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PubMed2001

Repeated social-defeat stress, cocaine or morphine. Effects on behavioral sensitization and intravenous cocaine self-administration "binges".

RATIONALE: Repeated social stress experiences engender "behavioral sensitization" and may also increase the potential for abuse of psychomotor stimulants, particularly cocaine use during "binges." OBJECTIVE: Experimental protocols were designed to induce behavioral sensitization through exposures to social-defeat stress or injections of cocaine or morphine. The impact of stress, cocaine or morphine sensitization on cocaine self-administration was assessed using several protocols. METHODS: Behavioral sensitization was induced in male Long-Evans rats by four social-defeat stress episodes, each separated by 72 h. Expression was assessed following a challenge of D-amphetamine (1.0 mg/kg) or cocaine (7.5 mg/kg or 10.0 mg/kg), 10-15 days after the last defeat. Sensitization to cocaine (15.0 mg/kg) or morphine (10.0 mg/kg) was induced via daily administrations for 10 days and later assessed by challenges with cocaine or morphine. Subsequently, i.v. self-administration of cocaine was analyzed for (i) rates of acquisition, (ii) sensitivity to various doses, (iii) "breaking points" during a progressive ratio schedule of cocaine reinforcement, and (iv) patterns of intake during a 24-h binge, in sensitized and control rats. RESULTS: Social-defeat stress, cocaine or morphine administrations increased the locomotor response to stimulant challenges. During 24-h cocaine self-administration binges, sensitization to social-defeat stress or to cocaine prolonged responding, resulting in more cocaine intake. In addition, cocaine sensitization increased the rate of acquisition to cocaine self-administration and the breaking point during a progressive ratio schedule. CONCLUSION: The process of sensitization to social-defeat stress or cocaine intensifies cocaine intake during a binge, supporting the hypothesis that sensitization may facilitate the transition to compulsive drug taking.

Animals↗
PubMed2003

Choosing to take cocaine in the human laboratory: effects of cocaine dose, inter-choice interval, and magnitude of alternative reinforcement.

Cocaine abuse involves a variety of behaviors including the initiation of cocaine-seeking, the self-selected patterning of cocaine administrations, and the cessation of cocaine-taking. To date, most human laboratory models of cocaine self-administration have only assessed the amount of cocaine consumed under a fixed set of conditions. This double-blind, randomized, within-subject, inpatient study evaluated a novel model of human cocaine self-administration that aimed to quantify the reinforcing value of cocaine after cocaine-taking was initiated. Cocaine-dependent volunteers (n=8) sampled cocaine (12.5, 25 or 50 mg per 70 kg i.v.) or placebo and were subsequently allowed to choose between another injection of the same dose or money over six trials during 12 experimental sessions. The value of the monetary alternative increased with each trial from US dollars 1 to 16. Each cocaine dose was assessed under three inter-choice intervals: 15 min, 30 min, and an interval selected by the volunteer. Injection choices increased dose dependently; however, there was little relationship between the value of the alternative reinforcer and the choice to take cocaine. Most volunteers exclusively chose injections when active cocaine was available and money when placebo was available. Inter-choice interval did not affect cocaine choices. These results illustrate the persistence of cocaine self-administration once cocaine-taking has been initiated.

Adult↗
PubMed2003

Association of cocaine withdrawal symptoms with more severe dependence and enhanced subjective response to cocaine.

The purpose of this two part study was to better characterize cocaine users based on self-reported cocaine withdrawal symptoms by examining screening data and response to smoked cocaine in the human laboratory. The first study sample included male and female non-treatment seeking cocaine users who were screened as potential subjects for inpatient studies. Of the 555 subjects, 462 (82%) endorsed symptoms consistent with DSM-IV criteria for cocaine withdrawal. Cocaine users who met criteria for cocaine withdrawal, compared with those who did not, reported a significantly higher amount of cocaine use and a history of medical and psychosocial problems. Cocaine users meeting DSM-IV withdrawal criteria, which included endorsement of depression, were also more likely to have a history of depression, to have seriously considered suicide, and to have had chemical dependency treatment even when amount spent on cocaine was covaried. The second study sample, which was a subset of Study I, included those who participated in human cocaine studies following the phone screening. Cocaine users who met criteria for cocaine withdrawal (n=34), compared with those who did not (n=10), had enhanced subjective ratings of 'high' and 'feel the effect of last dose' in response to a single delivery of 0.4 mg/kg of smoked cocaine. These results suggest that history of cocaine withdrawal symptoms may be associated with enhanced cocaine responses and greater severity of cocaine dependence.

Adult↗
PubMed1994

Responsiveness to cocaine challenge in adult rats following prenatal exposure to cocaine.

Adult rats that were gestationally exposed to cocaine and control offspring were examined for their sensitivity to challenge doses of cocaine. Offspring were derived from Sprague-Dawley dams that had received subcutaneous injections of 40 mg/kg per 3 cc cocaine hydrochloride daily on gestational days 8-20, pair-fed dams that were injected with saline, and nontreated control dams. In order to investigate the sensitivity to challenge doses of cocaine, offspring were assessed in adulthood for locomotor activity, cocaine drug discrimination, and the time course of cocaine in brain tissue following acute cocaine challenge. Adult offspring prenatally exposed to cocaine were observed to exhibit a reduced sensitivity to the discriminative stimulus effects of cocaine as evidenced by a significant shift to the right in the dose-response curve of cocaine discrimination. No prenatal treatment effects were observed in terms of the temporal patterns of cocaine discrimination or with regard to brain levels of cocaine. In addition, baseline locomotor activity and locomotor responses to challenge doses of cocaine were comparable across the prenatal treatment groups. Thus, prenatal cocaine exposure reduced sensitivity of offspring to the discriminative stimulus properties of cocaine without altering either the distribution of cocaine to the brain or the sensitivity of the offspring to the locomotor stimulant effects of cocaine.

Animals↗
PubMed2001

Repeated self-administered cocaine "binges" in rats: effects on cocaine intake and withdrawal.

RATIONALE: Repeated access to cocaine may engender behavioral sensitization, which emerges as an enhanced response to the effects of cocaine. Repeated exposure to prolonged self-administration sessions has been shown to produce an escalation in cocaine intake. OBJECTIVE: The objective of the present study was to identify the consequence of repeated exposure to prolonged access to self-administered cocaine. METHODS: Pairs of rats that were matched for training, housing, and surgery were treated as a single experimental unit, and these pairs were separated into groups for two separate experiments. In the first experiment, one animal of the pair acquired and maintained a stable rate for i.v. cocaine self-administration (0.5 mg/infusion), while the second rat was yoked such that it passively received saline infusions in the same pattern. After acquisition, the active self-administration rats were given free access to cocaine for 16 h (binge), while the yoked animal continued to receive infusions of saline. Twenty-four hours after the binge, both animals were exposed to tactile startle stimuli, and ultrasonic vocalizations (USVs) and startle reflexes were measured. The animals were exposed to three cocaine binges and 24 h post-binge startle tests with an interval of 10 days between binges, and then a fourth binge, with an interval of 24 h separating binges three and four. In the second experiment, pairs of rats were separated into three groups (A, B, and C). The active cocaine rats acquired self-administration and were allowed access to a 16-h cocaine binge while their yoked controls received saline. Twenty-four hours after the binge, all animals were tested for emission of USVs and startle reflexes with an identical protocol as that in experiment 1. Immediately after exposure to the startle stimuli, the self-administering animals were again allowed to self-administer cocaine for either 16 (group A), 12 (group B), or 8 h (group C). RESULTS: In experiment 1, the total amount of cocaine self-administered was significantly decreased when the cocaine binges were separated by 10 days, but total cocaine intake during the binge significantly increased when the drug-free interval was 24 h. The pattern of self-administration and the withdrawal response remained unchanged over consecutive binges. In experiment 2, rats that self-administered cocaine for either 16 or 12 h emitted significantly less USVs immediately after renewed access than they emitted 24 h after the first access period. CONCLUSION: It appeared that consecutive prolonged self-administration was insufficient to produce sensitization, as measured by cocaine intake and renewed access to self-administered cocaine was sufficient to reduce the large number of USVs that characterize withdrawal from a cocaine binge.

Animals↗
PubMed1999

Cocaine-opioid interactions in groups of rats trained to discriminate different doses of cocaine.

RATIONALE: The growing abuse of cocaine combined with morphine-like opiates ("speedballs") in human addicts has prompted efforts to characterize the roles of different opioid receptor subtypes in mediating their combined effects. Previous drug discrimination studies in rats have been inconsistent in showing significant interactions between cocaine and opioid agonists in subjects trained to discriminate a relatively high dose of cocaine from vehicle. It is known, however, that the training dose of cocaine can play a key role in drug-substitution and drug-interaction profiles and, therefore, training rats to discriminate a relatively low dose of cocaine may influence its interactions with opioid agonists. OBJECTIVES: The objectives of this study were to examine the degree to which a relatively high (10 mg/kg) versus a relatively low (3.0 mg/kg) cocaine training dose influenced the interactions between cocaine and either the mu opioid agonist morphine or the kappa opioid agonist U50,488. METHODS: Substitution tests with cumulative doses of cocaine, morphine and U50,488 were conducted, as were studies in which selected doses of morphine or U50,488 were administered prior to cumulative doses of cocaine. RESULTS: In substitution tests, cocaine was 2.9 times more potent under the low- than the high-dose training condition. Morphine substituted fully for cocaine in the majority of subjects trained to discriminate the low, but not the high, dose of cocaine. U50,488 engendered mainly saline-lever responses under both training conditions. In pretreatment studies, morphine enhanced and U50,488 attenuated the discriminative stimulus effects of cocaine in low-dose, but not high-dose, trained rats. In low-dose trained rats, cocaine was five- to eightfold more potent after morphine and three- to fourfold less potent after U50,488 pretreatments. CONCLUSIONS: The results demonstrate that cocaine-opioid interactions are dependent on the training dose of cocaine in rats and suggest an opposing influence of mu and kappa opioid receptors in modifying the discriminative stimulus effects of cocaine.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

Effects of cocaine and its quaternary derivative cocaine methiodide on cardiovascular function in squirrel monkeys.

The effects of cocaine and its quaternary derivative cocaine methiodide, which does not cross the blood-brain barrier, were studied on cardiovascular function in squirrel monkeys. In conscious monkeys, cocaine produced clear dose-dependent increases in blood pressure and heart rate, while cocaine methiodide did not. Both cocaine and cocaine methiodide enhanced the effects of norepinephrine in anesthetized animals, suggesting that both inhibit neuronal uptake of norepinephrine; cocaine was approximately 30 times more potent than cocaine methiodide. In anesthetized monkeys both cocaine and cocaine methiodide produced small, short duration pressor effects, although cocaine was at least 10 times more potent than cocaine methiodide. Cocaine's effects in anesthetized animals were clearly blunted in comparison to its effects in conscious animals. These effects of cocaine on blood pressure occurred at doses lower than those required to enhance norepinephrine's effects, indicating that the norepinephrine uptake blocking effects of the drugs cannot fully account for their cardiovascular effects. The greatly enhanced effect of cocaine in conscious animals and the finding that cocaine methiodide had little effect in conscious animals indicates that central mechanisms are involved in the effects of cocaine on cardiovascular function in conscious animals.

Animals↗
PubMed1998

The effects of cocaine preexposure on the acquisition of cocaine-induced taste aversions.

In separate experiments, rats received either five intraperitoneal or five subcutaneous injections of cocaine (once daily or spaced every fourth day) prior to receiving repeated saccharin-cocaine pairings (during taste aversion conditioning). Both spaced and massed subcutaneous cocaine preexposure attenuated the subsequent acquisition of taste aversions induced by cocaine. Specifically, aversions in the preexposed subjects were acquired at a slower rate and/or to a lesser degree than those acquired by subjects preexposed to the cocaine vehicle and injected with cocaine during conditioning. Spaced and massed intraperitoneal cocaine preexposure had only a weak or no effect, respectively, on the subsequent acquisition of cocaine-induced taste aversions. Specifically, subjects receiving spaced intraperitoneal injections of cocaine during preexposure differed from nonpreexposed subjects on only a single conditioning trial, and subjects receiving massed intraperitoneal injections of cocaine during preexposure displayed aversions comparable to those of nonpreexposed subjects. Although the effects of subcutaneous cocaine preexposure were similar to those reported with other drugs within the aversion design, it is clear that the preexposure effect with cocaine is dependent upon the specific parameters of preexposure. Several possibilities for these differential effects of cocaine preexposure were discussed, including the influence of changing the route of administration from preexposure to conditioning (i.e., from i.p. to s.c.) and the differential masking of the aversive effects of cocaine during conditioning by differential sensitization to cocaine's reinforcing properties following s.c. and i.p. preexposure. Although the present series of experiments did not directly address the mechanism(s) underlying the attenuating effects of cocaine preexposure on aversion learning, several possibilities were noted, including adaptation or tolerance to the aversive effects of cocaine and sensitization to its rewarding effects.

Animals↗
PubMed1999

Issues in the pharmacological modification of cocaine conditioning: evidence that the stimulus properties of drugs can interact with contextual cues to activate or inactivate cocaine conditioned stimuli.

Cocaine conditioned stimuli are capable of eliciting cocaine craving in individuals with a history of cocaine use. As a consequence, there have been a number of attempts using animal models to identify pharmacological treatments which can attenuate cocaine conditioned effects. The emphasis in these studies has been to employ drug doses which do not have response effects that could directly alter the conditioned drug response. A drug treatment may not have a response effect but still have drug stimulus effects which could interact with and modify the cocaine conditioned stimulus. In order to experimentally investigate this important issue, two experiments are reported. In one experiment, rats were co-administered 0.1 mg/kg MK-801 either with cocaine (10 mg/kg) or with saline; in the other experiment 3.0 mg/kg buspirone was co-administered with either cocaine (10 mg/kg) or with saline. The MK-801 and buspirone treatments did not affect spontaneous activity levels or alter the unconditioned cocaine stimulant effect. In tests for conditioning, however, the effects of buspirone and MK-801 depended upon their association with cocaine. If MK-801 and buspirone had no association with cocaine then these drugs inactivated the cocaine conditioned stimulant response. If MK-801 and buspirone had been co-administered with cocaine, then, in saline conditioning tests, no cocaine conditioning was observed. If the conditioning tests were conducted following MK-801 or buspirone treatment, however, cocaine conditioning was elicited. Altogether, these studies demonstrate that the stimulus properties of drugs can interact with contextual stimuli to inactivate or activate cocaine conditioned stimuli. In the search for drugs which may prevent cocaine craving, therefore, the stimulus properties of drugs provide an important mechanism for the modification of cocaine conditioned stimuli.

Animals↗
PubMed2006

Previous exposure to cocaine enhances cocaine self-administration in an alpha 1-adrenergic receptor dependent manner.

Noradrenergic transmission is implicated in the biochemical and behavioral effects of cocaine. Recently, we demonstrated that the alpha 1-adrenergic receptor antagonist prazosin attenuates cocaine-induced reinstatement of drug-seeking behavior. We now assessed whether prazosin could counter the effect of previous exposure to cocaine to enhance subsequent self-administration behavior. Rats were pre-exposed to systemic injections of either saline, prazosin (0.3 mg/kg), saline+cocaine (10 mg/kg), or prazosin+cocaine for 5 days. Starting 15-18 days after the last pre-exposure injection, rats were trained to self-administer cocaine (0.5 mg/kg/infusion) under a fixed ratio 3 (FR3) schedule of reinforcement. Several tests were conducted. First, responding for cocaine under an FR3 schedule was assessed across several doses (0.125-1.0 mg/kg/infusion). Second, responding for cocaine (0.5 mg/kg/infusion) under a progressive-ratio (PR) schedule was examined for 6 consecutive days. Finally, responding for cocaine (0, 0.5, and 1.0 mg/kg/infusion) was determined under the PR schedule of reinforcement. Results showed that cocaine pre-exposed rats self-administer more cocaine compared to saline pre-exposed rats when tested under both the FR and PR schedules. Rats pre-exposed to cocaine plus prazosin did not show enhanced cocaine self-administration. These rats, as well those pre-exposed to prazosin alone, showed levels of cocaine self-administration similar to saline pre-exposed rats. Thus, previous exposure to cocaine enhanced cocaine self-administration, an effect that appears to involve activation of alpha 1-adrenergic receptors. These data, along with several recent studies, show further support for the contribution of noradrenergic transmission in the behavioral effects of cocaine.

Adrenergic alpha-Antagonists↗
PubMed2002

Increased vulnerability to self-administer cocaine in mice prenatally exposed to cocaine.

RATIONALE: At least 40,000 infants born each year in the U.S. are estimated to have been exposed to crack cocaine and, therefore, may be at risk for increased vulnerability to cocaine addiction. OBJECTIVES: The present study tested the hypothesis that prenatal exposure to cocaine significantly increased subsequent cocaine-taking behavior in mice. METHODS: Swiss Webster male mice that had been exposed to cocaine in utero were tested at 5 months of age in the cocaine self-administration paradigm. They were the offspring of dams that received one of the following treatments during gestation days 8-17: cocaine (40 mg/kg or 20 mg/kg per day; COC40 and COC20 mice, respectively), saline with access to food ad libitum (SAL mice), or saline with access to food restricted to that of the COC40 dams (i.e., pair-fed; SPF40 mice). Mice were initially trained to lever press for a condensed-milk solution, were implanted with an indwelling intravenous (i.v.) catheter and, subsequently, allowed to self-administer cocaine (0.25, 0.5, 1.0, or 2.0 mg/kg per injection) under a fixed ratio (FR) 1 schedule of reinforcement. RESULTS: Latency for acquisition of food-reinforced responding appeared to be independent of prenatal treatment, as was acquisition of cocaine self-administration, which was found to be dose dependent. Both COC40 and SAL mice reached cocaine self-administration criteria at 1.0 mg/kg or 2.0 mg/kg per injection doses, while neither group did so at lower doses. It was also observed that, at each of the doses tested, a higher number of COC40 mice reached criteria for acquisition. A logistic regression analysis confirmed that the likelihood for acquiring cocaine self-administration was positively correlated to prenatal exposure to cocaine and the dose of cocaine tested. CONCLUSIONS: These data provide evidence, for the first time, that prenatal exposure to higher doses of cocaine increase the probability of acquiring cocaine self-administration at moderate doses during adulthood and modulate vulnerability to cocaine-taking behavior in mice.

Animals↗
PubMed1999

U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking.

RATIONALE: Previous research has shown that kappa-opioid receptor agonists decrease intravenous cocaine self-administration. These agents also block the development of sensitization that occurs following repeated exposure to cocaine, which is thought to be important in the maintenance and reinstatement of compulsive drug-seeking behavior. OBJECTIVES: This study was designed to determine the effects of the kappa-opioid receptor agonist, U69593, on the maintenance of cocaine self-administration and on the ability of a priming injection of cocaine to reinitiate drug-seeking. METHODS: During daily test sessions, the dose-effect curve (0.015-1.0 mg/kg per infusion) was obtained by either repeatedly reducing the cocaine dose from a starting dose of 1.0 mg/kg per infusion or by repeatedly doubling the cocaine dose from a starting dose of 0.015 mg/kg per infusion. The effect of U69593 (0.0 or 0.32 mg/kg) on responding reinforced by different cocaine doses was determined. The effect of U69593 on the reinstatement of extinguished cocaine-taking behavior was measured in other groups. RESULTS: U69593 decreased responding maintained by low doses of cocaine, regardless of whether cocaine doses were presented in an ascending or descending order. Responding maintained by high doses was unaffected. In animals which received pretreatment with U69593, the priming effects of cocaine were significantly attenuated. The effects of U69593 were specific, since amphetamine-induced cocaine-seeking was not altered by prior administration of U69593. CONCLUSIONS: These findings demonstrate that U69593 attenuates cocaine self-administration and the reinstatement of drug-taking behavior which occurs in response to experimenter-administered cocaine. It is suggested that U69593 may decrease low dose cocaine self-administration by decreasing the priming effects of cocaine.

Amphetamine↗
PubMed1994

Prenatal cocaine eliminates the sex-dependent differences in activation observed in adult rats after cocaine challenge.

In the adult rat, acute administration of cocaine results in enhanced expression of certain behaviors. This activation is often referred to as "stereotypy" because of its repetitive nature. Repeated exposure to the same dose of cocaine does not result in tolerance or a dimunition of these behavioral responses. Rather, an increased responsiveness to cocaine, termed "sensitization," is observed. Female rats, in comparison to male rats, display greater activation to a given dose of cocaine and greater sensitization with repeated exposure. As prenatal cocaine exposure can involve repeated exposure to the drug, we examined the behavioral activation induced by an acute dose of cocaine. Young adult rats of both sexes received a challenge dose of cocaine to determine the long-term effects of repeated in utero exposure to cocaine (30 mg/kg daily, SC) given between gestational days 8-20. As expected, female offspring of dams exposed to saline in utero displayed greater activation to a 20 mg/kg SC dosage of cocaine than their male counterparts. However, these sex differences were completely eliminated by prenatal exposure to cocaine. That is, female rats receiving cocaine during the prenatal period showed no more activation to an acute dose of cocaine as young adults than either control males or those males receiving cocaine in utero. Males exposed in utero to cocaine showed activation to cocaine challenge equivalent to that displayed by males exposed to saline in utero. Prenatal exposure to cocaine may alter sexual differentiation of the brain.

Animals↗
PubMed2005

Stimulus gated cocaine sensitization: interoceptive drug cue control of cocaine locomotor sensitization.

Repeated cocaine treatments typically generate sensitization effects which are environment specific. In this study, we investigated whether drug treatments with highly selective receptor specificity can also function as contextual cues to control the expression of cocaine sensitization effects. Two experiments were conducted in which separate groups of rats (N=10) received ten paired or unpaired cocaine (10.0 mg/kg) treatments. In the experiments, autoreceptor preferring low doses of either the 5-HT1A agonist, 8-OHDPAT (8OH) (0.05 mg/kg) or the D1/D2 agonist apomorphine (APO) (0.05 mg/kg) were administered 20 min prior to cocaine administration and test environment placement (paired treatment). Under these conditions, the drug cues generated by the 8OH/APO treatments were associated with the cocaine stimulant effect in the test environment. The unpaired treatment groups received the same drug treatments but the cocaine was administered after testing, in the homecage. Consequently, for these groups, the 8OH/APO drug cues generated by the drug treatments would not become associated with the cocaine stimulant effect in the test environment. Critically, both 8OH and APO pretreatments elicited equivalent unconditioned response effects which were opposite to the cocaine unconditioned response effects; that is, behavioral inhibition vs. behavioral stimulation. Initially, the 8OH and APO pretreatments prevented the locomotor stimulant effects of cocaine; but, these inhibitory effects were reversed in the paired groups with repeated cocaine treatments, consistent with the emergence of cocaine sensitization effects. In the unpaired 8OH and APO pretreatment groups, behavioral suppression persisted throughout the treatment protocol. Subsequently, paired and unpaired groups were compared in four conditioning/sensitization tests. The conditioning tests included: a saline/saline test; and a 8OH/saline test (Experiment 1); and, a saline/saline test and a APO/saline test (Experiment 2). There were no paired/unpaired group differences in these conditioning tests. The sensitization tests included: a saline/cocaine test; and a 8OH/cocaine test (Experiment 1); and, a saline/cocaine test and a APO/cocaine test (Experiment 2). There were no paired/unpaired group differences in the saline/cocaine test for sensitization but paired/unpaired group differences were found in both the 8OH/cocaine and APO/cocaine sensitization tests. In these tests the paired but not the unpaired groups exhibited cocaine locomotor sensitization effects. Critically when, in an additional test, the pretreatments in the cocaine tests were reversed (i.e., 8OH paired group received APO and APO paired group received 8OH prior to cocaine), then there was no evidence for cocaine sensitization. Since the 8OH/APO pretreatments had equivalent inhibitory response effects, it was the stimulus properties of these drugs which controlled the expression of the cocaine locomotor sensitization effects. These findings support the critical role of associative processes in the stimulus-gating of psychostimulant drug sensitization. Importantly, this report incorporates a new methodology in which context can be specified in terms of highly specific brain receptor targets rather than in terms of global environmental situational cues.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2004

The modulation of cocaine-induced conditioned place preferences by alcohol: effects of cocaine dose.

Busse and Riley [Biol. Psychiatry 26 (2002) 1373] have recently reported that alcohol dose dependently attenuated cocaine-induced place preferences. Although the mechanism for this effect is not known, it is possible that it is due to alcohol potentiating the aversive properties of cocaine, a potentiation that masks or abates cocaine's rewarding effects in this preparation. Given that the affective properties of cocaine (both aversive and rewarding) have been reported to be dose dependent, it might be expected that alcohol's ability to affect cocaine-induced place preferences would be influenced by changes in cocaine dose. To address this possibility, the following experiments assessed the effects of alcohol (0.5 g/kg) on place preferences induced by high (20, 30 and 40 mg/kg: Experiment 1) and low (2.5 and 5 mg/kg; Experiment 2) doses of cocaine. Specifically, every other day for four cycles male Sprague-Dawley rats were injected with cocaine, alcohol or one of several cocaine/alcohol combinations immediately before being placed on one side of a two-compartment place preference chamber. On alternate days, they were placed on the other side of the chamber after being injected with the drug vehicle(s). In Experiment 1, all doses of cocaine (20, 30 and 40 mg/kg) produced a significant preference for the drug-paired compartment, whereas alcohol alone produced no effect. When given in combination, alcohol attenuated the cocaine-induced place preference (at 30 and 40 mg/kg cocaine). In Experiment 2, neither cocaine (2.5 or 5 mg/kg) nor alcohol produced a significant effect when given alone. However, animals receiving the combination of alcohol and cocaine (5 mg/kg) displayed a significant place preference. These findings indicate that alcohol can both weaken and strengthen cocaine-induced place preferences, possibly via its effects on the rewarding and aversive properties of cocaine. The effect of alcohol is dependent on the dose of cocaine.

Animals↗
PubMed2002

Effects of mu-opioid agonists on cocaine- and food-maintained responding and cocaine discrimination in rhesus monkeys: role of mu-agonist efficacy.

Mu-opioid agonists decrease cocaine self-administration in laboratory studies and cocaine use by many cocaine- and opioid-dependent polydrug abusers. To assess the role of mu-agonist efficacy as a determinant of these effects, this study evaluated cocaine- and food-maintained responding by rhesus monkeys (Macaca mulatta) during chronic treatment with saline or the high-efficacy mu-agonist fentanyl (0.001-0.01 mg/kg/h), the intermediate-efficacy mu-agonist morphine (0.032-0.32 mg/kg/h), or the low-efficacy mu-agonists nalbuphine (0.1-1.0 mg/kg/h) and butorphanol (0.0032-0.032 mg/kg/h). Responding was maintained by cocaine and food under a second order schedule of reinforcement during multiple daily sessions of cocaine and food availability. Saline and each opioid dose were administered continuously for 7 consecutive days during availability of each cocaine dose. All four mu-agonists produced dose-dependent and sustained decreases in cocaine self-administration across a range of cocaine doses (0.0032-0.1 mg/kg/injection). Nalbuphine and butorphanol produced the greatest decreases in cocaine self-administration and the smallest effects on food-maintained responding. Morphine and fentanyl produced smaller decreases in cocaine self-administration, and undesirable effects precluded evaluation of higher fentanyl and morphine doses. Decreases in cocaine self-administration produced by nalbuphine and butorphanol probably did not reflect a general blockade of cocaine's abuse-related effects, because nalbuphine and butorphanol did not block the discriminative stimulus effects of cocaine in monkeys trained to discriminate 0.4 mg/kg cocaine from saline in a food-reinforced drug discrimination procedure. These results suggest that low-efficacy mu-agonists may decrease cocaine self-administration to a greater degree and with fewer undesirable effects than high-efficacy mu-agonists.

Analgesics, Opioid↗
PubMed1993

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

Mazindol is a catecholamine reuptake inhibitor that blocks binding of cocaine at the dopamine reuptake site. This study was conducted to determine whether the acute administration of mazindol modulates the pharmacological effects of intravenous cocaine in humans. In a crossover study, twelve acute drug conditions were tested in randomized order under double-blind, double-dummy conditions in eight cocaine abusers. Cocaine (0, 12.5, 25 and 50 mg, i.v.) was administered in combination with mazindol (0, 1 and 2 mg given orally 2 hr before the cocaine injection). Physiological and subject- and observer-rated responses were measured. Cocaine and mazindol alone both significantly increased heart rate and blood pressure. Cocaine increased ratings on stimulant-like subjective effect measures, including desire for cocaine; mazindol had mild, stimulant-like subjective effects. There were significant interactions between the effects of cocaine and mazindol on heart rate and blood pressure, with combinations producing significantly large and more sustained increases compared with cocaine alone. There was no evidence that mazindol substantially altered the magnitude or profile of the subjective effects of cocaine, including cocaine-induced craving for cocaine. These results do not support the utility of acute administration of mazindol in the treatment of cocaine abusers through a mechanism of modulation of cocaine's subjective effects. Furthermore, mazindol treatment may increase the cardiovascular risks of cocaine.

Adult↗
PubMed1998

Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine.

Second order schedules of IV cocaine reinforcement in rats provide a reliable method for evaluating the effects of conditioned stimuli on cocaine-seeking behaviour, and for measuring the motivational aspects of cocaine reinforcement. In the procedure established here, each infusion of cocaine (0.25 mg/infusion) was initially made contingent on a lever press and was paired with a 20-s light conditioned stimulus (CS). When rats acquired stable rates of cocaine self-administration, the response requirement for cocaine was increased progressively to a second-order schedule of the type FI15 min(FR10:S), whereby the IV cocaine infusion was self-administered following the completion of the first FR10 responses (and CS presentation) after a 15-min fixed interval (FI) had elapsed. Evaluation of the animals' responding during the first, drug-free interval of each daily session provided a measure of cocaine-seeking behaviour, independent of other pharmacological effects of the self-administered drug. Thus, a dose-response study (dose range: 0.083, 0.25 and 0.50 mg/infusion) revealed that responding under this schedule during the initial, drug-free interval changed monotonically with dose, whereas an inverse relationship between cocaine dose and response level tended to appear during the rest of the session, after rats had self-administered the drug. Responding under this schedule was also shown to occur under the control of the CS, which had acquired conditioned reinforcing properties. Thus, a decrease in responding and an increase in the latency to initiate responding followed the omission of the CS for 3 consecutive days. In addition, extinction of cocaine-seeking behaviour was slower when contingent CS presentations occurred compared to extinction when the CS was not present. Furthermore, the reinstatement of responding for cocaine, which followed a brief period of non-contingent CS presentations, was retarded when this conditioned reinforcer had been extinguished together with cocaine. Finally, cocaine-seeking behaviour decreased markedly for the first 6 h that followed a 12-h period of continuous access to cocaine, when compared to responding 6 h after a 90-min session of limited access to the drug. Responding subsequently increased to baseline levels within 72 h. These results emphasise the utility of second-order schedules for studying drug-seeking behaviour and the importance of drug-associated cues in maintaining such responding for cocaine.

Animals↗