized in animals that had been pretreated chronically with the combination of cocaine + haloperidol. 6. The results suggest that the coadministration of SCH23390 with cocaine was able to block indirectly dopamine D2 receptor inhibition (subsensitivity) induced during the early withdrawal period from chronic cocaine, despite the fact that by itself SCH23390 did not have an effect on haloperidol catalepsy. Accordingly, the stimulatory effects of dopamine D2 receptors by a single administration of cocaine may be mediated mainly by an indirect stimulation of dopamine D2 receptor function via its D1 receptor stimulating action. 7. The coadministration of SCH23390 with cocaine rather aggravate the subsensitive effect of dopamine D1 receptors (increased SCH23390 catalepsy) produced during long-term withdrawal period from chronic cocaine, but did not affect that of the dopamine D2 receptor. On the other hand, the coadministration of haloperidol with cocaine normalized both D1 and D2 receptor subsensitive effect. 8. These result suggest that a single administration of SCH23390 or haloperidol after long-term withdrawal periods from chronic cocaine may not be effective as antipsychotic drugs because of further aggravation of suppressive behaviors. These results also provide evidence that D2 receptor antagonists may be more effective as antipsychotic drugs than dopamine D1 receptor antagonist, since the coadministration of haloperidol with cocaine normalized the abnormal behaviors seen during early and long-term withdrawal periods from chronic cocaine.

Animals↗
PubMed2003

Detection and time course of cocaine N-oxide and other cocaine metabolites in human plasma by liquid chromatography/tandem mass spectrometry.

Gas chromatography/mass spectrometry (GC/MS) is often used for detection and measurement of cocaine metabolites in biological specimens. However, cocaine N-oxide, a recently identified metabolite of cocaine, is thermally degraded when introduced into a GC/MS. The major degradation products are cocaine and norcocaine. When cocaine N-oxide was measured in rat plasma using liquid chromatography in combination with electrospray ionization-mass spectrometry (LC/ESI-MS), the cocaine N-oxide concentrations in the rat plasma were reported to be as high as 30% of the cocaine concentrations. However, in our study involving LC/ESI-MS/MS analysis of plasma collected from human subjects following administration of oral cocaine, we determined that the concentrations of cocaine N-oxide relative to the cocaine concentrations never exceeded 3%. This suggests that determination of cocaine concentration in human plasma by GC/MS analysis will not significantly distort the actual cocaine concentrations due to thermal conversion of cocaine N-oxide to cocaine. In the work reported here, we compared results obtained using GC/MS, LC/ESI-MS/MS, and liquid chromatography/atmospheric pressure chemical ionization-tandem mass spectrometry (LC/APCI-MS/MS) to determine thermal degradation of cocaine N-oxide. LC/ ESI-MS/MS was selected to determine cocaine, benzoylecgonine, and cocaine N-oxide, and LC/APCI-MS/MS was selected to determine ecgonine methyl ester and norcocaine in plasma collected from three human subjects participating in a clinical study. The resulting time course data provide additional information into kinetic interrelationships between cocaine N-oxidation and cocaine hydrolysis.

Animals↗
PubMed1996

Cocaine concentration-effect relationship in the presence and absence of lidocaine: evidence of competitive binding between cocaine and lidocaine.

UNLABELLED: To better understand the interaction between cocaine and lidocaine, we studied the cocaine's concentration-effect relationship for action potential duration (APD) and the rate of rise of phase 0 of the action potential (Vmax) of canine papillary muscle in the presence and absence of lidocaine. We measured APD and Vmax during programmed stimulation and superfusion with normal Tyrode's, 30 microM cocaine and 30 microM cocaine + 30 microM lidocaine. Using two microelectrodes, we simultaneously recorded action potentials from two sites during programmed stimulation and measured the conduction velocity and effective refractory period during exposure to normal Tyrode's, cocaine and cocaine + lidocaine. Cocaine with or without lidocaine delayed the plateau of the APD restitution curve. At 1000 msec cycle length, the addition of 30 microM lidocaine to the superfusate containing 30 microM cocaine shortened the time constant for reactivation of Vmax from 514 +/- 63 to 234 +/- 28 msec (P < .01). Lidocaine also improved the conduction velocity decreased by cocaine, but did not significantly change the effective refractory period. The configuration of cocaine concentration-effect curve for APD was biphasic. For cocaine concentrations < 100 microM, APD progressively shortened prolonged with increasing concentrations. As cocaine concentrations increased > 100 microM, APD progressively shortened. The addition of lidocaine to the superfusate with cocaine > 100 microM tended to attenuate the progressive APD shortening due to cocaine. Lidocaine shifted the curve correlating cocaine concentration and reduction of Vmax rightward, but preserved Emax at cocaine concentration > 225 microM. These findings suggest competitive antagonism between cocaine and lidocaine at a single sodium channel receptor. CONCLUSION: lidocaine displaces cocaine from the sodium channel receptor through competitive binding. Lidocaine may prove to be beneficial in reversing cocaine-induced slowing of ventricular conduction.

Action Potentials↗
PubMed2002

Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens.

One of the major determinants of reinstatement to cocaine use among human addicts is acute reexposure to the drug, which often precipitates cocaine craving and relapse. We used an animal model of cocaine relapse to determine the role of the glutamatergic pathway from the medial prefrontal cortex (mPFC) to the nucleus accumbens in the reinstatement of cocaine-seeking behavior after a cocaine priming injection. Rats were trained to self-administer cocaine intravenously on a second order schedule. Responding was extinguished subsequently by substituting saline for cocaine. During subsequent reinstatement sessions, drug-seeking behavior was assessed after noncontingent priming injections. Results indicated that reinstatement induced by a systemic cocaine injection was blocked by intra-mPFC administration of the dopamine antagonist flupenthixol. Consistent with this finding, administration of cocaine directly into the mPFC reinstated cocaine-seeking behavior. Administration of cocaine into the nucleus accumbens also reinstated drug seeking, whereas microinjection of cocaine into the neostriatum or lateral septum did not. Reinstatement of cocaine seeking induced by intra-mPFC cocaine was blocked by administration of the AMPA receptor antagonist CNQX into the nucleus accumbens. Administration of the NMDA receptor antagonist AP-5 into the nucleus accumbens had variable effects on reinstatement induced by intra-mPFC cocaine in that AP-5 had no effect in some animals but augmented reinstatement in others. Subsequent experiments showed that intra-accumbal microinjection of AP-5 alone dose-dependently reinstated cocaine seeking. These data indicate that the glutamatergic pathway from the mPFC to the nucleus accumbens plays an important role in cocaine priming-induced reinstatement of drug seeking. Moreover, the present results demonstrate that AMPA and NMDA receptors in the nucleus accumbens have opposing roles in the reinstatement of cocaine-seeking behavior.

Anesthetics, Local↗
PubMed2006

Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes.

BACKGROUND: Cocaine dependence is associated with high rates of relapse. Stress and drug cue exposure are known to increase cocaine craving and stress arousal, but the association between these responses and cocaine relapse has not been previously studied. OBJECTIVE: To examine whether stress-induced and drug cue-induced cocaine craving and hypothalamic-pituitary-adrenal axis responses evoked in the laboratory are associated with subsequent cocaine relapse. DESIGN: Prospective study design assessing cocaine relapse and drug use during a 90-day follow-up period after discharge from inpatient treatment and research. Data were analyzed by Cox proportional hazards regression and multiple regression. SETTING: Inpatient treatment and research unit in a community mental health center. PATIENTS: Forty-nine treatment-seeking cocaine-dependent individuals. MAIN OUTCOME MEASURES: Time to cocaine relapse, number of days of cocaine use, and amount of cocaine used per occasion in the follow-up phase. RESULTS: Greater stress-induced, but not drug cue-induced, cocaine craving was associated with a shorter time to cocaine relapse. Stress-induced corticotropin and cortisol responses predicted higher amounts of cocaine use per occasion in the 90-day follow-up. CONCLUSIONS: These results demonstrate that stress-related increases in cocaine craving and hypothalamic-pituitary-adrenal axis responses are each associated with specific cocaine relapse outcomes. The findings support the use of stress-induced drug craving and associated hypothalamic-pituitary-adrenal axis responses to evaluate cocaine relapse propensity. Furthermore, treatments that address stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses could be of benefit in improving relapse outcomes in cocaine dependence.

Adrenocorticotropic Hormone↗
PubMed1996

Effects of dopamine agonists and antagonists on cocaine-induced operant responding for a cocaine-associated stimulus.

The present study examined the effects of receptor subtype-selective dopamine agonists and antagonists on (i) cocaine-induced responding for a cocaine-associated stimulus and (ii) on responding for food and cocaine reinforcement. Rats implanted with intravenous catheters were trained to lever-press for food or cocaine reinforcers on an FR5-FR5 multiple schedule, which was preceded by a 5-min component during which only stimuli previously associated with the primary reinforcers were available response-contingently. (i) Non-contingent delivery of cocaine at the beginning of the stimulus component significantly increased responding for the cocaine-associated stimulus, compared to responding for the food-associated cue. Changes in the dose of cocaine administered non-contingently before the stimulus component resulted in an inverted U-shaped dose-effect curve in responding for the cocaine-associated cue. In subsequent experiments, pretreatment with the dopamine D2 receptor agonist bromocriptine (4.0-16.0 mg/kg IP) attenuated the cocaine-induced increase in responding for the cocaine-associated cue. In contrast, pretreatment with low doses of SDZ 208-911, a dopamine D2 partial agonist (0.025-0.1 mg/kg SC), further potentiated the cocaine-induced response. Pretreatment with low and medium doses of the dopamine D1 and D2 receptor subtype-selective antagonists SCH 23390 (D1; 5-10 micrograms/kg SC) and raclopride (D2; 100-200 micrograms/kg SC) blocked responding for cocaine-associated cues, with SCH 23390 acting more selectively than raclopride. At higher doses (SCH 23390: 20 micrograms/kg SC; raclopride: 400 micrograms/kg SC), both drugs produced non-selective effects by inhibiting responses for the food-associated cue. (ii) Varying the dose of cocaine self-administered during the multiple schedule resulted in an inverted U-shaped dose-effect curve during the cocaine components, while the number of food pellets earned remained unchanged. Pretreatment with bromocriptine selectively reduced the number of cocaine infusions obtained. The compensatory increases in responding for cocaine typically associated with SCH 23390, raclopride or SDZ 208-911 pretreatment were also observed under the present schedule conditions, although the effect did not reach statistical significance in the case of SCH 23390 and raclopride, possibly due to methodological constraints. The results indicate that the present rat model of cocaine-seeking behavior is sensitive to pharmacological manipulations and may yield important information regarding the neurobiological mechanisms underlying conditioned and unconditioned reinforcing aspects of cocaine addiction.

Animals↗
PubMed1997

Protection against cocaine and combined cocaine-ethanol toxicities in mice by imidazobenzodiazepine Ro 15-4513.

The effects of Ro 15-4513 in preventing cocaine and combined cocaine-ethanol toxicities were examined in mice. Ro 15-4513 is a partial inverse agonist of benzodiazepine receptors, which has been implicated in ethanol lethality and cocaine-induced seizures. Ro 15-4513 (5 mg/kg, 10 mg/kg, or 15 mg/kg) was administered intraperitoneally 10 min before the administration of saline and cocaine (75 mg/kg) in the cocaine groups, or before ethanol (3 g/kg) and cocaine (75 mg/kg) in the cocaine-ethanol groups. In both cocaine and cocaine-ethanol groups, two distinct groups of dead animals meeting the same criteria, the IL (immediate lethal) and DL (delayed lethal) groups, could be differentiated, depending on their survival times, observed disorders, and drug levels at the time of death. Differences in the seizure scores further subdivided the two groups. Ro 15-4513 protected mainly against the immediate lethality in the cocaine groups and mainly against the delayed lethality in the cocaine-ethanol groups. The dose of Ro 15-4513 providing the maximal protection against the lethal effects of these drugs was 10 mg/kg in the cocaine groups, and 5 mg/kg in the cocaine-ethanol groups. The sum of the lethalities was still higher with the maximal effective dose of Ro 15-4513 in the cocaine-ethanol groups than in the cocaine groups. In the cocaine-ethanol groups, 5 mg/kg of Ro 15-4513 attenuated both brain and liver cocaethylene levels. Cocaine-induced seizures were also attenuated by any dose of Ro 15-4513 used in the cocaine groups. Although some discrepancies were observed in the protective properties, some validity for the use of Ro 15-4513, a drug with more than one mode of protective action, was demonstrated in this study.

Animals↗
PubMed1991

Emerging patterns of cocaine use and the epidemic of cocaine overdose deaths in Dade County, Florida.

With the increasing use of cocaine in the United States, cocaine overdose deaths are being reported with increasing frequency. To describe patterns of cocaine use involved in cocaine overdose deaths, we reviewed the postmortem records from the Metropolitan Dade County Medical Examiner Department, Miami, Fla. We identified 239 cocaine overdose deaths from 1971 through 1987. During this period, the incidence of cocaine overdose deaths increased 20-fold, with the largest proportional increases occurring among persons aged older than 24 years, white persons, and men. The percentage of deaths that involved use of cocaine by nonparenteral routes, as well as newer and unknown preparations of cocaine (such as "crack" and "free-base" cocaine), increased. For example, the percentage of deaths that involved use of crack or free-base cocaine increased from 8% in 1981 to 20% in 1987. Persons who died after smoking crack or free-base cocaine had lower blood cocaine levels at autopsy (median level, 0.3 mg/L) than persons who died as a result of using cocaine hydrochloride (median level, 3.7 mg/L). Patterns of cocaine use involved in the epidemic of cocaine overdose deaths are changing. The data suggest that the newer preparations of cocaine, such as crack or free-base cocaine are playing an increasingly important role in this epidemic and that these preparations may be more toxic than cocaine hydrochloride.

Age Factors↗