Behavioral effects of self-administered cocaine: responding maintained alternately by cocaine and electric shock in squirrel monkeys.

Squirrel monkeys responded under a fixed-interval schedule of intravenous cocaine injection that alternated with a fixed-interval schedule of either presentation of electric shock or termination of a stimulus associated with electric shock. As the dose of cocaine was increased from 10 to 1000 microgram/kg/injection, responding maintained by cocaine injection or alternately by electric shock first increased and then decreased. The lowest doses of cocaine that reliably maintained self-administration often increased responding maintained by electric shock; the highest doses of cocaine that continued to maintain self-administration often decreased responding maintained by electric shock. When saline was substituted for cocaine, responding that had previously been maintained by cocaine injection occurred irregularly and at very low rates, whereas rates and patterns of responding maintained by electric shock were characteristic of fixed-interval schedules. When the fixed-interval schedule of cocaine injection was replaced by intravenous injections that occurred without regard to antecedent responding, the effects of cocaine on responding maintained by electric shock were found to be independent of the way in which cocaine was administered.     

Effects of desipramine maintenance on cocaine self-administration by humans

Six research volunteers with histories of cocaine use were tested in a cocaine choice paradigm to investigate the effects of desipramine maintenance on cocaine-taking behavior. Subjects were allowed to self-administer i.v. saline or cocaine (8, 16 or 32 mg) in daily 3-hr sessions to establish baseline levels of self-administration, self-reported effects of the drug and changes in heart rate and blood pressure. Each subject was then maintained on daily doses of desipramine for 3 to 4 weeks, after which a second cocaine self-administration dose-response curve was generated under desipramine maintenance. This maintenance had no effect on cocaine self-administration. There was, however, a significant increase in heart rate and blood pressure during desipramine maintenance. Desipramine maintenance also resulted in a change in the profile of cocaine's self-reported effects. In some cases (e.g., Arousal and Vigor on the Profile of Mood States, Benzedrine Group scale on the Addiction Research Center Inventory), reports of cocaine's effects were significantly reduced under conditions of desipramine maintenance, and in others (e.g., Anxiety, Anger and Confusion on the Profile of Mood States), those reports were significantly increased. Furthermore, there was a significant decrease in subjects response to an "I want cocaine" question while under desipramine maintenance. The data suggest that desipramine does not affect the reinforcing properties of cocaine, but may interfere with its other stimulus properties. Furthermore, the cardiovascular effects of desipramine appear to have the potential for toxicity when that drug is administered in combination with cocaine.     

Pharmacokinetics of cocaine in maternal and fetal rhesus monkeys at mid-gestation

We compared pharmacokinetics of cocaine and its metabolite, benzoylecgonine, in pregnant rhesus monkeys and their fetuses at mid-gestation: 1) after a single intravenous dose of cocaine, 2) after a single oral dose of cocaine, 3) after the last oral cocaine administration of a 50-day-long chronic cocaine treatment, and 4) on the last day of a 50-day-long chronic treatment with five daily intravenous cocaine injections. We found that intravenous administrations of cocaine produced maximal maternal levels of benzoylecgonine below the plasma levels for cocaine. In contrast, oral administrations resulted in the maximal maternal plasma levels of this metabolite significantly above those of cocaine. The bioavailability of the orally administered cocaine was calculated as 25%. Cocaine was detectable in the fetal plasma at maximal levels of approximately 1/5 of peak maternal levels for both single intravenous and single oral administrations. The maximal plasma levels of benzoylecgonine for the fetuses of the intravenously treated mothers were close to those of cocaine, whereas peak levels of this metabolite in the plasma of the fetuses of the mothers receiving the oral treatments were above those of cocaine. The chronic treatments resulted in significantly higher maximal levels of cocaine in the fetal circulation compared with those produced by single drug administrations.     

Acute tolerance to cocaine in humans

There is controversy as to whether acute tolerance develops to the principal effects of cocaine in humans. The studies described here demonstrate the phenomenon of acute tolerance to cocaine chronotropic and subjective effects and the rate and extent of tolerance development. Stable plasma cocaine concentrations were produced and then maintained in volunteer cocaine users by administering an intravenous cocaine injection followed by a cocaine infusion designed to compensate for the plasma clearance of cocaine. The euphoric effect (high) intensified to a peak at about 1 hour and then declined toward baseline at 4 hours despite the presence of constant plasma cocaine levels. The chronotropic effect reached a peak within 10 minutes and then declined, with a half-life of 31 +/- 13 (mean +/- SD) minutes toward a plateau at 33% +/- 21% of its peak intensity. Tolerance development was quantified as an exponential process, with a rate constant (tolerance factor) accounting for the progressive alteration of the cocaine concentration-effect relationship.     

Acute tolerance development to the cardiovascular and subjective effects of cocaine

Eight normal adult volunteer subjects received an intranasal pretreatment of either 4 (placebo) or 96 mg of cocaine. Sixty minutes later 16, 32 or 48 mg of cocaine was injected i.v. Cocaine plasma levels were determined periodically over a 2-hr period and both cardiovascular effects and verbal report of drug effects were monitored for 8 hr daily. The plasma concentrations of cocaine were always related to the dose administered. When i.v. cocaine was given after a 96-mg intranasal pretreatment, the increase in heart rate was not as great as when an i.v. injection followed a 4-mg inhalation. Comparable changes were obtained in subjective effects as measured on the Addiction Research Center Inventory, the Profile of Mood States and a subjective effects questionnaire. These results suggest that there is a decrease in physiological and subjective effects of cocaine when administered repeatedly in humans. This acute tolerance appeared to have dissipated within 24 hr.     

Self-administration of cocaine by humans: choice between smoked and intravenous cocaine.

Ten healthy adult male research volunteers reporting smoked and i.v. cocaine use resided on a Clinical Research Center for 2 weeks and participated in nine daily sessions. A session consisted of seven choice trials. The first two trials were sampling trials in which subjects received one dose each of i.v. cocaine hydrochloride (0, 16 and 32 mg) and smoked cocaine base (0, 25 and 50 mg). Each of the remaining five trials was a choice trial in which subjects could choose to self-administer either of the doses from the initial two trials. Subjects 1) reliably chose active doses of cocaine compared to placebo, 2) chose to self-administer the low-smoked cocaine dose about as often as either the low or high i.v. cocaine doses and 3) reliably chose the high-smoked cocaine dose when compared to either active i.v. dose. With few exceptions, both low doses and high doses produced similar subjective and cardiovascular effects after the initial dose, regardless of the route of administration. This suggests that initial effects were not predictive of subsequent choice. Cumulative doses of smoked cocaine increased scores on a number of subjective-effects measures that were not similarly increased by cumulative doses of i.v. cocaine. These differences were predictive of smoked cocaine self-administration. After session ratings of drug "Liking" and "Quality" differentiated smoked from i.v. cocaine, reflecting route choice. However, there were no significant differences between these ratings for low and high doses. These results provide information about the relationship between subjective drug effects and drug self-administration, and demonstrate the utility of a choice procedure in analyzing these relationships.     

Antagonism of metabotropic glutamate 1 receptors attenuates behavioral effects of cocaine and methamphetamine in squirrel monkeys

Within the group I family of metabotropic glutamate receptors (mGluRs), substantial evidence points to a role for mGluR5 mechanisms in cocaine's abuse-related behavioral effects, but less is understood about the contribution of mGluR1, which also belongs to the group I mGluR family. The selective mGluR1 antagonist JNJ16259685 [(3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone] was used to investigate the role of mGluR1 in the behavioral effects of cocaine and methamphetamine. In drug discrimination experiments, squirrel monkeys were trained to discriminate cocaine from saline by using a two-lever, food-reinforced operant procedure. JNJ16259685 (0.56 mg/kg) pretreatments significantly attenuated cocaine's discriminative stimulus effects and the cocaine-like discriminative stimulus effects of methamphetamine. In monkeys trained to self-administer cocaine or methamphetamine under a second-order schedule of intravenous drug injection, JNJ16259685 (0.56 mg/kg) significantly reduced drug-reinforced responding, resulting in a downward displacement of dose-response functions. In reinstatement studies, intravenous priming with cocaine accompanied by restoration of a cocaine-paired stimulus reinstated extinguished cocaine-seeking behavior, which was significantly attenuated by JNJ16259685 (0.56 mg/kg). Finally, in experiments involving food rather than drug self-administration, cocaine and methamphetamine increased the rate of responding, and the rate-increasing effects of both psychostimulants were significantly attenuated by JNJ16259685 (0.3 mg/kg). At the doses tested, JNJ16259685 did not significantly suppress food-reinforced behavior (drug discrimination or fixed-interval schedule of food delivery), but did significantly reduce species-typical locomotor activity in observational studies. To the extent that the psychostimulant-antagonist effects of JNJ16259685 are independent of motor function suppression, further research is warranted to investigate other mGluR1 antagonists for potential therapeutic value in psychostimulant abuse.     

Language Delay and the Effect of Milieu Teaching on Children Born Cocaine Exposed: A Pilot Study

Children born prenatally exposed to cocaine are at-risk for poor developmental outcome, particularly in the domain of language development. The current pilot study was designed to examine feasibility and efficacy of a Milieu Teaching (MT) paradigm on the language development of children prenatally exposed to cocaine. Four children enrolled in an early intervention program were given 16 weeks of a MT language intervention, provided by an interventionist, and focused on the elicitation of both single and multi-spontaneous word production. Results indicated that from baseline to the end of the intervention, students made encouraging progress. This was demonstrated in both videotaped interactions and on the Receptive–Expressive Emergent Language Test (REEL). These results were particularly significant given results of previous cohorts on the REEL. Finally, discussion is presented concerning feasibility of MT and its true efficacy in children born prenatally exposed to cocaine. This research was supported in part by Grant No.H023C30079 from the Office of Special Education and Rehabilitative Services, Department of Education; Grant No. SPO8984 from the Center for Substance Abuse Prevention, Substance Abuse and Mental Health Services Administration; by funds from Infants In Need, Inc., the Florida Diagnostic Learning Resources System, Florida Department of Education; the Miami Dade County Public Schools; the Dade Community Foundation; and from members of the Miami philanthropic community. Data from the current study was presented at the Annual Gatlinburg Conference on Research and Theory in Mental Retardation and Developmental Disabilities. Thank you to all the research staff at the Linda Ray Intervention Center for all of their time and effort.     

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.     

Effects of intravenous cocaine and cigarette smoking on luteinizing hormone,testosterone, and prolactin in men

Cocaine and nicotine have a number of similar behavioral and neurobiological effects. This study compared the acute effects of cocaine and cigarette smoking on luteinizing hormone (LH), testosterone (T), and prolactin. Twenty-four men who met American Psychiatric Association Diagnostic and Statistical Manual criteria for cocaine abuse or nicotine dependence were given intravenous cocaine (0.4 mg/kg) or placebo-cocaine, or smoked a low or high nicotine cigarette under controlled conditions. Placebo-cocaine or low nicotine cigarette smoking did not change LH, T, or prolactin. Peak plasma levels of 254 +/- 18 ng cocaine/ml and 22.6 +/- 3.4 ng nicotine/ml were measured at 8 and 14 min, respectively. LH increased significantly after both i.v. cocaine and high nicotine cigarette smoking (P < 0.01). These LH increases were significantly correlated with increases in cocaine and nicotine plasma levels (P < 0.001-0.003), and high nicotine cigarette smoking stimulated significantly greater increases in LH release than i.v. cocaine (P < 0.05). Testosterone levels did not change significantly after either cocaine or after high nicotine cigarette smoking. After i.v. cocaine, prolactin decreased significantly and remained below baseline levels throughout the sampling period (P < 0.05-0.01). After high nicotine cigarette smoking, prolactin increased to hyperpro-lactinemic levels within 6 min and remained significantly above baseline levels for 42 min (P < 0.05-0.03). The rapid increases in LH and reports of subjective "high" after both i.v. cocaine and high nicotine cigarette smoking illustrate the similarities between these drugs and suggest a possible contribution of LH to their abuse-related effects.     

Repeated administration of a mutant cocaine esterase: effects on plasma cocaine levels, cocaine-induced cardiovascular activity, and immune responses in rhesus monkeys

Previous studies have demonstrated the capacity of a long-acting mutant form of a naturally occurring bacterial double mutant cocaine esterase (DM CocE) to antagonize the reinforcing, discriminative, convulsant, and lethal effects of cocaine in rodents and reverse the increases in mean arterial pressure (MAP) and heart rate (HR) produced by cocaine in rhesus monkeys. This study was aimed at characterizing the immunologic responses to repeated dosing with DM CocE and determining whether the development of anti-CocE antibodies altered the capacity of DM CocE to reduce plasma cocaine levels and ameliorate the cardiovascular effects of cocaine in rhesus monkeys. Under control conditions, intravenous administration of cocaine (3 mg/kg) resulted in a rapid increase in the plasma concentration of cocaine (n = 2) and long-lasting increases in MAP and HR (n = 3). Administration of DM CocE (0.32 mg/kg i.v.) 10 min after cocaine resulted in a rapid hydrolysis of cocaine with plasma levels below detection limits within 5 to 8 min. Elevations in MAP and HR were significantly reduced within 25 and 50 min of DM CocE administration, respectively. Although slight (10-fold) increases in anti-CocE antibodies were observed after the fourth administration of DM CocE, these antibodies did not alter the capacity of DM CocE to reduce plasma cocaine levels or ameliorate cocaine's cardiovascular effects. Anti-CocE titers were transient and generally dissipated within 8 weeks. Together, these results suggest that highly efficient cocaine esterases, such as DM CocE, may provide a novel and effective therapeutic for the treatment of acute cocaine intoxication in humans.     

Cocaine and scleroderma

I have described a patient with scleroderma whose sex, age at onset of symptoms, and history of long-term intravenous use of cocaine suggest a possible causative role of cocaine in his disease.     

Smoked and intravenous cocaine in humans: acute tolerance, cardiovascular and subjective effects

Ten healthy adult male research volunteers with histories of smoked and i.v. cocaine use participated in four daily sessions. After resting base line, subjects received the same cocaine dose twice with a 14-min interval between doses. Cocaine hydrochloride (16 and 32 mg) was injected or cocaine base (25 and 50 mg) was smoked. Heart rate, blood pressure, subjective effects and venous blood were sampled repeatedly. The potency of smoked cocaine was about 60% of that of i.v. cocaine, i.e., a 50-mg dose of smoked cocaine had effects similar to a 32-mg dose of i.v. cocaine. Cocaine plasma level increased after each dose up to 425 ng/ml with peaks observed 4 min after the second dose. Plasma levels 44 min after the first dose were similar to plasma levels seen 4 min after the first dose. Smoked and i.v. cocaine produced similar increases in heart rate, blood pressure and rate pressure product at similar cocaine venous plasma levels. VAS ratings of "stimulated" and "high" were greater at similar plasma levels after smoked cocaine compared to i.v. cocaine. In addition VAS ratings of cocaine "liking" were also greater for smoked than i.v. cocaine. Otherwise the subjective effects of smoked and i.v. cocaine were similar. The effects of specific cocaine plasma levels on cardiovascular activity and some subjective reports were diminished across the session, demonstrating the development of acute tolerance to cocaine.     

The effects of inhibition of plasma cholinesterase and hepatic microsomal enzyme activity on cocaine, benzoylecgonine, ecgonine methyl ester, and norcocaine blood levels in pigs.

We measured the blood levels of cocaine and its three major metabolites, benzoylecgonine, ecgonine methyl ester, and norcocaine, in three groups of male pigs weighing about 26 kg (25.75 +/- 0.25 kg) to determine the effects of inhibition of plasma cholinesterase and hepatic microsomal enzyme activity on cocaine metabolism. In addition, systemic elimination half-life, volume of distribution, and clearance of cocaine were calculated for the three groups. Group 1 pigs (n = 4) were pretreated with normal saline solution, group 2 pigs (n = 4) were pretreated with tetraisopropyl pyrophosphoramide, a specific plasma cholinesterase inhibitor, and group 3 pigs (n = 4) were pretreated with cimetidine, a hepatic microsomal enzyme inhibitor, all administered intramuscularly. Pigs were anesthetized with intravenous sodium thiopental; a carotid arterial cannula and an external jugular catheter were then inserted for the administration of cocaine and for blood sampling. Forty-five minutes later, when pigs were again completely awake, cocaine 3 mg/kg was given intravenously. Arterial blood samples were collected for the analysis of cocaine and cocaine metabolite levels just before and at 5, 10, 15, 30, 45, 60, 120, 180, and 1440 minutes after the administration of cocaine. Cocaine and cocaine metabolite blood levels were analyzed with high-pressure liquid chromatography methods and plasma cholinesterase activity was measured with a colorimetric method. The blood levels of cocaine and cocaine metabolites were significantly different among the three groups (p less than 0.05, analysis of variance). Statistically significant differences in half-life, volume of distribution and clearance were also seen among the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diltiazem in the prevention and treatment of cocaine-induced cardiotoxicity in dogs

Cocaine can induce serious cardiovascular sequelae, including myocardial depression and coronary artery constriction. The objective of this study was to determine, in the experimental canine model, whether the calcium channel blocker diltiazem, administered intravenously, can ameliorate cocaine-induced cardiotoxicity. The study was conducted in two parts. In the first part of the study, the protective effect of diltiazem against cocaine-induced cardiotoxicity was evaluated. Dogs given pentobarbital were pretreated with either diltiazem 0.25 mg/kg or saline, and then given a 10-mg/kg intravenous bolus of cocaine. In the second part of the study, the role of diltiazem in the treatment of cocaine-induced left ventricular myocardial dysfunction was evaluated. All dogs received a 10-mg/kg intravenous bolus of cocaine. The dogs then received either diltiazem 0.25 mg/kg intravenously or saline. Administration or diltiazem before cocaine reduced the cardiotoxic effects of cocaine. Compared with the control group, there was less depression of the first derivative of left ventricular pressure (LV dP/dt), cardiac output, and left ventricular end diastolic pressure. ST segment elevation occurred in the majority of the control animals after cocaine injection but in none of the animals pretreated with diltiazem. In the second part of the study, cocaine produced left ventricular dysfunction in all animals and ST segment elevation on the electrocardiogram in a majority of the animals. Treatment with diltiazem after the onset of cocaine-induced myocardial dysfunction did reverse the ST segment elevation. It did not, however, improve the hemodynamics significantly compared with the control group. Partial recovery of left ventricular function occurred at 15 minutes in both groups. It was concluded that, in the canine model, administration of diltiazem before injection of cocaine prevents myocardial depression and ST segment elevation. Diltiazem is also effective as treatment to reverse cocaine-induced ST segment elevation but not cocaine-induced myocardial depression.     

Tolerance Develops to the Sympathomimetic But Not the Local Anesthetic Effects of Cocaine

Objectives: The cardiovascular effects of cocaine are complex and include sympathomimetic as well as local anesthetic effects. The aim of the present study was to delineate cocaine toxicity in a model simulating cocaine binging patterns. Design: Prospective laboratory investigation. Twelve dogs were randomized to receive 6 intravenous boluses of cocaine 5.25 mg/kg (high dose, n = 5), 3.5 mg/kg (low dose, n = 4), or placebo (n = 3) at 15-minute intervals. Arterial pressure, electrocardiogram, and serum cocaine were measured at control, then at fixed time intervals after each bolus of cocaine or placebo. Statistical significance was determined by ANOVA. Results: Peak serum cocaine concentrations were 3500 ng/mL and 2167 ng/mL in the high- and low-dose groups. There were progressive decreases in mean arterial pressure in the high-dose cocaine group by as much as 32% (p =. 003) after each cocaine bolus. However, in the low-dose group, increases in mean arterial pressure were observed after the initial cocaine boluses by as much as 31% (p =. 013). Significant QRS prolongation was observed in both the high- and low-dose cocaine groups by as much as 65% (p <. 001) and 10% (p <. 03), respectively. However, the prolongation observed in the high-dose group was more pronounced and cumulative, while in the low-dose group the prolongation was transient. Conclusions: At low doses, cocaine's sympathomimetic properties predominate but tolerance develops. At high doses, cocaine's local anesthetic properties predominate, become more pronounced with repeated administration, and may have implications for cocaine-related dysrhythmias, cardiovascular collapse, and sudden death.     

The Hemodynamic Effects of Cocaine During Acute Controlled Hemorrhage in Conscious Rats

Background: Cocaine is often associated with trauma; however, little is known about how its use alters the response to blood loss. The effect of cocaine on hemodynamics following acute hemorrhage was studied in a rat model. Methods: Following baseline measurements, rats were administered either intravenous cocaine, or saline as a control. Both groups then underwent arterial catheter hemorrhage of 30% of total blood volume. Outcome variables include blood pressure, heart rate, hematocrit, pH, Pco₂, Po₂, and serum bicarbonate. Results: Following hemorrhage, blood pressure decreased in both groups but the hypotension was significantly greater in the saline group than the intravenous cocaine group at 0 and 5 minutes posthemorrhage. Heart rate was increased significantly for the intravenous cocaine group compared to the saline group starting at 15 minutes postcocaine and lasting for the next 25 minutes. No difference was noted for hematocrit, pH, Po₂, or serum bicarbonate. Conclusion: Although transient, cocaine blunted the hypotensive response to acute controlled hemorrhage and resulted in tachycardia.     

Effects of cocaine alone and in combination with bromocriptine in human cocaine abusers.

This study was conducted to determine whether the acute administration of bromocriptine, a dopamine agonist, modulates the acute pharmacologic effects of i.v. cocaine in humans. Eight current users of i.v. cocaine who were not seeking treatment for their cocaine abuse completed the study while they were inpatients on a research unit. Twelve drug conditions were tested in all subjects in randomized order under double-blind, double-dummy conditions and included cocaine (0, 12.5, 25 and 50 mg, i.v.) in combination with bromocriptine (0, 1.2 and 2.5 mg given orally 2 hr before the cocaine injection). Physiologic and subject- and observer-rated responses were measured. Cocaine alone significantly increased pupil diameter, heart rate and blood pressure, and ratings of drug effect, good effects, liking and rush. Bromocriptine alone significantly increased pupil diameter and heart rate, decreased blood pressure and had only minor effects on subjective measures. There were significant cocaine/bromocriptine interactions on diastolic and mean arterial blood pressure, with combinations producing significantly smaller increases compared to cocaine alone, and on heart rate, with combinations producing significantly larger increases compared to cocaine alone. The physiologic and subjective effects of cocaine were not modified by pretreatment with bromocriptine in any other way that might indicate either a therapeutic benefit or a safety concern. However, bromocriptine alone produced undesirable effects (fainting) that should be considered before administration to outpatient cocaine abusers. Any possible therapeutic benefits of acute administration of bromocriptine in cocaine abuse are not likely to be due directly to modulation of the acute effects of cocaine.     

Pharmacotherapeutics directed at deficiencies associated with cocaine dependence: focus on dopamine, norepinephrine and glutamate

Much effort has been devoted to research focused on pharmacotherapies for cocaine dependence yet there are no FDA-approved medications for this brain disease. Preclinical models have been essential to defining the central and peripheral effects produced by cocaine. Recent evidence suggests that cocaine exerts its reinforcing effects by acting on multiple neurotransmitter systems within mesocorticolimibic circuitry. Imaging studies in cocaine-dependent individuals have identified deficiencies in dopaminergic signaling primarily localized to corticolimbic areas. In addition to dysregulated striatal dopamine, norepinephrine and glutamate are also altered in cocaine dependence. In this review, we present these brain abnormalities as therapeutic targets for the treatment of cocaine dependence. We then survey promising medications that exert their therapeutic effects by presumably ameliorating these brain deficiencies. Correcting neurochemical deficits in cocaine-dependent individuals improves memory and impulse control, and reduces drug craving that may decrease cocaine use. We hypothesize that using medications aimed at reversing known neurochemical imbalances is likely to be more productive than current approaches. This view is also consistent with treatment paradigms used in neuropsychiatry and general medicine.     

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.