Effects of SCH 23390 and eticlopride on cocaine-seeking produced by cocaine and WIN 35,428 in rats

Rationale. Exposure to a small amount of cocaine can trigger relapse, and so an understanding of the mechanisms underlying cocaine-seeking are important for the development of effective anti-relapse treatments. Objectives. The present study sought to compare the contributions of dopamine D₁- and D₂-like receptors in drug-seeking produced by cocaine and WIN 35,428. Methods. Reinstatement of extinguished cocaine self-administration was measured for rats that received injections of cocaine (5.0–20.0 mg/kg) or WIN 35,428 (0.1–1.0 mg/kg) following extinction. Prior to the injection of cocaine or WIN 35,428, rats received an injection of the D₁-like antagonist, SCH 23390 (0.001–0.010 mg/kg) or the D₂-like antagonist, eticlopride (0.01–0.30 mg/kg). Effects of SCH 23390 (0.01 mg/kg) on cocaine-produced locomotor activation were also measured in separate groups of rats. Results. The ability of both cocaine and WIN 35,428 to produce cocaine-seeking was dose-dependent. Within the range of doses tested, SCH 23390 failed significantly to attenuate the ability of either cocaine or WIN 35,428 to reinstate extinguished cocaine self-administration, although cocaine-produced locomotor activation was significantly attenuated by pretreatment with the highest dose of SCH 23390. Eticlopride attenuated both cocaine and WIN 35,428 produced cocaine-seeking but lower doses were required to decrease WIN 35,428-produced cocaine-seeking. Conclusions. These results suggest that dopamine D₂ mechanisms are involved in cocaine-seeking produced by both cocaine and WIN 35,428. The lower potency of eticlopride in attenuating cocaine-produced cocaine-seeking suggest that cocaine's effects at sites other than the dopamine transporter contribute to its ability to elicit drug-seeking.     

Oral self-administration of ethanol and cocaine in rats

Most laboratory animal studies on self-administration of drugs of abuse use only one drug, whereas humans frequently engage in polydrug use. For this reason, we studied oral self-administration of ethanol (E) and cocaine (C) with the free choice bottle method using a single drug alone, a combination (E and C in separate bottles) or a mixture of both drugs in a single bottle. Young female rats (45 days) consumed similar amounts of C if offered alone (12.4 +/- 7.5 mg/kg/day), in the presence of ethanol (10.6 +/- 3.5) or as E/C mixture (8.0 +/- 4.0). They also consumed similar amounts of E if offered alone (3.8 +/- 1.6 ml/kg/day), in the presence of C (2.3 +/- 0.8) or E/C mixture (2.4 +/- 1.1). Voluntary consumption of both drugs varied markedly among animals but was consistent in a given rat. No correlation occurred between consumption of E and C. Young male rats behaved similarly and consumed similar amounts of E and C alone, in combination and as mixture. While E consumption was similar, C consumption was higher in female rats. Old male rats (180 days) were similar to young male rats. The presence of a saccharin solution as a distracter had no effect on intake of E or C in young females but reduced E intake only in young male rats. In young animals, prior voluntary consumption of either E or C had no effect on subsequent voluntary consumption of the same or other drug offered in combination. These results indicate that this model may be useful to study polydrug use in humans, that consumption of both E and C is strongly controlled by an individual animal, that prior exposure to one drug had no or little effect on a subsequent consumption of the same or other drug in combination and that intake of E or C seems to be independent of each other suggesting two independent reward centers.     

Reinstatement of cocaine self-administration in rats: sex differences

Rationale: Results obtained with both humans and animals suggest that rates of relapse, or levels of reinstatement responding, may differ between males and females. However, the results obtained with humans are equivocal, and few studies have compared male and female animals on reinstatement responding. Objectives: The present experiment was designed to compare male (n=8) and female (n=8) rats on reinstatement of extinguished cocaine-reinforced responding. Methods: Reinstatement of responding was examined using a priming model in which lever pressing for cocaine (0.2 mg/kg) was extinguished by replacing cocaine infusions (2 h) with saline infusions (5 h). After responding extinguished during hour 3, reinstatement of responding was tested by administering one of several priming injections of cocaine (0.32, 1.0 and 3.2 mg/kg) or an equal volume of saline. Results: Although males and females did not differ in the number of saline infusions self-administered after either saline or 0.32 mg/kg cocaine-priming injections, female rats self-administered significantly more saline infusions than males after 1.0 mg/kg and 3.2 mg/kg cocaine-priming injections. Additionally, the effects of 0.32 mg/kg cocaine-priming injections were significantly different from those of saline-priming injections for female, but not male, rats. There was no significant difference between males and females in total cocaine self-administered during hours 1 and 2. Conclusions: These findings indicate that female rats are more sensitive than males during the reinstatement phaseof drug abuse. Received: 14 June 1999 / Final version: 13 August 1999     

Chlordiazepoxide alters intravenous cocaine self-administration in rats

This investigation was designed to examine the effects of benzodiazepines on intravenous cocaine self-administration in rats. Pretreatment with low doses of the benzodiazepine receptor agonist, chlordiazepoxide (0.3 to 1.0 mg/kg, IP), resulted in small but nonsignificant increases in drug intake with 0.5 mg/kg cocaine, while higher doses (10 mg/kg, IP) significantly decreased drug intake in all rats tested. The effects of chlordiazepoxide on self-administration were attenuated when the concentration of cocaine was increased to 1.0 mg/kg, suggesting that chlordiazepoxide was opposing rather than augmenting the pharmacological actions of cocaine. Pretreatment with the benzodiazepine receptor antagonist, Ro 15-1788 (1.0 to 10 mg/kg, IP), had no effect on self-administration, suggesting that the reinforcing properties of cocaine do not result from direct interactions with benzodiazepine receptors. The result of this investigation demonstrate that chlordiazepoxide alters intravenous cocaine self-administration in rats. Although additional research will be necessary to confirm these data, the results of this investigation suggest that chlordiazepoxide may decrease the reinforcing efficacy of cocaine through indirect actions on dopaminergic neuronal activity potentially mediated through GABAergic mechanisms via benzodiazepine receptor activation.     

Levo-tetrahydropalmatine attenuates cocaine self-administration and cocaine-induced reinstatement in rats

Rationale Levo-tetrahydropalmatine (l-THP) is an alkaloid constituent of plants from the botanical genera Corydalis and Stephania and is contained in many traditional Chinese herbal preparations. In addition to its low-affinity antagonism of D2 dopamine (DA) receptors, we report that l-THP functions as a higher-affinity antagonist at D1 DA receptors and interacts with D3 DA receptors, suggesting that it may be effective for the treatment of drug addiction. Accordingly, l-THP has been reported to reduce heroin craving and relapse in recovering addicts. Objective This study investigated the effects of l-THP (3.75, 7.5, and 15.0 mg/kg, i.p.) on cocaine self-administration (SA) and cocaine-induced reinstatement. Materials and methods Rats were trained to self-administer cocaine and food by pressing separate response levers during sessions consisting of a multiple schedule of alternating 30-min FR4 cocaine and 15-min FR4 food reinforcement. During the cocaine components of each session, the available cocaine dose varied such that rats had access to low and high dose ranges in varying sequence on alternating days. After SA, cocaine-reinforced responding was extinguished, and effects of l-THP on cocaine-induced reinstatement (10 mg/kg, i.p.) were examined. Results l-THP produced a rightward and downward shift in the dose–response curve for cocaine SA and attenuated cocaine-induced reinstatement. l-THP also reduced food-reinforced responding and locomotor activity. However, reductions in cocaine SA were found at doses that failed to alter food-reinforced responding, and significant effects were not observed on food responding during reinstatement. Conclusions These findings suggest that l-THP is potentially useful for treating cocaine addiction. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Wheel-running attenuates intravenous cocaine self-administration in rats: sex differences

This experiment examines the effect of access to a running-wheel on intravenous cocaine self-administration in male and female rats. Rats maintained at 85% of their free-feeding body weight were first exposed to the running-wheel alone during the 6-h sessions until behavior stabilized for 14 days. Intravenous cannulae were then implanted, and the rats were trained to self-administer a low dose of cocaine (0.2 mg/kg) under a fixed-ratio (FR 1) schedule during the 6-h sessions, while the wheel remained inactive and cocaine self-administration stabilized (cocaine-only condition). Next, the wheel access and cocaine self-administration were concurrently available followed by a period of cocaine-only. Behavior was allowed to stabilize for 10 days at each phase. During wheel access, cocaine infusions decreased by 21.9% in males and 70.6% in females compared to the cocaine-only condition; the effect was statistically significant in females. Infusions increased to baseline levels when wheel access was terminated. When cocaine infusions were concurrently available, wheel revolutions were reduced by 63.7% and 61.5% in males and females, respectively, compared to the wheel-only condition. This result did not differ due to sex, but it was statistically significant when data from males and females were combined. These results indicate that wheel-running activity had a greater suppressant effect on cocaine self-administration in females than in males, and in females, wheel-running and cocaine self-administration are substitutable as reinforcers.     

Nicotine reinforcement in rats with histories of cocaine self-administration

Few reports have described conditions under which nicotine self-administration occurs in rats. In this study, rats which initially lever pressed for cocaine infusion (0.05 mg/kg) during 1 h experimental sessions continued to obtain similar infusion numbers when nicotine (0.03 mg/kg) was available. When saline was substituted for nicotine, infusions decreased from 11.8±4.5/h to 5.4±1.1/h but returned to pre-saline levels when it was reintroduced (12.0±5.5/h). These results indicate that nicotine can serve as a positive reinforcer for rats under the historical and schedule conditions described.     

Ketoconazole reduces low dose cocaine self-administration in rats

Ketoconazole is an oral antimycotic agent approved by the FDA for the treatment of fungal disease which also blocks the synthesis of adrenocorticosteroids and functions as a glucocorticoid receptor antagonist. In these experiments, adult male Wistar rats were allowed alternating 15-min periods of access to food reinforcement and cocaine self-administration (0.125, 0.25 or 0.5 mg/kg per infusion) during daily 2-h sessions. A 1-min timeout separated access to the two reinforcers. Pretreatment with ketoconazole (25 mg/kg, i.p.) significantly decreased plasma corticosterone and reduced low dose (i.e. 0.125-0.25 mg/kg per infusion) cocaine self-administration without affecting food-reinforced responding. In fact, pretreatment with ketoconazole resulted in rates and patterns of self-administration at these doses that were indistinguishable from those observed during cocaine extinction. However, cocaine self-administration at the highest dose tested in these experiments (i.e. 0.5 mg/kg per infusion) was not significantly affected by ketoconazole. These data suggest the potential utility of ketoconazole or related drugs as adjuncts in the treatment of cocaine abuse and further underscore the role for corticosterone in cocaine reinforcement.     

Voluntary self-administration of both morphine and cocaine by rats

Voluntary self-administration of cocaine and/or morphine was studied in rats. Male rats were offered water bottles or bottles containing either cocaine or morphine, both cocaine and morphine (combination) or cocaine and morphine as a mixture. Alternating the three drug-containing bottles had no effect on drug choice. When offered alone, rats consumed about 12 +/- 8 mg/kg/day of cocaine or 0.3 +/- 0.3 mg/kg/day of morphine. When both drugs were offered in combination, they consumed a higher amount of cocaine (22 +/- 7), but the same amount of morphine (0.4 +/- 0.3). Availability of cocaine/morphine mixture kept morphine consumption constant (0.3 +/- 0.1), but markedly decreased cocaine intake (0.3 +/- 0.2). Addition of saccharin to the drug solutions only slightly increased consumption of both drugs, whereas saccharin added as a competitor or distracter to the drug solution reduced cocaine but not morphine self-administration. Animals showed wide interindividual variations but surprisingly small intraindividual variations in self-administration of cocaine or morphine under all conditions. No correlation between cocaine and morphine intake was apparent in the combination situation. Forcing animals first with cocaine had no effect on subsequent intake of cocaine or morphine presented in combination. However, forcing animals first with morphine subsequently increased morphine and reduced cocaine intake. In conclusion, morphine intake was the same if offered alone, in combination or as a mixture, whereas cocaine intake increased during a combination but decreased in the mixture situation. Cocaine pre-exposure had no effect on subsequent voluntary morphine or cocaine choice, whereas morphine pre-exposure increased subsequent voluntary morphine but decreased cocaine intake. These results suggest the possibility of two reward centers, one for each drug, the morphine center exerting a dominant influence over the cocaine center.     

Binge cocaine self-administration in humans: intravenous cocaine

Cocaine is frequently used in intermittent cycles of repeated dosing, or “binges.” This pattern of cocaine use has been difficult to study in humans because currently available laboratory models use only one daily session during which a single dose or multiple doses are administered. In the present study, seven adult male IV cocaine users completed a protocol investigating changes in cardiovascular and subjective responses during the repeated self-administration of cocaine. Volunteers participated in a 2-day and a 3-day access condition. On each day of access, they participated in two 2.5-h sessions, one at 1200 and another at 1600 hours. In the 2- and 3-day conditions, participants had access to cocaine on 2 or 3 consecutive days, respectively. During sessions, participants could self-administer up to six doses of IV cocaine (32 mg/70 kg) every 14 min. Participants chose not to self-administer cocaine on only 10% of the 420 trials. Acute tolerance developed to the cardiovascular and several subjective effects of cocaine. Heart rate was the only measure that tended to decrease across days of repeated cocaine self-administration. Ratings of “I want cocaine” decreased at the end of the last self-administration session during both 2- and 3-day conditions. There was no difference between the 2- and 3-day conditions for any measure. The laboratory model of “binge” cocaine use established in this study can be used to describe changes in cardiovascular and subjective effects of cocaine within and between bouts of repeated cocaine use. Received: 14 November 1996/Final version: 8 March 1997     

Levo-tetrahydropalmatine attenuates cocaine self-administration under a progressive-ratio schedule and cocaine discrimination in rats

Levo-tetrahydropalmatine (l-THP) is an alkaloid found in many traditional Chinese herbal preparations and has a unique pharmacological profile that includes dopamine receptor antagonism. Previously we demonstrated that l-THP attenuates fixed-ratio (FR) cocaine self-administration (SA) and cocaine-induced reinstatement in rats at doses that do not alter food-reinforced responding. This study examined the effects of l-THP on cocaine and food SA under progressive-ratio (PR) schedules of reinforcement and the discriminative stimulus effects of cocaine. In adult male Sprague-Dawley rats self-administering cocaine (0.5 or 1.0 mg/kg/inf), l-THP significantly reduced breaking points at the 1.875, 3.75 and 7.5 mg/kg doses. l-THP also reduced the breaking point and response rate for PR SA of sucrose-sweetened food pellets, although the decrease was significant only at the 7.5 mg/kg l-THP dose. In rats trained to discriminate cocaine (10 mg/kg, ip) from saline, l-THP (1.875, 3.75 and 7.5 mg/kg) produced a rightward shift in the dose-response curve for cocaine generalization. During generalization testing, l-THP reduced response rate, but only at the 7.5 mg/kg dose. l-THP also prevented substitution of the dopamine D2/D3 receptor agonist, (±) 7-OH-DPAT, for cocaine suggesting a potential role for antagonism of D2 and/or D3 receptors in the effects of l-THP. These data further demonstrate that l-THP attenuates the reinforcing and subjective effects of cocaine at doses that do not produce marked motor effects and provide additional evidence that l-THP may have utility for the management of cocaine addiction.     

Impulsivity predicts the escalation of cocaine self-administration in rats

Impulsivity, as measured by the delay-discounting task, predicts the acquisition of cocaine self-administration and reinstatement of cocaine seeking in rats. The purpose of this study was to extend these results to the escalation phase of drug self-administration. Female rats were initially screened for high (HiI) or low (LoI) impulsivity for food reinforcement using a delay-discounting procedure. They were then implanted with i.v. catheters and trained to lever press for cocaine infusions (0.8 mg/kg). Once cocaine intake stabilized, rats were allowed to self-administer cocaine (0.4 mg/kg) under a fixed-ratio 1 (FR 1) schedule during three, 2 h short-access sessions. Subsequently, performance was briefly assessed under a progressive ratio (PR) schedule for 3 doses of cocaine (0.2, 0.8, and 3.2 mg/kg). Following PR testing, the cocaine dose was then changed to 0.4 mg/kg. Session length was then extended to 6 h for 21 days (extended access), and 0.4 mg/kg cocaine was available under a FR 1 schedule. After the 21-day extended access phase, responses and infusions under the short access FR and PR dose-response conditions were reassessed. The results indicated that HiI rats escalated cocaine-reinforced responding during the extended access condition, but LoI rats did not. HiI rats also earned significantly more infusions than LoI rats under the post-escalation short access FR condition. However, HiI and LoI rats did not differ under the pre- and post-extended access PR conditions. This study suggests that individual differences in impulsivity predict escalation of cocaine self-administration in female rats, which may have implications in the prediction of binge-like patterns of cocaine intake in women.     

Effects of serotonergic manipulations on cocaine self-administration in rats

Rats were trained to self-administer cocaine (0.5 mg/kg/infusion) and were then pretreated with the 5-HT_1A agonist 8-OH-DPAT (0.125, 0.25 or 0.5 mg/kg, SC). 8-OH-DPAT pretreatment produced a decrease in reinforced response rates. When the effect of 8-OH-DPAT (0.5 mg/kg, SC) on responding for a range of cocaine doses was assessed, the drug produced a decrease in response rates when lower doses of cocaine served as the reinforcer. Fluoxetine (10 mg/kg, IV), an indirect 5-HT agonist, also reduced reinforced response rates for a low dose infusion of cocaine. Rates of responding for infusions of higher cocaine doses were not affected by fluoxetine pretreatment during an FR1 schedule of reinforcement. When an FR10 schedule of reinforcement was imposed, reinforced response rates for infusions of higher doses of cocaine were also reduced. Thus, under conditions that produce high rates of responding (low dose infusion or high ratio requirements for an infusion) fluoxetine reduced responding. This effect may be due to the effects at the 5-HT_1A receptor, since 8-OH-DPAT produced a similar effect on cocaine self-administration. Given that the effects of these 5-HT agonists are observed only when low doses of cocaine serve as the reinforcer or when task demands are high, it is possible that the suppression of responding reflects an effect that is not specific to the reinforcing impact of cocaine. An alternative explanation for these effects incorporates a concept of unit cost/cocaine infusion that allows for direct comparison across studies that employ different reinforcement schedules.     

Dietary additives and the acquisition of cocaine self-administration in rats

 The effects of dietary caffeine and the amount and palatability of food on the acquisition of cocaine (0.2 mg/kg) self-administration were examined. Using an autoshaping procedure, seven groups of 13 rats each were trained to press a lever resulting in a cocaine (0.2 mg/kg infusion under a fixed-ratio 1 (FR 1) schedule. One group had ad libitum access to caffeine- (0.2% w/w) admixed food. Three groups had access to 10 g, 20 g or ad lib food each day. Another three groups had the same three amounts of ground food with powdered saccharin (0.2% w/w) added. During daily 6-h autoshaping sessions, ten infusions were delivered each hour under a random-time 90-s schedule after a brief (15 s) extension of a retractable lever. These were followed by 6-h self-administration sessions, when the lever remained extended and cocaine infusions were available under an FR 1 schedule. The acquisition criterion was self-administration of a mean of 100 infusions over 5 days. Cocaine self-administration was accelerated in the caffeine group compared to the regular chow group. However, by 30 days nearly the same percentage of rats in the caffeine and regular food groups met the acquisition criterion. In the other six groups, as the amount of food increased, the rate of acquisition and percentage of rats per group meeting the acquisition criterion decreased. In the ad lib group, acquisition was further reduced when saccharin was added to food. In summary, dietary caffeine accelerated acquisition and a greater amount and increased palatability of food independently interfered with acquisition of cocaine self-administration in rats. Received: 9 August 1997 / Final version: 14 November 1997     

The effects of aerobic exercise on cocaine self-administration in male and female rats

Rationale  

In drug self-administration procedures, extended-access test sessions allow researchers to model maladaptive patterns of excessive and escalating drug intake that are characteristic of human substance-abusing populations.     

Evidence for learned skill during cocaine self-administration in rats

Rationale  

It has been proposed that cocaine abuse results in skilled or “automatic” drug-taking behaviors. Brain regions important for skill learning are implicated in cocaine self-administration. However, the development of skill during self-administration has not been investigated.     

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 ofl-tryptophan (2, 4, and 8%) were tested in different groups of five rats each. Three other groups of five rats each received the samel-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 concentrationsl-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 thel-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 ofl-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 ofl-tryptophan. The results of this experiment indicate thatl-tryptophan reduces behavior reinforced by IV cocaine infusions.     

Food deprivation and stimulant self-administration in rats: differences between cocaine and d-amphetamine

The effects of food deprivation (24 h) on response rates of rats self-administering d-amphetamine and cocaine were compared. Food deprivation clearly increased rates of responding for both drugs but did so to a significantly greater extent for cocaine than for d-amphetamine. Consistent with other findings, the results suggest that the neural substrates underlying cocaine and d-amphetamine reinforcement are not identical.     

Heroin and cocaine intravenous self-administration in rats: Mediation by separate neural systems

The hypothesis that separate neural systems mediate the reinforcing properties of opiate and psychomotor stimulant drugs was tested in rats trained to lever-press for IV injections of either cocaine or heroin during daily 3-h sessions. Pretreatment with the opiate receptor antagonist drug naltrexone produced dose-dependent increases in heroin self-administration, but had no effect on the rate or pattern of cocaine self-administration. Similarly, pretreatment with low doses of the dopamine antagonist drug alpha-flupenthixol produced dose-dependent increases in cocaine but not heroin self-administration. High doses of alpha-flupenthixol eliminated all responding for cocaine and slightly reduced heroin self-administration. The specificity with which the two antagonist drugs exerted their behavioral effects strongly suggests that independent neural substrates are responsible for the reinforcing actions of heroind and cocaine.