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PubMed2006

Pharmacological stimulation of group ii metabotropic glutamate receptors reduces cocaine self-administration and cocaine-induced reinstatement of drug seeking in squirrel monkeys.

Group II metabotropic glutamate receptors (mGluRs) have been implicated in regulating the psychopharmacologic effects of cocaine and other drugs of abuse. The present study investigated the interactions between the group II mGluR agonist LY379268 [(-)-2-oxa-4-aminobicyclo [3.1.0] hexane-4,6-dicarboxylate] and cocaine in squirrel monkeys whose operant behavior was maintained under a second order schedule of i.v. cocaine self-administration with or without presentations of a cocaine-paired visual stimulus, extinguished and subsequently reinstated by priming injections of cocaine with or without presentations of a cocaine-paired stimulus, and controlled by cocaine trained as a discriminative stimulus. Antagonism studies with the group II mGluR antagonist LY341495 [2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl) propanoic acid] investigated the extent to which the cocaine-modulating effects of LY379268 could be reversed by blocking group II mGluRs. Quantitative observational studies investigated the effects of LY379268 and LY341495 on species-typical behaviors, balance, and muscle resistance. Pretreatment with LY379268 reduced cocaine self-administration and cocaine-induced reinstatement of drug seeking in a dose-dependent, LY341495-reversible manner. Significant effects of LY379268 were observed both in the presence and absence of the cocaine-paired stimulus. LY379268 did not alter the discriminative stimulus effects of cocaine, nor did it markedly affect observed behavior, with the exception of an increase in visual scanning. Emesis frequently was observed after the highest dose of LY379268 (1.0 mg/kg). The results suggest that LY379268, by stimulating group II mGluRs, can attenuate the reinforcing and priming effects of cocaine at doses that do not alter its perceptibility or markedly suppress other behaviors.

Amino Acids↗
PubMed2000

Differential effects of cocaine and cocaine alcohol on neurocognitive performance.

OBJECTIVE: To investigate the dose-related effects of cocaine with or without alcohol use on the CNS by measuring performance on neurobehavioral tests. BACKGROUND: Chronic use of cocaine is associated with persistent decrements in cognitive function that are most pronounced in heavy users. Specific neurobehavioral deficits in areas such as executive function and impulsivity would make it difficult for the cocaine abuser to discontinue using drugs. Because alcohol is often used in conjunction with cocaine, the CNS effects of alcohol when taken with cocaine deserve further investigation. METHOD: The authors evaluated the dose-related effects of cocaine and alcohol use on performance in a variety of neuropsychological tests after 1 to 3 days of abstinence and again after 4 weeks of abstinence. Fifty-six chronic cocaine abusers who had used cocaine during the past 24 to 48 hours volunteered to perform a battery of neuropsychological tests on two separate occasions during a period of enforced abstinence. In addition to using cocaine, most of the volunteers consumed alcohol. Approximately half of the participants consumed more than 10 alcohol-containing drinks per week. RESULTS: After controlling for the effects of age, sex, and intelligence on performance, the authors found dose-related associations between neurobehavioral performance and cocaine dose and alcohol dose. When the influences of cocaine and alcohol on neurobehavioral performance were taken separately, cocaine and alcohol each selectively affected performance on different neurobehavioral tests after 1 to 3 days of abstinence, with these effects persisting after 4 weeks of abstinence. CONCLUSION: The concomitant use of cocaine and alcohol may have additive negative effects on the brain as compared to the use of only one of these two substances.

Adult↗
PubMed1999

Subjective and physiological effects of intravenous nicotine and cocaine in cigarette smoking cocaine abusers.

The subjective and physiological effects of intravenously administered cocaine and nicotine were compared in 10 cigarette-smoking cocaine abusers. Subjects abstained from smoking at least 8 h before each session. Under double blind conditions, subjects received placebo, cocaine (10, 20, and 40 mg/70 mg), or nicotine (0.75, 1.5, 3.0 mg/70 kg) in mixed order. Physiological and subjective data were collected before and repeatedly after each intravenous drug administration. Subjects also completed a drug versus money multiple-choice procedure in which they chose between that day's drug and 44 monetary values. Both drugs increased blood pressure and heart rate and decreased skin temperature. Nicotine showed a more rapid onset of subjective effects than cocaine. Overall, although both cocaine and nicotine increased subjective ratings of "drug effect", "rush", "good effects", "liking", "high", and "stimulated", only nicotine increased ratings of "bad effects" and "jittery". Although the highest nicotine dose produced greater effects than the highest cocaine dose on most subjective measures, the highest cocaine dose produced somewhat greater ratings of drug liking. At doses that produced comparable ratings of drug effect (40 mg/70 kg cocaine versus 1.5 mg/70 kg nicotine), cocaine produced significantly greater good effects, whereas nicotine produced greater bad effects. All three cocaine doses and the intermediate and high nicotine doses were frequently categorized as producing effects similar to those of cocaine or amphetamine. The drug versus money measure showed that the highest cocaine dose was worth twice as much as the highest nicotine dose. Thus, intravenous cocaine and nicotine can be differentiated by their subjective and reinforcing effects.

Adult↗
PubMed2001

Spatiotemporal analysis of Fos expression associated with cocaine- and PTZ-induced seizures in prenatally cocaine-treated rats.

We previously reported that prenatal cocaine exposure (40 mg/kg s.c., E10-E20) increased susceptibility to convulsant-induced seizures later in life, with female rats becoming more sensitive to seizures induced by cocaine and pentylenetetrazol (PTZ), and males more sensitive to PTZ-induced seizures (Snyder-Keller and Keller, 1995, 2000). In order to determine the locus of enhanced seizure susceptibility in the brains of prenatally cocaine-treated rats, we examined the distribution and density of Fos-immunoreactive cells after cocaine- and PTZ-induced seizures in mature rats. Subconvulsive cocaine doses induced c-fos in cortical areas as well as densely dopamine-innervated regions such as striatum and nucleus accumbens. Following cocaine-induced seizures, intense c-fos induction was observed in piriform cortex, amygdala, and hippocampus. Quantification of the number of Fos-immunoreactive cells in the brains of prenatally cocaine-treated versus prenatally saline-treated rats revealed differences in piriform cortex and amygdala that were indicative of a lower threshold in prenatally cocaine-treated female rats. Following PTZ-induced seizures, the same pattern of limbic structures were recruited with increasing seizure severity. Only females exhibited changes in the number of Fos-immunoreactive cells as a result of prenatal cocaine treatment. Pretreatment with the noncompetitive NMDA antagonist MK-801 blocked both cocaine- and PTZ-induced seizures, and Fos expression in limbic areas was also blocked. The dopamine D1 antagonist SCH 23390 blocked cocaine-induced seizures and associated c-fos induction, but not PTZ-induced seizures or Fos. Examination of the pattern of Fos expression at 15-20 min postseizure revealed that the initial site of c-fos induction associated with PTZ-induced seizures appeared to be the piriform cortex, whereas cocaine-induced seizures induced early expression in both piriform cortex and lateral amygdala. These findings suggest that neural alterations residing in the piriform cortex and amygdala are likely to account for the increased seizure susceptibility of prenatally cocaine-treated rats.

Animals↗
PubMed1989

Fetal and maternal brain and plasma levels of cocaine and benzoylecgonine following chronic subcutaneous administration of cocaine during gestation in rats.

The distribution of cocaine and the cocaine metabolite benzoylecgonine (BE) in brain and plasma of Sprague-Dawley rat dams and their near-term fetuses was assessed 0.5 and 2 h post-injection on gestational day 20 following chronic daily subcutaneous injections of 10, 20, or 40 mg/kg/3 ml cocaine hydrochloride beginning on gestational day 8. Plasma concentrations of cocaine reached in the dams were found to be in the range of, or to exceed, those reported in human cocaine users. Dose-related increases in plasma and brain levels of cocaine in the dams and the fetuses were observed, particularly at 2 h post-injection. Fetal concentrations of cocaine in brain and plasma were approximately 2-3-fold less than those of the dams, suggesting that the placenta may somewhat restrict cocaine entry into fetal circulation. Brain/plasma cocaine ratios, however, were generally equivalent in the dams and fetuses, suggesting that once cocaine enters the circulation, its affinity for brain tissue is similar in the fetus and dam. Whereas plasma levels of BE, like cocaine levels per se, were greater in the dams than fetuses, BE concentrations in fetal brain were greater than those observed in maternal brain. These high levels of BE may contribute to the production of neurobehavioral alterations in cocaine-exposed offspring, given that this active cocaine metabolite has been shown to form molecular complexes with calcium ions (Misra and Mule 1975), thereby having the potential to influence a multiplicity of calcium-regulated developmental events.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Binge cocaine self-administration in humans: intravenous cocaine.

Cocaine is frequently used in intermittent cycles of repeated dosing, or "binges." This pattern of cocaine use has been difficult to study in humans because currently available laboratory models use only one daily session during which a single dose or multiple doses are administered. In the present study, seven adult male IV cocaine users completed a protocol investigating changes in cardiovascular and subjective responses during the repeated self-administration of cocaine. Volunteers participated in a 2-day and a 3-day access condition. On each day of access, they participated in two 2.5-h sessions, one at 1200 and another at 1600 hours. In the 2- and 3-day conditions, participants had access to cocaine on 2 or 3 consecutive days, respectively. During sessions, participants could self-administer up to six doses of IV cocaine (32 mg/70 kg) every 14 min. Participants chose not to self-administer cocaine on only 10% of the 420 trials. Acute tolerance developed to the cardiovascular and several subjective effects of cocaine. Heart rate was the only measure that tended to decrease across days of repeated cocaine self-administration. Ratings of "I want cocaine" decreased at the end of the last self-administration session during both 2- and 3-day conditions. There was no difference between the 2- and 3-day conditions for any measure. The laboratory model of "binge" cocaine use established in this study can be used to describe changes in cardiovascular and subjective effects of cocaine within and between bouts of repeated cocaine use.

Adult↗
PubMed1998

Sensitivity to cocaine and amphetamine among mice selectively bred for differential cocaine sensitivity.

Selective breeding of mice for differences in response to a drug offers a powerful means for testing hypotheses regarding underlying mechanisms and relationships between drug-induced behaviors. Starting from a heterogeneous stock of mice, we have selectively bred lines of mice for extreme differences in their locomotor response to 10 mg/kg cocaine HCl. Selection pressure has been maintained for 12 generations and has resulted in two cocaine sensitive (CAHI) and two cocaine insensitive (CALO) lines. Across the generations of selection, the CAHI lines showed progressively greater amounts of cocaine-induced locomotion, with mice from the S12 generation traveling over 21,000 cm/30 min. following 10 mg/kg cocaine. The CALO lines, in contrast, did not substantially diverge from control values until the S8 generation. By generation 12, however, the LO lines traveled no further following 10 mg/kg cocaine (7000 cm/30 min), than they did following an initial saline injection. Cocaine and amphetamine dose-response analyses were conducted on drug-naive mice from the tenth generation. The CAHI lines were extremely sensitive to the locomotor activating effects of all doses of cocaine, displaying from 2- to 6-fold greater amounts of cocaine-induced locomotion than the CALO lines. The CALO lines, in contrast, were completely insensitive to the psychomotor stimulant effects of cocaine. The CAHI lines were also more sensitive to the locomotor activating effects of amphetamine. Both lines showed dose-dependent amphetamine-induced locomotion that peaked at 3 mg/kg. However, at all doses, the CAHI lines showed a 2- to 4-fold greater amount of locomotion than CALO lines. Thus, the sensitivity to cocaine developed through selection using a single dose of cocaine has generalized to a range of doses of cocaine and to at least one other psychostimulant.

Amphetamine↗
PubMed1994

Differential temporal dynamics of serum and brain cocaine: relationship to behavioral, neuroendocrine and neurochemical cocaine induced responses.

Rats administered cocaine 10 mg/kg i.p. exhibited hyperlocomotion which occurred within 5 min post injection. Subsequently, rats were injected with 10 mg/kg cocaine and brain and serum concentrations of cocaine were measured at 5, 10, and 20 min post injection. Within this time frame, cocaine concentration in limbic brain tissue was maximal at 5 min post injection and then declined substantially by 20 min post injection. In contrast, serum cocaine concentration increased from 5 to 20 min post injection. Neurochemical effects of cocaine upon limbic dopamine turnover and plasma corticosterone had a time course similar to serum cocaine. Brain cocaine concentrations paralleled the locomotor stimulant cocaine response whereas cocaine neuroendocrine effects paralleled serum cocaine concentrations. These findings point to the importance of brain cocaine concentration determinations in neurobehavioral studies of cocaine.

Animals↗
PubMedDate not supplied

Long-term learning deficits and changes in unlearned behaviors following in utero exposure to multiple daily doses of cocaine during different exposure periods and maternal plasma cocaine concentrations.

Although the possible behavioral neurotoxic effects of in utero exposure to cocaine have been the subject of numerous experiments, only a limited number of different types of animal models of cocaine exposure, critical periods, or long-term effects of such exposures have been investigated. In the present experiment, the effects of multiple daily SC exposures to cocaine (20 mg/kg/dose x 5 doses per day) were investigated when administered to gravid Sprague-Dawley CD rats on embryonic days E7-12 or E13-18 compared to weight-matched, vehicle injected, pair-fed controls. Effects of exposure were assessed on general development, olfactory orientation behavior, early locomotion, startle reactivity, spontaneous motor activity, and learning on two different tasks (Morris and Cincinnati water mazes). The multiple cocaine dosing regimen produced maternal peak serum concentrations of cocaine 3 times higher than that of a single dose (approximately 1550 vs. approximately 550 ng/mL). Early-exposed cocaine offspring had lower olfactory orientation scores and reduced postweaning rearing and hole-poke motor activity, whereas late-exposed cocaine offspring had increased postweaning locomotor, rearing, and hole-poke activity. On the Morris hidden platform maze, the cocaine early-exposed females had longer latencies on acquisition than controls. On the Cincinnati multiple-T water maze, the early-exposed cocaine females and the late-exposed cocaine males had increased errors, whereas the early-exposed cocaine males had reduced errors. The effects on measures of learning, when taken together, and in light of their being in the early-exposed group, suggest that embryonic cocaine exposure may have subtle effects on cognition in the offspring as adults. Such effects represent a form of neurotoxicity not previously associated with prenatal cocaine exposure.

Animals↗
PubMed2003

Prolonged effects of repeated cocaine on medial prefrontal cortex dopamine response to cocaine and a stressful predatory odor challenge in rats.

The present study examined the effects of seven daily saline (1 ml/kg, i.p.) or cocaine injections (15 mg/kg, i.p.) on extracellular dopamine levels in the medial prefrontal cortex (mPFC) after challenge with cocaine or stressful predatory odor presentation given 1 week (early withdrawal) or 3 weeks later (late withdrawal). Cocaine challenge at early withdrawal produced an increase in dopamine levels that was temporally shifted so that maximal levels of dopamine were significantly higher and attained 20 min earlier in the cocaine-pretreated group (maximal levels of saline controls=378% increase, cocaine=494% increase above baseline). Cocaine challenge at late withdrawal produced a similar effect on the temporal shift of maximal dopamine levels, with a significantly higher maximal percent increase of dopamine in cocaine-pretreated rats (saline-pretreated=420% increase, cocaine-pretreated=515% increase). Challenge with TMT, a predatory odor from fox that produces a stress response in rats, produced a maximal 75-200% increase in basal dopamine levels in both groups at both early and late withdrawal times. As with cocaine challenge, daily cocaine produced a leftward shift in the time at which maximal dopamine levels were attained in response to TMT. Cocaine-pretreated animals demonstrated maximal dopamine levels 40-80 min after TMT removal, while saline-pretreated rats showed maximal levels 100-140 min after TMT removal. These results suggest that there are long-term changes in the mPFC dopamine response to subsequent challenge with cocaine as well as a stressful predatory odor. The altered response of mPFC dopamine after repeated daily cocaine may impact relapse to drug-seeking or drug-taking behavior.

Animals↗
PubMed2005

Cocaine-induced sex differences in D1 receptor activation and binding levels after acute cocaine administration.

Although it is established that female rats have a more robust behavioral response to acute cocaine administration than male rats, the neurobiological mechanisms underlying these differences remain unclear. The purpose of the present study was to determine whether dopamine (DA) receptor activation influences sex differences in cocaine-induced behaviors. A second study was performed to determine sex differences in D1/D2 receptor levels prior to and post-cocaine administration. Male and female Fischer rats were pre-treated with the D1 antagonist SCH-23390 (0.05, 0.1, and 0.25 mg/kg, i.p.), the D2 antagonist eticlopride (0.03, 0.1 mg/kg, i.p.), or vehicle (saline) 15 min before acute cocaine (20 mg/kg, i.p.) or saline administration. Cocaine-induced ambulatory and rearing activity was greater in female than male rats. Pre-treatment with SCH-23390 affected cocaine-induced ambulatory, rearing, and stereotypic activity in a sex-dependent manner; cocaine-induced ambulatory and stereotypic behavior in female rats was reduced by the lowest dose of SCH-23390. Eticlopride did not alter behavioral responses to cocaine in male or female rats. These results suggest that in both male and female rats, activation of the D1, but not the D2, receptor modulates cocaine's motor effects. There were no sex differences in baseline levels of D1, D2, and DA transporter binding in the caudate putamen (CPu) and the nucleus accumbens (NAc). Cocaine administration reduced D1 binding levels in the CPu only in male rats. Our findings suggest that the regulation of striatal D1 binding levels after acute cocaine administration is a sexually dimorphic process. We also hypothesize that the greater sensitivity to D1 receptor blockade in female rats, as compared to male rats, may contribute to their overall increased hyperactivity in response to acute cocaine. Taken together, the D1 receptor may be an important substrate in the regulation of sex differences to cocaine-induced locomotor activity.

Animals↗
PubMed2006

Influence of abstinence and conditions of cocaine access on the reinforcing strength of cocaine in nonhuman primates.

The development of addiction is marked by a transition from recreational to uncontrolled drug use. Investigators modeling this phenomenon in rodents observed increases in cocaine self-administration when conditions of drug access were altered as well as after abstinence. The present studies were designed to extend this research to nonhuman primates by examining whether the reinforcing strength of cocaine could be altered by changing conditions of cocaine availability or by introducing abstinence periods. Rhesus monkeys self-administered cocaine (0.03-0.3 mg/kg per injection) under a progressive-ratio (PR) schedule of reinforcement in evening sessions, with the number of injections earned serving as a measure of reinforcing strength. Alterations in the reinforcing strength of cocaine were assessed after additional access to cocaine under a fixed-ratio (FR) schedule was provided in morning sessions and following various periods of abstinence (3, 7 and 14 days) from regimens of self-administration that resulted in a range of cocaine intakes. Under baseline PR conditions, the maximum number of cocaine injections increased dose-dependently, peaking when 0.3 mg/kg per injection cocaine was available. No increases in the reinforcing strength of cocaine were observed under any condition. In contrast, a statistically significant decrease in the reinforcing strength of cocaine was observed following 14 days of abstinence under one condition. These results fail to support the views that increasing access to cocaine or abstinence enhances the reinforcing strength of cocaine.

Animals↗
PubMed2005

Priming with BTCP, a dopamine reuptake blocker, reinstates cocaine-seeking and enhances cocaine cue-induced reinstatement.

N-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP), a potent dopamine reuptake inhibitor, substitutes for the reinforcing effects of cocaine and meets other criteria for possible agonist pharmacotherapeutic potential. The purpose of this study was to determine (1) whether BTCP modifies reinstatement of cocaine-seeking elicited by cocaine-related environmental stimuli and (2) whether this compound produces priming effects. Male Wistar rats were trained to associate discriminative stimuli (S(D)) with cocaine availability (0.25 mg/infusion) versus non-reward and then were subjected to repeated extinction sessions during which the reinforcer and S(D) were withheld. Subsequent presentation of the cocaine S(D) produced recovery of cocaine-seeking. BTCP (2.5-30 mg/kg; i.p.) did not attenuate the conditioned reinstatement induced by the cocaine S(D) but, rather, potentiated this effect at 10 mg/kg. To test whether BTCP, by itself, exerts priming effects, different groups of rats were trained to self-administer cocaine (0.25 mg/infusion) for 2 weeks. After a 2-week extinction period, BTCP (5, 10 and 20 mg/kg, i.p.) reinstated cocaine-seeking, showing that BTCP not only increases cocaine-seeking induced by cocaine-related stimuli but also produces priming effects following abstinence. The results suggest that, in cocaine abstinent rats, BTCP produces cocaine-like effects.

Animals↗
PubMedDate not supplied

Attenuation of cocaine-induced genomic and functional responses in prenatal cocaine-exposed rabbits.

The effects of in utero cocaine exposure on cocaine-induced genomic and functional responses in postnatal life were examined. Pregnant Dutch Belted rabbits were injected intravenously, twice daily, with cocaine hydrochloride (4 mg/kg) or saline from day 8 through day 29 of pregnancy. Prenatally exposed kits were challenged with cocaine on postnatal day 20. In prenatal saline-exposed kits, cocaine induced time- and dose-dependent c-fos gene expression in both frontal cortex and striatum. Prenatal cocaine exposure reduced cocaine-induced c-fos responses by 35-58% in the frontal cortex and 37-41% in the striatum. Cocaine-induced functional responses that included head bobbing, seizure, and locomotor activity were also attenuated in prenatal cocaine-exposed kits. Cocaine-induced c-fos expression and functional responses were blocked by the D(1) dopamine receptor antagonist, SCH23390, or by the serotonin receptor antagonist, methysergide, but not by the D(2) dopamine receptor antagonist, L-sulpride. The results indicate that in utero cocaine exposure leads to diminished responses to cocaine challenge in the offspring, which may be mediated by prenatal cocaine-induced alterations in one or more components of the D(1) dopamine and/or serotonin receptor signaling systems during early postnatal life.

Animals↗
PubMed1998

Cocaine sensitization can accelerate the onset of peak cocaine behavioral effects.

The development of sensitization to the behavioral effects of cocaine occurs with repeated intermittent usage. In the present study rats were given five daily i.p. injections of cocaine (10 mg/kg) immediately prior to placement in an open-field environment for 20 min to induce cocaine sensitization. Control groups received saline injections or cocaine injections (10 mg/kg) 30 min after testing in the home cage. One week later the animals were given a challenge test with 10 mg/kg cocaine. The animals that had received cocaine in the test environment exhibited a more rapid onset of cocaine-induced behavioral effects than either animals previously treated with saline or animals that had received cocaine in the home cage. In a second experiment, the same sensitization protocol was followed except that during the interval between the end of the cocaine/saline treatments and the challenge test, the animals were given six daily 20-min saline tests to assess the contribution of differential habituation and/or Pavlovian conditioning to the sensitization effect. Neither habituation or Pavlovian conditioning altered the more rapid onset of cocaine stimulant effects induced by repeated cocaine treatments. It is suggested that the faster onset of cocaine effects is another way in which cocaine sensitization contributes to cocaine abuse liability.

Analysis of Variance↗
PubMed2002

Cocaine mechanisms: enhanced cocaine, fluoxetine and nisoxetine place preferences following monoamine transporter deletions.

Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine, serotonin and norepinephrine, producing subjective effects in humans that are both euphoric/rewarding and also fearful, jittery and aversive. Mice with gene knockouts of each of these transporters display cocaine reward, manifest by cocaine place preferences that are at least as great as wildtype values. Norepinephrine and serotonin receptor knockouts even display enhanced cocaine reward. One explanation for these observations could be that cocaine produces aversive or anhedonic effects by serotonin or norepinephrine receptor blockade in wildtype mice that are removed in serotonin or norepinephrine receptor knockouts, increasing net cocaine reward. Adaptations to removing one transporter could also change the rewarding valence of blocking the remaining transporters. To test these ideas, drugs that block serotonin transporter (fluoxetine), norepinephrine transporter (nisoxetine) or all three transporters (cocaine) were examined in single- or multiple-transporter knockout mice. Fluoxetine and nisoxetine acquire rewarding properties in several knockouts that are not observed in wildtype mice. Adding serotonin transporter knockout to norepinephrine transporter knockouts dramatically potentiates cocaine reward. These and previous data provide evidence that serotonin and norepinephrine transporter blockade can contribute to the net rewarding valence of cocaine. They identify neuroadaptations that may help to explain the retention of cocaine reward by dopamine and serotonin transporter knockout mice. They are consistent with emerging hypotheses that actions at the three primary brain molecular targets for cocaine each provide distinct contributions to cocaine reward and cocaine aversion in wildtype mice, and that this balance changes in mice that develop without dopamine, norepinephrine or serotonin transporters.

Animals↗
PubMed1997

A laboratory model of cocaine withdrawal in humans: intravenous cocaine.

Seven adult intravenous (IV) cocaine users completed a protocol investigating changes in behavior after the self-administration of cocaine. During sessions, the participants could self-administer up to 6 doses of IV cocaine (32 mg/70 kg) twice each day. Both 2- and 3-day binge conditions were tested. At 39 hr after the 3-day but not the 2-day binge of cocaine use, total Beck Depression Inventory scores were increased and participants reported increased ratings of Irritable and decreased ratings of I Want Cocaine. Exposure to stimulus cues associated with IV cocaine increased ratings of I Want Cocaine during periods of abstinence after both 2- and 3-day binges and increased ratings of Depressed only after the 3-day binge of cocaine use. The cessation of binge cocaine use produced modest changes in mood and cocaine craving that were related to the length of the binge and varied as a function of time since last cocaine use. Responsiveness to cocaine cues also varied as a function of the length of the previous cocaine binge.

Adult↗
PubMed2003

Effects of mixed-action kappa/mu opioids on cocaine self-administration and cocaine discrimination by rhesus monkeys.

kappa-Opioid agonists may functionally antagonize some behavioral effects of cocaine, but the role of mixed kappa/mu receptor activity is unclear. The effects of three mixed kappa/mu agonists (MCL-101, (-)cyclorphan, and Mr2034) and one kappa-selective agonist (enadoline) on cocaine self-administration and cocaine discrimination were compared in rhesus monkeys. Acute treatment with all kappa agonists dose dependently reduced cocaine-maintained responding and produced a downward shift in the cocaine self-administration dose-effect curve (0.001-0.32 mg/kg/inj, i.v.). During 7 days of chronic treatment, (-)cyclorphan (0.0032-0.032 mg/kg/h) and MCL-101 (0.0032-0.032 mg/kg/h) each dose dependently reduced cocaine self-administration maintained by a dose near the peak of the cocaine self-administration dose-effect curve. MCL-101 (0.032 mg/kg/h) produced selective and sustained decreases in cocaine self-administration, whereas (-)cyclorphan (0.032 mg/kg/h) had selective but transient effects. In addition, these mixed kappa/mu agonists produced fewer side effects (some salivation) than the kappa-selective agonist (sedation, salivation, emesis). However, none of these kappa agonists substituted for or antagonized cocaine's discriminative stimulus effects in monkeys trained to discriminate cocaine (0.4 mg/kg, i.m.) from saline. Thus, kappa and mixed kappa/mu-opioid agonists may reduce cocaine self-administration without altering cocaine's discriminative stimulus effects. Mixed kappa/mu agonists appear to offer some advantages over selective kappa agonists as potential treatments for cocaine abuse.

Analgesics, Non-Narcotic↗