Unit Dose Of Cocaine Research Articles

Effect of gonadectomy and gonadal hormone replacement on cocaine self-administration in female and male rats.

Both sex and gonadal steroid hormones may influence the abuse-related behavioral effects of cocaine under some conditions, but there is considerable inconsistency in the literature. In the present study, rats were trained under a fixed ratio (FR) 5 schedule of food presentation and were then allowed to self-administer cocaine (1.0 mg/kg/injection) until behavior stabilized. Subsequently, complete dose-effect functions for cocaine self-administration (0.032-3.2 mg/kg/injection) were determined in female and male rats before and after gonadectomy, and in gonadectomized female and male rats before and during chronic treatment with estradiol or testosterone, respectively. Sex, gonadectomy, and gonadal hormones did not alter the shape or position of dose-effect functions for cocaine self-administration. These results suggest that sex, estrogen, and testosterone levels are not critical determinants of cocaine's reinforcing effects in rats under these conditions. This study differed from earlier studies in that complete dose-effect functions for cocaine were determined. These findings suggest that the behavioral training history, the unit dose of cocaine, and the schedule of reinforcement are important variables in studies of sex and gonadal hormone effects on cocaine self-administration.

Acquisition of lever pressing for cocaine in C57BL/6J mice: effects of prior Pavlovian conditioning

The purpose of this study was to determine (1) if C57BL/6J (C57) mice would lever-press for intravenous cocaine infusions in a limited-access paradigm without previously establishing the instrumental response with natural reinforcers and (2) if prior Pavlovian conditioning of cocaine to the response contingent stimulus complex used in the cocaine self-administration sessions would facilitate acquisition of lever responding for cocaine. After implanting jugular catheters, some mice received Pavlovian conditioning during which 12 passive cocaine infusions (0.1 or 1 mg/kg unit doses) were paired with the tone/light/pump sound stimulus complex used in the self-administration sessions. The remaining mice simply began the cocaine self-administration sessions for 0.1 or 1 mg/kg unit doses of cocaine. Twenty-seven of the 33 mice with patent catheters acquired stable lever responding within an average of 5 to 6 days without previously establishing the instrumental response with natural rewards. Prior Pavlovian pairing of cocaine with the response contingent stimulus complex used in the self-administration sessions did not influence the acquisition of cocaine self-administration at the highest cocaine dose (1 mg/kg). This conditioning procedure using the low cocaine dose (0.1 mg/kg/infusion) reduced the number of mice acquiring cocaine self-administration to 50%, and the number of mice developing stable response patterns was only 25%. The results establish that C57 mice can acquire cocaine self-administration over several unit doses in a limited-access paradigm without previously establishing the instrumental response with natural reinforcers. Furthermore, prior pairing of response contingent cues with cocaine via Pavlovian conditioning did not facilitate the acquisition of cocaine self-administration.

Effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a second-order schedule in rhesus monkeys

Effective treatment of opioid dependence with methadone and of tobacco dependence with nicotine illustrates the potential usefulness of agonist medications for drug abuse treatment. The monoamine-releaser d-amphetamine is one drug under consideration as an agonist pharmacotherapy for cocaine dependence. To assess the concordance between preclinical evaluations and ongoing clinical trials, the present study examined the effects of chronic treatment with saline or d-amphetamine on cocaine- and food-maintained responding in rhesus monkeys. Cocaine injections and food pellets were available under a second-order schedule during alternating daily sessions of cocaine and food availability. d-Amphetamine (0.01–0.1 mg/kg per h i.v. for 7 consecutive days) dose-dependently decreased self-administration of a unit dose of cocaine (0.01 mg/kg per injection) at the peak of the cocaine self-administration dose–effect curve. d-Amphetamine (0.032–0.1 mg/kg per h for 7 days) also decreased self-administration of a broad range of cocaine doses (0.0032–0.1 mg/kg per injection) and produced rightward and downward shifts in the cocaine dose–effect curve. Food-maintained responding was usually decreased less than cocaine self-administration, and few signs of toxicity were noted. To evaluate the effects of a longer treatment regimen, d-amphetamine (0.1 mg/kg per h) was administered for 28 consecutive days. d-Amphetamine nearly eliminated self-administration of cocaine (0.01 mg/kg per injection) throughout this treatment, whereas food-maintained responding returned to baseline levels after approximately 9 days. These preclinical findings are concordant with recent clinical studies and suggest that chronic d-amphetamine may selectively decrease cocaine-taking behavior in rhesus monkeys, possibly by producing a selective decrease in the reinforcing effects of cocaine.

The pharmacokinetic determinants of the frequency and pattern of intravenous cocaine self-administration in rats by pharmacokinetic modeling.

We investigated the pharmacokinetic determinants of the frequency of intravenous cocaine self-administration in 2.5-h sessions. Two groups of rats were implanted with dual catheters that permitted cocaine infusion and blood sampling via the femoral and jugular vein catheters, respectively. Half of the animals in each group self-administered one of the two cocaine unit doses (0.5 and 1 mg/kg/infusion) by pressing a lever under a continuous schedule of reinforcement. To monitor serum cocaine concentrations, the remaining animals received concurrent, response-independent infusions whenever the matched animals self-administered cocaine infusions. Multiple concentration-time data in two successive self-administrations were determined to monitor the extent of fluctuation in concentrations by pharmacokinetic modeling. Behavioral analyses revealed the higher unit dose (1 mg/kg) resulted in less frequent cocaine self-administration, and a longer interinfusion interval, whereas the total doses were similar for the two groups (24.5-27.0 mg/kg/2.5 h). Cocaine decayed biexponentially. Both the values of clearance and terminal elimination rate constant for the self-administration paradigm were significantly greater than those after the bolus cocaine dosing series (0.5 and 1 mg/kg, separated by 3 days). The regularity in cocaine self-administration produced relatively stable serum cocaine concentrations that oscillated between maximum (C(max)) and minimum (C(min)) values regardless of dose size and interinfusion interval. Although the C(max) for the 1-mg/kg unit dose (1.47 microg/ml) was significantly higher than that for the 0.5-mg/kg dose (0.82 microg/ml), the C(min) values between the groups approximated each other (0.28, and 0.34 microg/ml, respectively). Hence, the C(min) is the determinant of the initiation of the next drug-taking behavior.

Influence of buprenorphine, butorphanol and nalbuphine on the initiation of intravenous cocaine self-administration in drug naive mice

The influence of different mixed μ–κ-opioid receptor agonists–antagonists on cocaine reinforcement was studied using the method of initiation of intravenous cocaine self-administration in naive mice. Self-administration of cocaine was readily initiated according to an inverted U-shaped unit dose–response curve. Buprenorphine, butorphanol and nalbuphine tested against the optimal unit dose of cocaine (0.8 μg per infusion), inhibited initiation of cocaine self-administration in a dose-dependent manner. When tested against a scale of cocaine unit doses (0.2 –1.6 μg per infusion) buprenorphine (0.1 mg/kg, s.c.) and nalbuphine (2 mg/kg, s.c.) produced a shift of the optimal cocaine dose from 0.8 to 0.4 μg/inf, while butorphanol (1 mg/kg, s.c.) shifted the optimal unit dose of cocaine to the right along the cocaine unit doses axis. Co-administration of naloxone (0.1 mg/kg, s.c.) significantly reduced the effect of buprenorphine but failed to influence the effect of nalbuphine and butorphanol on cocaine intake. Taken together, these results suggest that nalbuphine is capable of affecting cocaine’s reinforcing properties in the same manner as buprenorphine during the initiation phase of cocaine self-administration behavior, while butorphanol causes the opposite effect. Although the exact opioid profile of action of the mixed opioid receptor agonists–antagonists is as yet not precisely known, the present findings suggest that multiple opioid receptor systems (i.e. μ and κ) play a role in reinforcing properties of cocaine and that a co-operative interaction between μ- and κ-opioid systems may be of importance during initiation of cocaine self-administration.

Response requirements and unit dose modify the effects of GBR 12909 on cocaine-maintained behavior.

Previous studies found that GBR 12909 can decrease cocaine-maintained responding at doses that do not affect food-maintained responding. In this study, the effects of GBR 12909 (0.3-3.0 mg/kg) were further examined by varying the response requirement and unit dose of cocaine. Rhesus monkeys earned food or cocaine under a multiple fixed-ratio (FR) schedule. The FR for food was always 30, but the FR for cocaine was varied from 10-130 and the unit dose was varied from 5.6-56.0 microg/kg per injection. Doses of GBR 12909 were tested in an ascending order, for 5 consecutive sessions each. GBR 12909 selectively decreased cocaine-maintained responding in all monkeys in at least 1 condition. These effects were enhanced with large response requirements and/or small unit doses. The results demonstrate that environmental variables can influence the selectivity of GBR 12909's effects and contribute to a growing debate concerning the evaluation of potential pharmacotherapies for drug abuse.

Effects of phentermine on responding maintained by progressive-ratio schedules of cocaine and food delivery in rhesus monkeys.

Previous reports indicate that intravenous pretreatment with phentermine can decrease cocaine-maintained responding without affecting food-reinforced responding under fixed-ratio schedules. The present experiments were designed to explore the generality of this effect using progressive-ratio schedules of reinforcement and different routes of phentermine administration. Unit doses of cocaine and food-pellet magnitudes were identified that maintained similar breaking points, and the effects of acute exposure to phentermine were assessed. In Experiment 1, a 'conventional' (one-trial) progressive-ratio schedule was used, in which response requirements increased after each reinforcer delivery; in Experiment 2, a 'modified' (five-trial) progressive-ratio schedule was used, in which response requirements increased after every five reinforcer deliveries. In one group of monkeys, responding was maintained by food; in another, cocaine infusions maintained responding. Phentermine (0.1-5.6mg/kg, intramuscularly (i.m.)) dose-dependently decreased breakpoints on both progressive-ratio schedules. There were no differences in phentermine's effects on cocaine- and food-maintained behavior. In Experiment 3, intravenous administration of phentermine had largely similar effects. Taken together with results from previous reports, these data suggest that the effects of phentermine pretreatment are influenced by the behavioral procedure used to maintain responding and/or by the efficacy of the food and cocaine reinforcers.

Site-specific NMDA receptor antagonists produce differential effects on cocaine self-administration in rats

The effects of site-specific NMDA receptor antagonists on intravenous cocaine self-administration were examined in rats trained to self-administer cocaine (0.25 mg/infusion) on a fixed ratio (FR) 5 schedule with a 20-s time-out (TO) after each reinforcer. The non-competitive NMDA receptor antagonists, dizocilpine (MK-801, (+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]cyclohepten-5,10-imine hydrogen maleate) (0.05–0.2 mg/kg i.p.) and memantine (1,3-dimethyl-5-amino-adamantane hydrochloride) (2.5–20 mg/kg i.p.), dose-dependently decreased cocaine self-administration, while the competitive NMDA receptor antagonist, CGP 39551 ( dl-( E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid carboxyethylester) (2.5–15 mg/kg i.p.), and the NMDA/glycine receptor antagonist, L-701,324 (7-chloro-4-hydroxy-3(3-phenoxy)-phenyl-2( H)quinolone) (1.25–10 mg/kg p.o.), were without effect. Under a progressive ratio (PR) schedule, dizocilpine (0.15 mg/kg i.p.) increased the number of cocaine infusions in a manner similar to increasing the unit dose of cocaine, suggestive of potentiation of cocaine reward. Conversely, memantine (10 mg/kg i.p.) produced rate-decreasing effects on the PR schedule. These results demonstrate that NMDA receptor antagonists acting at different modulatory sites of the NMDA receptor do not share dizocilpine's cocaine reward enhancing effects although they are all known to be effective blockers of NMDA receptor activity.

Serotonin1BReceptor Stimulation Enhances Cocaine Reinforcement

The effects of serotonin1B [5-hydroxytryptamine1B (5-HT1B)] receptor activation on cocaine reinforcement were investigated using intravenous cocaine self-administration by rats. The 5-HT1B receptor agonists 5-methoxy-3-1,2,3,6-tetrahydro-4-pyridinyl-1H-indole (RU 24969) (0.3-3 mg/kg), 3-(1,2,5, 6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94,253) (0.3-3 mg/kg), and 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3, 2-b]pyridine (CP 93,129) (3 and 10 micrograms, i.c.v.) each dose-dependently reduced the self-administration of a cocaine dose on the descending limb of the fixed-ratio 5 (FR-5) cocaine dose-effect function, in a manner similar to the effect produced by increasing the unit dose of cocaine. In addition, each of these 5-HT1B agonists lowered the threshold dose of cocaine that supported self-administration. These results are consistent with a 5-HT1B agonist-induced potentiation of cocaine reinforcement. On a progressive ratio schedule of reinforcement, RU 24969 and CP 94,253 dose-dependently (0.3-3 mg/kg) increased the highest completed ratio for cocaine self-administration, again by producing behavioral alterations similar to those induced by increasing the unit dose of cocaine. The effect of CP 94,253 was dose-dependently blocked by the 5-HT1B/1D receptor partial agonist 2'-methyl-4'-(5-methyl[1,2, 4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid[4-methodoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127, 935) (0.3-10 mg/kg) but was unaffected by the 5-HT1A receptor antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl- benzamide (p-MPPI; 1-10 mg/kg). Self-administration behavior was not maintained when either RU 24969 or CP 94,253 was substituted for cocaine, indicating that these 5-HT1B agonists do not produce significant reinforcing effects alone. Together, these findings indicate that 5-HT1B receptor stimulation facilitates the reinforcing properties of cocaine. These results are in opposition to recent findings with 5-HT1B receptor knock-out mice and may have important ontogenic implications in the area of drug abuse research.

Acquisition of i.v. amphetamine and cocaine self-administration in rats as a function of dose.

The effect of dose on the acquisition of i.v. amphetamine and cocaine self-administration was examined. Three unit doses of amphetamine (0.03, 0.06 and 0.12 mg/kg) and three unit doses of cocaine (0.05, 0.2 and 0.8 mg/kg) were tested in separate groups of ten (amphetamine) or 13 (cocaine) rats. Autoshaping methods were used to train rats to press a lever that resulted in drug infusion under a fixed-ratio (FR) 1 schedule. A daily 6-h autoshaping component non-contingently delivered 60 infusions according to a 60-s random time schedule with ten infusions delivered during the first half of each h. Each day autoshaping sessions were followed by a 6-h self-administration session. The criterion for acquisition was a 5-day period during which a daily mean of 100, 50 or 25 infusions for the three amphetamine doses and 400, 100 or 25 infusions were earned during the 6-h self-administration period for the three cocaine doses, respectively. As dose increased, more rats per group acquired drug self-administration and the mean number of days to meet the acquisition criterion decreased. The percentage of rats acquiring amphetamine self-administration increased with dose and ranged from 80 to 100%. Only one rat at the lowest cocaine dose met the acquisition criterion, but 100 percent of the rats at the two higher doses acquired. During the last 2 days of acquisition, mean infusions decreased and mean drug intake (mg/kg) increased as dose increased. On the last day of acquisition, the time course of infusions during the 6-h self-administration component was characterized by a steady rate of infusions per hour, and number of infusions was inversely related to dose. These findings indicate that the initial available dose of a drug is an important determinant of the rate and probability that successful acquisition will occur.

A neuroendocrine role in cocaine reinforcement.

Cocaine stimulates the secretion of corticosterone and ACTH, probably through a CRF-related mechanism, indicating that the drug activates the HPA axis. Indeed, cocaine has been reported to produce anxiety and to precipitate episodes of panic attack during chronic use and withdrawal in humans and to induce anxiogenic behavior in animals. Cocaine also alters benzodiazepine receptor binding in discrete regions of the rat brain. Some of these changes in binding are obviously related to the convulsions and seizures which are often observed in an acute cocaine overdose. However, data from behavioral studies have suggested that some of these effects may be related directly to cocaine reinforcement since receptor changes also were observed when binding in the brains of rats that self-administered cocaine was compared with that from animals that had received identical yoked, but non-contingent infusions of the drug. In this regard, pretreatment with the benzodiazepine receptor agonists chlordiazepoxide and alprazolam decreased cocaine self-administration without decreasing food-reinforced responding, suggesting that these effects were specific for cocaine. Since this attenuation of self-administration was reversed by increasing the unit dose of cocaine, it is likely that these drugs were decreasing cocaine reinforcement. In contrast, exposure to stress increases vulnerability to self-administer psychostimulants. In these experiments, low-dose cocaine self-administration was related directly to stress-induced increases in plasma corticosterone, such that plasma corticosterone was always greater than 150 ng/ml for rats which subsequently self-administered cocaine at doses of 0.125 mg/kg/infusion or lower, suggesting a threshold for the hormone in cocaine reinforcement. In other experiments, bilateral adrenalectomy completely abolished the acquisition of intravenous cocaine self-administration in naive rats, while metyrapone decreased ongoing self-administration. In addition, ketoconazole pretreatment resulted in patterns of self-administration that were virtually indistinguishable from that observed during saline extinction, suggesting that plasma corticosterone is not only important, but may even be necessary for cocaine reinforcement. The mechanisms through which adrenocorticosteroids alter cocaine reinforcement remain to be determined, but there is increasing evidence that the mesocorticolimbic dopaminergic system is involved. In particular, the medial prefrontal cortex appears to be at least one brain region where dopamine and adrenocorticosteroids may interact to affect cocaine reinforcement.

Effects of dopaminergic drugs on food- and cocaine-maintained responding. IV: continuous cocaine infusions

The effects of cocaine (continuously infused during the session with and without a pre-loading dose) on responding maintained under multiple fixed-ratio 30 schedules of limited access to food and cocaine delivery (10 or 56 μg/kg per injection) were studied in nine rhesus monkeys. When responding was maintained by 10 μg/kg per injection, cocaine decreased rates of cocaine-maintained responding in a dose-related manner while having no effect on food-maintained responding. When responding was maintained by 56 μg/kg per injection, cocaine decreased both cocaine- and food-maintained responding. These results show that the effects of continuous infusions of cocaine depend upon both the unit dose of cocaine and the event that maintains responding. As such, the effects of continuous infusions of cocaine are similar to those of other, longer-acting dopamine agonists. Such results support the development of long-acting agonist approaches to the pharmacotherapeutic treatment of cocaine abuse.

Effect of 6-hydroxydopamine lesions of the medial prefrontal cortex on intravenous cocaine self-administration under a progressive ratio schedule of reinforcement

Rats were trained to self-administer intravenous cocaine under a progressive ratio (PR) schedule of reinforcement. Under this schedule, an increasing number of lever responses had to be made to obtain each subsequent reinforcement (1.5 mg/kg per injection). Once stable responding was achieved with this schedule, bilateral 6-hydroxydopamine (6-OHDA) or vehicle-only injections were delivered into the medial prefrontal cortex (mPFC). Following recovery from surgery, the animals were given access to cocaine under the PR schedule. The effect of the lesion on self-administration behaviour was examined at various doses of cocaine (0.09–1.5 mg/kg per injection). 6-OHDA lesions of the mPFC had no effect on self-administration behaviour at the higher unit doses of cocaine. However, at the lower doses (0.09 and 0.19 mg/kg per injection), the lesion caused a significant increase in break point (BP), the number of responses made to obtain the last reinforcement of a self-administration session. The neurochemical results showed a significant reduction (57%) in mPFC levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) (53%), with no changes in noradrenaline or serotonin levels. In contrast, the lesion caused no changes in DA or DOPAC levels in the nucleus accumbens (NACC) or striatum. These results indicate that the DAergic innervation of the mPFC cortex has a role in cocaine self-administration behaviour; however, whether this role is contingent on NACC DA function remains to be elucidated.

Diurnal patterns of cocaine and heroin self-administration in rhesus monkeys responding under a schedule of multiple daily sessions

A number of non-pharmacological factors have been shown to influence drug self-administration in experimental animals. This report examines diurnal changes in drug self-administration by rhesus monkeys trained to self-administer food (1gm fruit-flavored pellets) and cocaine (0.01 or 0.032mg/kg/injection) under a second order FR4 (VR16:S) schedule during four daily food and drug self-administration sessions. Saline, different unit doses of cocaine (0.001-0.1mg/kg/injection) or different unit doses of heroin (0.0001-0.01mg/kg/injection) were substituted for the maintenance dose of cocaine during drug sessions. Dose-effect curves relating unit dose of cocaine or heroin to the number of injections per session displayed an inverted U-shape during each of the four daily drug sessions. When 0.032mg/kg/injection cocaine or 0.0032mg/kg/injection heroin were available, monkeys usually self-administered the maximum number of injections during all four drug sessions. Substitution of saline or lower unit doses of cocaine (0.001-0.01mg/kg/injection) or heroin (0.0001-0.001mg/kg/injection) decreased the number of injections/session; however, these decreases were consistently greater during the evening (20.00-21.00h) and morning (07.00-08.00h) sessions than during the afternoon sessions (12.00-13.00h and 16.00-17.00h). As a result, the ascending limbs of the cocaine and heroin dose-effect curves for the evening and morning sessions were shifted to the right of the ascending limbs of the dose-effect curves for the afternoon sessions. Moreover, when saline was substituted for cocaine for only two sessions per day, drug self-administration decreased more during the evening and morning sessions even when the cocaine was available during those sessions. These findings suggest a diurnal variation in cocaine and heroin self-administration. Specifically, drug self-administration during the evening and morning sessions appears to be more sensitive to a decrease in reinforcer magnitude than responding during the afternoon sessions. These findings confirm and extend previous reports of the influence of non-pharmacological factors on drug self-administration.

Buprenorphine-induced alterations of cocaine's reinforcing effects in rhesus monkey: a dose-response analysis

Buprenorphine reduces cocaine self-administration by rhesus monkeys, opiate- and cocaine-dependent men and polydrug abusers, but the mechanisms underlying these cocaine-opiate interactions are not well understood. In the present study, the effects of daily placebo or buprenorphine (0.1,0.3 and 1.0 mg/kg) treatment on cocaine self-administration (0.001–0.3 mg/kg/inject) were examined in five cocaine-experienced rhesus monkeys. Saline and each of six cocaine doses were available in an irregular order. Responding for cocaine (or saline) and food was maintained on a second order FR4 (VR 16:5) schedule of reinforcement. During placebo treatment, the daily number of cocaine injections increased as the unit dose was increased and then decreased at higher doses. Cocaine doses that maintained the highest rates of responding during placebo treatment were more resistant to buprenorphine's effects. The typical increase in response rate during the first five cocaine injections of a session also was attenuated by buprenorphine. The ascending limb of the cocaine dose-response curve was shifted downward and approximately one log unit to the right during low-dose buprenorphine treatment (0.1 mg/kg/day). In contrast, individual response rates for food pellets were unaffected. We conclude that buprenorphine selectively decreases self-administration of some unit doses of cocaine at doses that have minimal effects on food-maintained responding.

Pretreatment with the dopamine agonist 7-OH-DPAT shifts the cocaine self-administration dose-effect function to the left under different schedules in the rat

This study tested the hypothesis that administration of the dopamine agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) shifts the cocaine self-administration dose-effect function to the left, rather than producing nonspecific effects or exclusively enhancing the rate-decreasing effects of high doses of cocaine. Under fixed-ratio or progressive-ratio schedules, rats were allowed to intravenously self-administer cocaine, 7-OH-DPAT, or a combination of cocaine and 7-OH-DPAT. In additional tests under fixed-ratio schedules, cocaine self-administration followed subcutaneous pretreatment with 7-OH-DPAT. Cocaine dose-effect functions were obtained by varying the unit dose of cocaine either between test sessions or within a single session. Intravenous 7-OH-DPAT (1-4µg) decreased self-administration of the training dose of cocaine (0.25mg) under a fixed-ratio schedule, but failed to shift the entire cocaine self-administration dose-effect function to the left under fixed-ratio or progressive-ratio schedules. 7-OH-DPAT alone maintained i.v. self-administration under these schedules, but produced a shallow self-administration dose-effect function, relative to cocaine, under the progressive-ratio schedule. In contrast to intravenous 7-OH-DPAT, s.c. pretreatment with 7-OH-DPAT (0.1-0.4mg/kg) not only decreased self-administration of the training dose of cocaine but also lowered the minimum effective dose of cocaine under fixed-ratio schedules, producing a shift to the left of the cocaine self-administration dose-effect function; these effects were independent of whether the dose of cocaine was varied between sessions or within a single session. Likewise under a multiple schedule, in which responding was maintained by cocaine and food in alternate components, s.c. pretreatment with 7-OH-DPAT increased self-administration of the dose of cocaine on the ascending limb of the dose-effect function and decreased self-administration of doses of cocaine on the descending limb, while uniformly decreasing responding for food. These observations suggest that pretreatment with 7-OH-DPAT enhances the reinforcing properties of cocaine rather than producing nonspecific effects or enhancing exclusively the rate-decreasing effects of high doses of self-administered cocaine.

Effects of dopamine reuptake inhibitors on food- and cocaine-maintained responding: I. Dependence on unit dose of cocaine.

Effects of dopamine reuptake inhibitors on food- and cocaine-maintained responding: I. Dependence on unit dose of cocaine.

Effects of dopamine reuptake inhibitors on food- and cocaine-maintained responding: I. Dependence on unit dose of cocaine.

Effects of dopamine reuptake inhibitors on food- and cocaine-maintained responding: I. Dependence on unit dose of cocaine.

Chronic pretreatment with naltrexone facilitates acquisition of intravenous cocaine self-administration in rats

Opioid systems may be involved in the reinforcing effects of drugs of abuse. It has been shown that the opioid antagonist naltrexone attenuates acquisition of intravenous cocaine self-administration behaviour in rats. Using a similar experimental set-up the effect of chronic blockade of opioid systems prior to cocaine exposure was examined. Rats were tested for acquisition of self-administration of one of 3 graded unit doses of cocaine (0.08, 0.16 and 0.32 mg·kg −1 per infusion) or saline. Chronic pretreatment with naltrexone (10 mg·kg −1 per day for 12 days) enhanced acquisition of intravenous cocaine self-administration but only in rats tested with the medium cocaine unit dose. It is concluded that chronic blockade of opioid systems facilitates acquisition of cocaine self-administration, probably by enhancing the reinforcing effect of cocaine.

Intravenous cocaine self-administration in rats is reduced by dietaryl-tryptophan

Rats were trained to self-administer intravenously-delivered cocaine. Four lever-press responses resulted in a cocaine infusion (0.2 mg/kg) during daily 24-h sessions. The rats were also trained to obtain water from tongue-operated solenoid-driven drinking spouts. Ground food and water from a standard drinking bottle were also available. When cocaine injections reached stable levels, L-tryptophan was mixed with the rats' food for 5 days. Three concentrations of L-tryptophan (2, 4, and 8%) were tested in different groups of five rats each. Three other groups of five rats each received the same L-tryptophan treatments; however, in these rats saline was substituted for cocaine and a sweet drinking solution consisting of glucose and saccharin (G + S) replaced water in the automatic drinking device. Two other groups consisting of five rats each self-administered a higher (0.4 mg/kg) or lower (0.1 mg/kg) unit dose of cocaine and food adulterated with 4% tryptophan. At the two higher concentrations L-tryptophan reduced cocaine infusions by at least 50% during the 5 days of treatment, and cocaine infusions returned to baseline levels within 48 h after the regular diet was restored. Responding reinforced by the G + S solution was not altered by any of the L-tryptophan concentrations. Food intake was substantially lowered by the 8% L-tryptophan concentration; however, water intake, responding on an inactive lever, and the number of saline infusions were not affected by addition of L-tryptophan to the food. L-Tryptophan had the same magnitude of effect on self-administration of the 0.1 and 0.2 mg/kg unit doses of cocaine, but behavior maintained by the highest cocaine dose (0.4 mg/kg) was resistant to the effect of L-tryptophan. The results of this experiment indicate that L-tryptophan reduces behavior reinforced by IV cocaine infusions.