Various Doses Of Cocaine Research Articles

Conditioned taste avoidance induced by the combination of heroin and cocaine: Implications for the use of speedball

Speedball (heroin + cocaine) is a prevalent drug combination among intravenous drug users. Although its use is generally discussed to be a function of changes in the rewarding effects of either or both drugs, changes in the aversive effects of either drug may also be impacted (weakened) by the combination. To address this latter possibility and its potential role in the use of speedball, the present studies examined the interaction of cocaine and heroin in taste avoidance conditioning. In Experiment 1, male Sprague-Dawley rats were given access to a novel saccharin solution and then injected with either vehicle or heroin (3.2 mg/kg, IP) followed immediately by various doses of cocaine (10, 18 or 32 mg/kg, SC). At the two lowest doses of cocaine, only animals injected with the drug combination (H + C) displayed a taste avoidance relative to control subjects (taste avoidance was induced with both the combination and the high dose of cocaine). At no dose did animals injected with the combination of heroin and cocaine drink more than animals injected with cocaine alone. In Experiment 2, male Sprague-Dawley rats were similarly treated but injected with vehicle or cocaine (10 mg/kg) followed by injections of various doses of heroin (1.8, 3.2, 5.6 or 10 mg/kg). At the three highest doses of heroin, only animals injected with the drug combination (C + H) displayed significant avoidance relative to control subjects (no avoidance was evident with the combination of cocaine and the low dose of heroin). At no dose did animals injected with the combination of cocaine and heroin drink more than animals injected with heroin alone. Together, these results suggest that the aversive effects of heroin and cocaine are not attenuated by co-administration by cocaine and heroin, respectively. The importance of this for the use of speedball was discussed.

Self-administration of cocaine and remifentanil by monkeys under concurrent-access conditions.

Cocaine and opioids are often co-abused. Laboratory research has focused largely on the reinforcing effects of mixtures of drugs relative to the drugs alone. Less research has examined drug mixing by the subject under concurrent-access conditions. Self-administration of various doses of cocaine and remifentanil was examined under concurrent-access conditions. It was hypothesized that if cocaine and opioid combinations were more effective reinforcers than the single drugs, subjects would mix the two drugs by adjusting their responding to cocaine and an opioid alternative to maintain an optimal ratio of cocaine/remifentanil intake. Three male rhesus monkeys were allowed to self-administer cocaine (0.05-0.2 mg/kg/inj) or saline on one lever and remifentanil (0.05-0.4 μg/kg/inj) or saline on the other lever under concurrent fixed-ratio (FR) 10 schedules. Daily sessions lasted 2 h, and there was a 1-s timeout after every 10-s injection. When saline and drug were concurrently available, responding on the saline-associated lever was low relative to the drug alternative. When cocaine and remifentanil were concurrently available, both drugs were self-administered above saline levels. Cocaine intake decreased, and remifentanil intake increased as a function of the remifentanil dose that was available. Conversely, cocaine intake and remifentanil intake did not change systematically as a function of the cocaine dose that was available. Monkeys will mix cocaine and an opioid when the two drugs are available concurrently. However, there was no indication that monkeys titrated drug intake to maintain an optimal ratio of intake of the two compounds.

The effects of the 5-HT3 receptor antagonist tropisetron on cocaine-induced conditioned taste aversions

Although cocaine readily induces taste aversions, little is known about the mechanisms underlying this effect. Recent work has shown that cocaine's actions on serotonin (5-HT) may be involved. To address this possibility, the present experiments examined a role of the specific 5-HT receptor, 5-HT3, in this effect given that it is implicated in a variety of behavioral effects of cocaine. This series of investigations first assessed the aversive effects of the 5-HT3 receptor antagonist tropisetron alone (Experiment 1). Specifically, in Experiment 1 male Sprague–Dawley rats were given repeated pairings of a novel saccharin solution and tropisetron (0, 0.056, 0.18 and 0.56mg/kg). Following this, a non-aversion-inducing dose of tropisetron (0.18mg/kg) was assessed for its ability to block aversions induced by a range of doses of cocaine (Experiment 2). Specifically, in Experiment 2 animals were given access to a novel saccharin solution and then injected with tropisetron (0 or 0.18mg/kg) followed by an injection of various doses of cocaine (0, 10, 18 and 32mg/kg). Cocaine induced dose-dependent taste aversions that were not blocked by tropisetron, suggesting that cocaine's aversive effects are not mediated by 5-HT, at least at this specific receptor subtype. At the intermediate dose of cocaine, aversions appeared to be potentiated, suggesting 5-HT3 may play a limiting role in cocaine's aversive effects. These data are discussed in the context of previous examinations of the roles of serotonin, dopamine, and norepinephrine in cocaine-induced aversions.

Assessment of dopaminergic involvement in cocaine‐induced conditioned taste aversions

Although cocaine induces conditioned taste aversions (CTA), little is known about the mechanisms underlying this effect. It has been suggested that cocaine's actions as a nonselective monoamine transport inhibitor may be mediating this suppression. Given the role of dopamine (DA) in cocaine reward, this neurotransmitter system is of particular interest. The present experiments used direct pharmacological antagonism (with the DA antagonist haloperidol) to determine a role, if any, of DA in the induction of CTAs by cocaine. Following the determination of behaviorally active doses of haloperidol with no aversive effects on their own (Experiment 1), animals were given 1 mg/kg haloperidol prior to various doses of cocaine in a taste aversion procedure (Experiment 2). Under these conditions, haloperidol blocked cocaine‐induced CTAs (at the 18 and 32 mg/kg doses). These results suggest that DA has a role in cocaine‐induced CTAs. These data are discussed in the context of previous work demonstrating roles for both norepinephrine and serotonin in cocaine‐induced taste aversion learning as well as current research investigating DA transporter inhibitors and cocaine within the cross‐drug preexposure preparation.

Locomotion and self-administration induced by cocaine in 129/OlaHsd mice lacking galanin.

Previous studies have demonstrated that the galanin system modulates responses to drugs of abuse such as morphine. The current study examined whether genetic deletion of galanin could affect the locomotor and reinforcing effects of cocaine in mice. We analyzed spontaneous motor activity and cocaine-induced hyperactivity in wild-type (GAL-WT) and knockout mice lacking galanin (GAL-KO) maintained on the 129/OlaHsd background. Our results indicate that cocaine enhanced locomotion (defined as moving more than 5 cm) dose-dependently in GAL-WT and GAL-KO mice. However, general activity (total beam breaks) was increased by cocaine only in GAL-WT mice. An additional experiment indicated that galnon, a nonselective galanin receptor agonist, did not affect cocaine-induced hyperactivity. In a second set of experiments, mice of both genotypes were trained to self-administer cocaine under a fixed ratio schedule, tested with various doses of cocaine and under different schedules of reinforcement. This set of experiments showed that cocaine self-administration did not differ markedly between genotypes. However, while GAL-WT mice acquired cocaine self-administration, a median split analysis showed that mice could be divided into large and small drug takers, whereas all GAL-KO mice behaved as small drug takers. Our results indicate that wild-type and galanin knockout mice on a congenic 129/OlaHsd background are responsive to the locomotor effects of cocaine and can acquire intravenous cocaine self-administration. However, the phenotype observed in GAL-KO mice does not support a major role for galanin in cocaine-induced hyperlocomotion and self-administration.

Aerobic exercise decreases the positive-reinforcing effects of cocaine

Aerobic exercise can serve as an alternative, non-drug reinforcer in laboratory animals and has been recommended as a potential intervention for substance abusing populations. Unfortunately, relatively little empirical data have been collected that specifically address the possible protective effects of voluntary, long-term exercise on measures of drug self-administration. The purpose of the present study was to examine the effects of chronic exercise on sensitivity to the positive-reinforcing effects of cocaine in the drug self-administration procedure. Female rats were obtained at weaning and immediately divided into two groups. Sedentary rats were housed individually in standard laboratory cages that permitted no exercise beyond normal cage ambulation; exercising rats were housed individually in modified cages equipped with a running wheel. After 6 weeks under these conditions, rats were surgically implanted with venous catheters and trained to self-administer cocaine on a fixed-ratio schedule of reinforcement. Once self-administration was acquired, cocaine was made available on a progressive ratio schedule and breakpoints were obtained for various doses of cocaine. Sedentary and exercising rats did not differ in the time to acquire cocaine self-administration or responding on the fixed-ratio schedule of reinforcement. However, on the progressive ratio schedule, breakpoints were significantly lower in exercising rats than sedentary rats when responding was maintained by both low (0.3 mg/kg/infusion) and high (1.0 mg/kg/infusion) doses of cocaine. In exercising rats, greater exercise output prior to catheter implantation was associated with lower breakpoints at the high dose of cocaine. These data indicate that chronic exercise decreases the positive-reinforcing effects of cocaine and support the possibility that exercise may be an effective intervention in drug abuse prevention and treatment programs.

S(+)- and R(−) N-Methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) as discriminative stimuli: Effect of cocaine

Racemic N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (methylenedioxymethamphetamine, MDMA), a central stimulant and empathogenic agent, and cocaine are drugs of abuse that function as training drugs in drug discrimination studies. In tests of stimulus generalization (substitution), asymmetric generalization occurs between the two agents: a (±)MDMA stimulus generalized to cocaine, but a cocaine stimulus did not generalize to (±)MDMA. A possible explanation may be found, at least in part, in the stimulus effects of the optical isomers of MDMA. In the present study, groups of male Sprague–Dawley rats were trained to discriminate either S(+)MDMA (training dose = 1.5 mg/kg, i.p.; n = 10; ED 50 = 0.6 mg/kg) or R(−)MDMA (training dose = 1.75 mg/kg, i.p.; n = 7; ED 50 = 0.4 mg/kg) from saline vehicle using a VI-15s schedule of reinforcement. Tests of stimulus generalization with cocaine were conducted in each of the two groups. Cocaine only partially substituted for the S(+)MDMA stimulus (maximum = 39% drug-appropriate responding), and various doses of cocaine did not enhance the percent drug-appropriate responding produced by a low dose (0.5 mg/kg) of S(+)MDMA. In contrast, the R(−)MDMA stimulus generalized completely to cocaine (ED 50 = 1.3 mg/kg). Taken together with an earlier report that a (±)MDMA stimulus generalizes to cocaine, it would seem that the stimulus actions of cocaine might share greater similarity with R(−)MDMA than with S(+)MDMA.

Effects of High-Dose Methadone Maintenance on Cocaine Place Conditioning, Cocaine Self-Administration, and Mu-Opioid Receptor mRNA Expression in the Rat Brain

Methadone maintenance at appropriate doses can effectively reduce cocaine abuse in heroin-dependent individuals. In the present studies, we investigated the effect of high-dose methadone maintenance cocaine conditioned place preference (CPP) and cocaine intravenous self-administration. Rats implanted with methadone-filled osmotic mini-pumps (20 and 55 mg/kg/day, SC) and conditioned with cocaine (1, 5, and 20 mg/kg, i.p.) did not express cocaine CPP. Similarly, rats implanted with methadone pumps (55 mg/kg/day) after cocaine conditioning (20 mg/kg) displayed neither spontaneous nor cocaine-precipitated (20 mg/kg, i.p.) CPP. In contrast, methadone maintenance (30 and 55 mg/kg/day, SC) did not alter the intravenous self-administration (continuous schedule of reinforcement) of various doses of cocaine (0.1, 0.5, and 2.0 mg/kg/inf). To explore neuropharmacological interactions between methadone maintenance and cocaine conditioning, we quantitatively measured mRNA levels of mu-opioid receptor (MOR) and proopiomelanocortin genes 10 days after methadone maintenance. MOR mRNA levels in both the nucleus accumbens core and frontal cortex were significantly elevated in rats exposed to cocaine during CPP conditioning. However, upregulation of MOR mRNA levels in the nucleus accumbens core were reduced by methadone maintenance in a dose-dependent manner. In conclusion, our results suggest that high-dose methadone maintenance does not alter the direct reinforcing effect of cocaine, but blocks spontaneous and cocaine-precipitated cocaine-seeking, possibly by preventing MOR alterations in the nucleus accumbens core induced by cocaine conditioning.

Rapid and Persistent Sensitization to the Reinforcing Effects of Cocaine

The development of drug addiction involves a transition from recreational use to compulsive drug seeking and taking, and this progression can occur rapidly with cocaine use. These data highlight the importance of early drug exposure and the development of drug dependence; however, little experimental attention has been paid to this phenomenon in animal models of drug abuse. The present experiments demonstrate a progressive and rapid sensitization to the reinforcing strength of cocaine assessed using a progressive ratio (PR) schedule in rats. The first experiment found that rats show increased breakpoints over a 2-week period following acquisition. Subsequent experiments examined the role of total cocaine intake during the initial exposure period and found that low intakes (20 mg/kg/day x 5 days) resulted in sensitization, whereas relatively higher intake (60 or 100 mg/kg/day x 5 days) suppressed the development of sensitization. In contrast, this higher level of intake (60 mg/kg/day x 5 days) only transiently suppressed the expression of sensitization. Examination of breakpoints maintained by various doses of cocaine revealed an upward and leftward displacement of the cocaine dose-effect curve, relative to nonsensitized animals. These studies describe a form of sensitization that occurs rapidly to the reinforcing effects of cocaine, and provide a model to study the potential impact of initial experience on the development of drug dependence.

EFFECTS OF COCAINE ON PERFORMANCE UNDER FIXED‐INTERVAL SCHEDULES WITH A SMALL TANDEM RATIO REQUIREMENT

Daily administration of cocaine often results in the development of tolerance to its effects on responding maintained by fixed-ratio schedules. Such effects have been observed to be greater when the ratio value is small, whereas less or no tolerance has been observed at large ratio values. Similar schedule-parameter-dependent tolerance, however, has not been observed with fixed-interval schedules arranging comparable interreinforcement intervals. This experiment examined the possibility that differences in rate and temporal patterning between the two types of schedule are responsible for the differences in observed patterns of tolerance. Five pigeons were trained to key peck on a three-component multiple (tandem fixed-interval fixed-ratio) schedule. The interval values were 10, 30, and 120 s; the tandem ratio was held constant at five responses. Performance appeared more like that observed under fixed-ratio schedules than fixed-interval schedules. Effects of various doses of cocaine given weekly were then determined for each pigeon. A dose that reduced responding was administered prior to each session for 50 days. A reassessment of effects of the range of doses revealed tolerance. The degree of tolerance was similar across components of the multiple schedule. Next, the saline vehicle was administered prior to each session for 50 days to assess the persistence of tolerance. Tolerance diminished in all subjects. Overall, the results suggested that schedule-parameter-dependent tolerance does not depend on the temporal pattern of responding engendered by fixed-ratio schedules.

Cocaine affects prostaglandin production in human umbilical cord cell cultures

Objective: To investigate the possible effects of cocaine on prostacyclin and prostaglandin (PG) E2 production from endothelial cells derived from human umbilical cord.Study design:First-passaged endothelial cells derived from the umbilical vein were incubated with various doses of cocaine, procaine and lidocaine and 24 h later the supernatants were assayed for prostacyclin metabolites6-keto-PGF1α and PGE2. Cocaine concentrations tested were 0, 10, 100, 500 and 1000 μg/ml.Results: Cocaine produced a dose-dependent reduction in prostacyclin andPGE2 production from endothelial cells (p < 0.05). Acetylcholinesterase (a possible detoxifier of cocaine) abolished the effect of cocaine on prostacyclin production. Procaine, an esterol-typeanesthetic, produced a similar effect on prostacyclin production, an effect not observed with lidocaine.Conclusion: It is speculated that, when present in high concentrations, cocaine may affectvascular tone by inhibition of endothelial cell prostacyclin and PGE2 release.

Effects of cocaine on the coronary arteries

Background A number of studies have documented myocardial ischemia and infarction associated with cocaine use. Mismatch between myocardial oxygen supply and demand from cocaine-induced vasoconstriction and increased myocardial workload are often invoked as the major postulated mechanism by which cocaine induces myocardial ischemia. This article reviews the literature studying the effects produced by cocaine on the coronary arteries to provide insight into the various pathophysiologic mechanisms by which cocaine triggers acute cardiac ischemia or infarction. Methods We reviewed the published literature describing the effects of cocaine on the coronary arteries. A MEDLINE search of English language articles published between 1985 and 2000 was performed. Key words included coronary arteries, coronary vasoconstriction, vasospasm, coronary vasodilation, cardiac vasculature, myocardial ischemia, platelets, thrombosis, and cocaine. Both animal and human studies were included. The bibliographies of identified articles were also explored for additional sources of information. Results A recreational dose of cocaine increases the heart rate by approximately 30 beats/min. It also increases the blood pressure by 20/10 mm Hg. These increases are modest, are equivalent to mild exercise, and are not believed to be sufficient to result in myocardial ischemia in the majority of cases. Animal and human studies have documented cocaine-induced early coronary artery vasodilation as shown by a decrease in coronary perfusion pressure ranging from 13% to 68%. This was followed by a more sustained vasoconstriction demonstrated by a decrease in epicardial coronary artery diameter ranging from 5% to 30% with various doses of cocaine by various methods of administration. These changes alone are also an unlikely explanation for cocaine-induced myocardial ischemia. Therefore neither increases in myocardial workload nor hemodynamic changes are sufficient to explain cocaine-induced myocardial ischemia. However, evidence also exists that cocaine activates platelets and promotes thrombosis, resulting in intracoronary thrombus formation. Cocaine may also promote premature and more severe coronary atherosclerosis. Conclusion The etiology of cocaine-induced myocardial ischemia is complex and is likely to be multifactorial. It appears to be the result of coronary artery vasoconstriction, intracoronary thrombosis, and accelerated atherosclerosis. (Am Heart J 2001;142:402-10.)

Reinforcing effects of D2 dopamine receptor agonists and partial agonists in rhesus monkeys

Dopamine (DA) receptors play a role in the reinforcing effects of psychomotor stimulants and other drugs. Both D1 and D2 DA receptor agonists have been reported to function as positive reinforcers in maintaining self-administration in non-human subjects. The purpose of the present study was to evaluate, in monkeys, the reinforcing effects of DA D2 receptor agonists that vary in their efficacy as D2 agonists. Rhesus monkeys were prepared with venous catheters and lever pressing was maintained by i.v. cocaine ( n=5, 0.03 mg/kg/inj) in daily baseline sessions (2 h/day, fixed ratio 25). Various doses of cocaine or D2 agonists were then made available for at least four to seven sessions, and until responding was stable. At least one dose of the higher-efficacy D2 agonists, R(−)-propylnorapomorphine (NPA) ( n=4, 0.001–0.01 mg/kg/inj), R(−)-apomorphine (APO) ( n=4, 0.003–0.1 mg/kg/inj) and R(+)-3-(3-hydroxyphenyl)- N-propylpiperidine HCl [ R(+)-3-PPP] ( n=4, 0.03–0.3 mg/kg/inj), functioned as a positive reinforcer in all the monkeys tested. In contrast, no dose of the lower-efficacy D2 agonists, R(+)-terguride ( n=4, 0.001–0.3 mg/kg/inj) and S(−)-3-(3-hydroxyphenyl)- N-propylpiperidine HCl [ S(−)-3-PPP] ( n=4, 0.001–0.3 mg/kg/inj), maintained self-administration. In in vitro binding studies with monkey brain tissue NPA and terguride had high affinities for the D2 receptor, while APO had intermediate affinity, and the 3-PPPs had low affinity. Among the compounds that were reinforcers potency as a reinforcer was directly related to D2 affinity in three of the four monkeys, consistent with D2 receptor involvement in the reinforcing effect of these compounds. The data suggest that the efficacy at D2 receptors is directly related to the reinforcing effect.

Further studies of the reinforcing effects of benztropine analogs in rhesus monkeys.

Several halogenated analogs of benztropine (BZT) have previously been characterized as potent DA uptake inhibitors with behavioral profiles that indicate diminished psychomotor stimulant effects relative to cocaine. In a previous study using a fixed-ratio 10 schedule, two chloro-analogs (3'-Cl-BZT and 4'-Cl-BZT) maintained i.v. self-administration in monkeys but appeared to be weak positive reinforcers. The present experiments were designed to test the hypothesis that 3'-Cl-BZT and 4'-Cl-BZT are relatively weak reinforcers by evaluating reinforcing effects under increased response requirements. To examine further the effect of this halogen substitution on self-administration, 3',4"-diCl-BZT was also evaluated for reinforcing effects. Four rhesus monkeys self-administered cocaine (0.03 mg/kg per injection, i.v.) under a fixed-ratio 25 (FR25) schedule until stable responding was established. Saline, various doses of cocaine (0.003-0.2 mg/kg per injection), the BZT analogs (0.012-0.2 mg/kg per injection), GBR 12909 (0.012-0.2 mg/kg per injection), and compounds with known reinforcing effects (d-amphetamine, morphine, pentobarbital, ketamine) were then made available for self-administration. Various doses (0.01-0.3 mg/kg per injection) of the compounds that maintained self-administration under the FR schedule were then substituted for cocaine (0.1 mg/kg per injection) under progressive-ratio (PR) schedules. Reinforcing effects were evident under the FR schedule for 3'-Cl-BZT, 4'-Cl-BZT, GBR 12909, and the control compounds, but not by 3',4"-diCl-BZT. Results with the PR suggested that the rank order of these compounds for their effectiveness as reinforcers was cocaine > GBR 12909 > 3'-Cl-BZT = 4'-Cl-BZT >> 3',4"-diCl-BZT. This study confirms and extends previous results suggesting that compounds with high DAT affinity can have strong, moderate, weak, or no effectiveness as reinforcers. The mechanisms that may underlie this variation in reinforcing effectiveness of these DAT ligands remain to be established.

Cocaine vaccines: antibody protection against relapse in a rat model.

The efficacy of active immunization with the cocaine immunogen GNC-keyhole limpet hemocyanin (KLH) in preventing cocaine self-administration reinstatement was assessed in rats. An animal model of relapse was used where rats were trained to self-administer cocaine, subjected to a period of extinction by substituting the drug for saline, vaccinated, and re-exposed to cocaine. Compared with controls, animals immunized with GNC-KLH did not reinstate cocaine self-administration behavior when given a noncontingent cocaine infusion on two consecutive days. Upon double and triple infusions, 38-62% of vaccinated animals failed to reinstate as compared with full reinstatement in all control animals. Exposure to ad libitum cocaine reinstated baseline values in control animals and resulted in double to triple the baseline values of self-infusions in vaccinated animals, suggesting a partial antibody-mediated blockade of cocaine access to the central nervous system. This compensating effect was blocked by passive immunization pretreatment with the monoclonal IgG GNC92H2 in both vaccinated and control groups. To further assess the surmountability potential of GNC-KLH-induced antibody titers by cocaine self-administration, and the capacity of these titers to block the reinforcing effects of the drug, rats were tested at various doses of cocaine (0.015-0.5 mg/infusion). Active immunization with GNC-KLH produced approximately an 8-fold rightward shift of the dose-effect function for cocaine. The results reported suggest that immunopharmacotherapy may offer a promising means to treat cocaine abuse by aiding in the prevention of relapse.

Absence of Cocaine-induced Place Conditioning in Serotonin 1B Receptor Knock-out Mice

Absence of cocaine-induced place conditioning in serotonin 1B receptor knock-out mice. PHARMACOL BIOCHEM BEHAV 66(1) 221–225, 2000.—A large body of evidence suggests that genetic factors may affect the reinforcing properties of drugs of abuse. This study investigated the involvement of the serotonin 1B (5-HT1B) receptor in modulating cocaine-induced place conditioning by comparing the response of 5-HT1B receptor gene knock-out mice with wild type 129/Sv-ter mice. The rewarding effects of various doses of cocaine (0, 2.5, 5, 10, 20, and 40 mg/kg) were examined in both strains. Results clearly show that 5-HT1B receptor knock-out mice failed to display a conditioned place preference for stimuli paired with cocaine while wild type mice exhibited a conditioned place preference for the compartment paired with cocaine (5 and 20 mg/kg). As other studies showed that 5-HT1B knock-out mice self-administer cocaine, these results suggest a dissociation between the psychologic state linked to self-administration and the one measured in conditioned place preference.

Role of cerebral spermidine in the development of sensitization to convulsant activity of cocaine and lidocaine

We have previously shown that daily treatment with subconvulsant dose of cocaine resulted in the elevation of brain levels of polyamines such as putrescine and spermidine and the development of increased susceptibility to cocaine-induced seizures. The present study examined whether exogenously administered polyamines affect seizure activity caused by various doses of cocaine and lidocaine in mice. Thirty minutes after intracerebroventricular treatments with either saline, putrescine or spermidine (1–4 μmol), animals were injected intraperitoneally with cocaine or lidocaine (60–90 mg/kg); then the occurrence of clonic seizures was observed. Spermidine enhanced cocaine-induced seizure activity, while putrescine had no effect on it. Lidocaine-induced convulsions were also dose-dependently potentiated by spermidine. In addition, spermidine significantly enhanced seizure activity following an injection of N-methyl-dl-aspartate. The results suggest that spermidine plays an important role in the development of sensitization to convulsant activity by cocaine and lidocaine via modulation of N-methyl-d-aspartate receptors.

Modulation of the Discriminative Stimulus Properties of Cocaine: Comparison of the Effects of Fluoxetine with 5-HT 1A and 5-HT 1B Receptor Agonists

The present investigation examined the ability of serotonin (5-HT) agonists to substitute for, or alter (i.e. enhance or antagonize), the discriminative stimulus properties of a moderately low dose of cocaine (5 mg/kg) utilizing a two-lever, water-reinforced FR 20 drug discrimination procedure in rats. In substitution tests, the 5-HT 1A receptor partial agonists buspirone and gepirone, the 5-HT 1A/B receptor agonist RU 24969 and the 5-HT 1B/2C receptor agonist m-trifluoromethyl-phenylpiperazine (TFMPP) failed to substitute for the cocaine stimulus, although RU 24969 did engender a maximum of 72% cocaine-lever responding. Fluoxetine (4 mg/kg) engendered primarily saline-appropriate responding. In combination tests, a fixed dose of either fluoxetine (4 mg/kg), RU 24969 (0.5 mg/kg) or TFMPP (0.5 mg/kg) produced a leftward shift in the cocaine dose-response curve (0.313–5 mg/kg). In contrast, buspirone (2.5–20 mg/kg) resulted in a dose-dependent attenuation (approximately 60% reduction) of the cocaine stimulus. Moreover, a dose of 10 mg/kg of buspirone co-administered with various doses of cocaine (1.25–10 mg/kg) engendered a rightward shift in the cocaine dose-response curve. Gepirone in combination with cocaine neither enhanced nor antagonized the cocaine discriminative stimulus. Whereas 5-HT agonists do not fully substitute for cocaine, the present results demonstrate that 5-HT 1B, but not 5-HT 1A, receptor agonists can modulate the discriminative stimulus properties of cocaine in a manner similar to that observed following administration of the 5-HT reuptake inhibitor fluoxetine. The ability of buspirone, but not gepirone, to attenuate the cocaine stimulus probably reflects its dopamine (DA) D 2 receptor antagonist properties and not its efficacy at 5-HT 1A receptors. © 1997 Elsevier Science Ltd. All rights reserved.

Dextromethorphan reduces intravenous cocaine self-administration in the rat

Dextromethorphan is a widely used antitussive agent with non-competitive antagonistic effects at the excitatory amino acid receptors of the NMDA type. Since excitatory amino acid neurotransmission has been implicated in cocaine dependence, the aim of the present study was to evaluate the effects of acute systemic administration of dextromethorphan in rats trained to self-administer cocaine intravenously. The experiments were designed to evaluate the effects of dextromethorphan on responding for cocaine and cocaine reward magnitude. The hypothesis was that dextromethorphan could attenuate specific aspects of cocaine-seeking behavior thus providing a preclinical rationale for its clinical use. The results reported reveal that acute pretreatment with dextromethorphan (10–50 mg/kg i.p.) significantly reduced cocaine self-administration in rats self-administering the drug intravenously in a simple continuous reinforcement schedule. In addition, acute pretreatment with an effective dose of dextromethorphan (25 mg/kg) decreased cocaine self-administration in rats tested at various doses of cocaine (0.12–0.5 mg/injection). Finally, dextromethorphan (25 mg/kg) also reduced the absolute reward magnitude of cocaine as measured by responding for cocaine in a progressive ratio schedule. These results encourage further experimental and clinical studies to evaluate the potential use of dextromethorphan during various phases of the natural history of cocaine dependence in humans.

Discriminative stimulus effects of dopaminergic agents in rhesus monkeys

Recent reports have shown that treatment with dopamine reuptake inhibitors can selectively decrease responding maintained by low doses of cocaine in rhesus monkeys. This may occur because response-independent delivery of a reuptake inhibitor and response-dependent cocaine have common effects. One behavioral effect that dopamine reuptake inhibitors and cocaine share is their ability to serve as a discriminative stimulus. To compare discriminative effects of several dopaminergic agents with their ability to attenuate cocaine-maintained responding, three rhesus monkeys were first trained to discriminate intravenous injections of cocaine (0.1 mg/kg) from saline. Following generalization testing with various doses of cocaine (0.001–1.0 mg/kg), the relative potencies of phentermine (0.03–1.0 mg/kg), d-amphetamine (0.01–1.0 mg/kg), GBR 12909 (0.01–1.0 mg/kg), and buspirone (0.03–0.56 mg/kg) to substitute for cocaine were assessed. Each drug except buspirone resulted in predominantly cocaine-appropriate responding at doses that were generally without rate-decreasing effect. The ED 50 for the ability of these drugs to substitute for cocaine exhibited the same rank order as that for their effectiveness in decreasing cocaine-maintained responding. Thus, the current results show that the potencies of dopaminergic drugs to decrease cocaine-maintained responding and substitute for cocaine in a drug discrimination paradigm are related.