Sylvie T. Lac

Fluoxetine reduces intravenous cocaine self-administration in rats

Rats self-administered intravenously delivered cocaine (0.2 mg/kg) under a fixed-ratio (FR) 4 schedule during 24-hr sessions. Water was freely available from both a drinkometer and a standard water bottle. After behavior had stabilized, the rats were injected with fluoxetine HCl at 10:00 a.m. and 4:00 p.m. for 5 consecutive days. Three groups of 5 rats each received a different dose of fluoxetine (2.5, 5 or 10 mg/kg) via the IV cannula. In three other groups of rats a glucose and saccharin solution (G + S) was substituted for water in the automatic drinking device and saline was substituted for cocaine. These three groups of rats received the same fluoxetine doses as the cocaine self-injecting groups. In two additional groups of 5 rats each, the cocaine dose was changed to 0.1 or 0.4 mg/kg, and 5 mg/kg fluoxetine injections were given. The two higher doses of fluoxetine (5 and 10 mg/kg) reduced cocaine infusions (0.2 mg/kg) by at least 50 percent on all 5 days of treatment, and cocaine infusions returned to baseline levels within 48 hr after fluoxetine treatments were terminated. Behavior maintained by the G + S solution was also reduced by the two higher fluoxetine doses; however, this reduction did not reliably occur until the last two days of fluoxetine administration. The G + S intakes returned to baseline levels within 24 hr after fluoxetine treatment. Fluoxetine also reduced cocaine infusions in the group of rats that received the lower unit dose of cocaine (0.1 mg/kg); however, it had almost no effect on behavior maintained by a higher cocaine dose (0.4 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

A concurrently available nondrug reinforcer prevents the acquisition or decreases the maintenance of cocaine-reinforced behavior

Lever-Pressing responses of 55 rats were reinforced with IV-delivered cocaine (0.2 mg/kg) or saline under conditions of continuous access for 15 24-h sessions. The rats also responded on tongue-operated drinking devices for deliveries of a 3% (w/v) glucose +0.125% (w/v) sacharin (G+S) solution or water. The effects of removing these substances on behavior maintained by G+S, water, cocaine, or saline were compared in 11 groups. Terminating cocaine access produced a decrease in G+S drinking and an increase in food and water intake. In contrast, a group of rats that did not initially self-administer G+S showed increases in G+S drinking when cocaine was removed, and G+S-maintained responding persisted when cocaine was reinstated. Substitution of water for G+S produced a nearly two-fold increase in cocaine-reinforced behavior but no change in IV-delivered saline self-administration in a control group. A group that did not initially self-administer cocaine increased its infusion rate to over 400 infusions per day as soon as G+S was replaced with water. The effect of presenting cocaine to a group that responded for G+S alone was to decrease G+S intake, but there was only a a transient decrease in water intake in the control group. Likewise, presentation of G+S to a group of rats self-administering cocaine resulted in a decrease in infusions, but saline infusions did not change in a control group. Generally, there was an increase in food and water intake during cocaine removal, but food and water intake did not vary systematically with the removal or presentation of G+S. The results suggest that behavior reinforced by IV-delivered cocaine can be substantially altered by the discontinuation or presentation of G+S, an orally self-administered nondrug reinforcer.

Effects of baclofen on maintenance and reinstatement of intravenous cocaine self-administration in rats

Abstract  Rationale: Recent studies suggest that the GABAB receptor agonist, baclofen, may be a useful pharmacotherapy for cocaine abuse. Objectives: To investigate further the effects of baclofen on maintenance and reinstatement of cocaine-reinforced behavior in rats. Methods: Two groups of rats were trained to self-administer IV cocaine (0.2 or 0.4 mg/kg per infusion) during daily 7-h sessions under a fixed-ratio 1 schedule. Rats were pretreated with baclofen (1.25, 2.5 or 5 mg/kg IP) or saline before the session for 5 consecutive days. An additional group of rats was trained to self-administer IV cocaine (0.4 mg/kg per infusion) during the first 2 h of daily 7-h sessions. Cocaine was replaced by saline for the remaining 5 h of the session. Once behavior had stabilized over the 7-h period, priming injections of saline (IV), cocaine (3.2 mg/kg IV) or baclofen (1.25 or 2.5 mg/kg IP) were administered prior to hour 4. Injections of baclofen (1.25 or 2.5 mg/kg IP) or saline were also given before priming injections of cocaine. Results: Pretreatment with the two higher doses of baclofen (2.5 and 5 mg/kg) decreased the number of cocaine infusions in both maintenance groups (0.2 and 0.4 mg/kg) over the 5-day treatment period. Baclofen had a greater suppressant effect on responding maintained by the lower dose of cocaine. Priming injections of baclofen (1.25 and 2.5 mg/kg) or saline did not reinstate responding. However, these same doses of baclofen dose-dependently reduced the reinstatement of responding produced by priming injections of cocaine. Conclusions: 1) The magnitude of the suppressant effects of baclofen on maintenance of cocaine self-administration depends upon the maintenance dose, 2) baclofen may be useful in preventing reinstatement of cocaine-seeking behavior, and 3) compared to maintenance, reinstatement of responding is more sensitive to the suppressant effects of baclofen.

Acquisition of IV amphetamine and cocaine self-administration in rats as a function of dose

The effect of dose on the acquisition of IV 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.

Autoshaping i.v. cocaine self-administration in rats: effects of nondrug alternative reinforcers on acquisition

The purpose of this experiment was to examine the effects of a nondrug alternative reinforcer and feeding conditions on the acquisition of cocaine self-administration. Rats were autoshaped to press a lever that resulted in a 0.2 mg/kg IV cocaine infusion. Responses on the lever were monitored during six consecutive autoshaping sessions that occurred each day. A retractable lever was inserted into the operant chamber on a random time 60 s schedule 10 times per session for six sessions that began each hour. Each day the six autoshaping sessions were followed by a 6-h cocaine self-administration session. During self-administration the lever remained extended, and each response on the lever resulted in a cocaine infusion (0.2 mg/kg). The criterion for acquisition of cocaine-reinforced behavior was met when there were 5 consecutive days during which the mean number of infusions during the 6-h self-administration session was at least 100. This procedure was repeated daily until the criterion was met or 30 days elapsed. The rats were also trained to respond on lick-operated automatic drinking devices that delivered 0.05 ml water or a glucose and saccharin solution (G+S) contingent upon each lick response. Five groups of 12–14 rats were compared. The first four groups constituted a 2 × 2 factorial design whereby either G+S or water was available in the home cage for 3 weeks before autoshaping began and G+S or water was available in the operant chamber during autoshaping. These groups were limited to 20 g food per day and all had free access to water. A fifth group had only water available in the home cage and operant chamber, and they had unlimited access to food but no G+S. The results indicated that access to the G+S solution in the operant chamber substantially delayed autoshaping, and a large percentage of these rats did not meet the autoshaping criterion within 30 days. The data from groups that had G+S in the home cage were very similar to those that had only water in the home cage; thus, a history of access to G+S did not interfere with acquisition of cocaine self-administration. Autoshaping in the group that had free access to food was highly variable, but a high positive correlation was found between the amount of food consumed and the number of days taken to meet the acquisition criterion. When the rats from the group that consumed over 20 g were compared to the rats in another group that were limited to 20 g and had no G+S, it was found that the increased food intake markedly decreased the rate of acquisition of cocaine self-administration. These findings indicate that acquisition of cocaine-reinforced behavior is delayed or prevented in environments enriched with nondrug alternative reinforcers such as food and a preferred liquid.

Cocaine withdrawal produces behavioral disruptions in rats

There is currently no laboratory or clinical evidence from animal or human studies documenting a withdrawal syndrome associated with cocaine dependence, although many users report that withdrawal disturbances are responsible for their repeated use of the drug. In the present study rats self-administered i.v. cocaine and a sweetened drinking solution. When cocaine access was terminated there was a marked suppression in operant behavior reinforced by the sweetened solution, and this withdrawal disruption was immediately reversed when cocaine was reinstated. There were no physical signs of withdrawal, and food intake increased when cocaine was withdrawn. The results suggest that sensitive behavioral tests reveal aspects of drug dependence that may account for persistent abuse.

Effects of buprenorphine on self-administration of cocaine and a nondrug reinforcer in rats

Nine groups of rats self-administered intravenously-delivered cocaine (0.1, 0.2, or 0.4 mg/kg) during 24-h sessions contingent upon lever-press responses under a fixed-ratio (FR) 4 schedule. Three other groups of rats responded on tongue-operated drinking devices for deliveries (0.01 ml) of a solution of glucose and saccharin (G+S). There were an additional three groups that initially self-administered cocaine (0.2 mg/kg), and later saline replaced cocaine and extinction behavior was allowed to stabilize. All 15 groups of rats were injected twice daily for 5 days with one of three doses of buprenorphine (0.1, 0.2 or 0.4 mg/kg). Buprenorphine decreased cocaine self-administration, but the effect of the highest dose was only slightly greater than that of the lowest dose tested. Cocaine infusions were reduced on the first day of treatment, but they increased over the next 4 days of buprenorphine injections. Buprenorphine decreased G+S intake during the last 2 or 3 days of injections. When buprenorphine treatment was terminated, G+S intake decreased even further. These lower rates of intake persisted for at least 5 days, and they returned to baseline by 2 weeks. Saline self-administration was decreased by buprenorphine in all saline extinction groups. Food intake was not altered by buprenorphine in the groups self-administering IV cocaine or saline; however, food intake was reduced in the G+S groups. Water intake increased during buprenorphine treatment in some of the cocaine groups but not in the G+S groups. Responding on the inactive lever was not altered by buprenorphine during cocaine or G+S self-administration, but it decreased in the saline extinction group. These data indicate that buprenorphine is effective in reducing cocaine reinforced behavior, but it also produced decrements in behavior rewarded by nondrug substances.

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

Abstract 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.

Combined effects of buprenorphine and a nondrug alternative reinforcer on IV cocaine self-administration in rats maintained under FR schedules

Although previous studies have shown that pharmacological agents, such as buprenorphine, and alternative nondrug reinforcers, such as money or sweetened solutions, reduce cocaine self-administration, few studies have examined the combined effects of these two approaches. The purpose of the present study was to evaluate the effects of the opioid partial agonist buprenorphine (0.1 mg/kg) and concurrent access to either water or a glucose plus saccharin solution (G+S, 3% and 0.125% wt/vol) in rats self-administering intravenous (IV) cocaine (0.4 mg/kg per infusion) under fixed-ratio schedules (FR2, 8 or 32). One group had concurrent access to water and another group had concurrent access to G+S. After 3 consecutive days of stable cocaine self-administration, a single buprenorphine injection (0.1 mg/kg IV) was administered 30 min before the start of the experimental session for 3 consecutive days. To summarize the results, (1) the presence of an alternative non-drug reinforcer significantly reduced cocaine self-administration; (2) buprenorphine selectively decreased cocaine, but not water or G+S, self-administration; (3) the decrease in cocaine infusions by buprenorphine was greatest on the first day of buprenorphine administration; and (4) expressed as a percentage of baseline conditions, the combination of buprenorphine and G+S produced a greater decrease in cocaine self-administration than either buprenorphine or G+S alone. These results indicate that combined treatment with buprenorphine and concurrent access to a sweetened solution is a more effective strategy for reducing cocaine self-administration than either strategy alone.

Food deprivation history and cocaine self-administration: an animal model of binge eating

In this two-part study, an animal model of binge eating was first produced, then the rate of acquisition of cocaine self-administration was assessed. Initially, 16 female weanling rats were food deprived (DEPR) at 25, 95, and 143 days of age. Another group of 16 age-matched controls was allowed ad lib access to food. Each time the DEPR group was food deprived, they were allowed to recover to normal weight. They were then injected with butorphanol tartrate (BUTR), an opioid that stimulates feeding, and food intake was measured for 4 h. All rats given BUTR consumed significantly more food than those given saline. Animals with DEPR history consumed food over a longer period of time, and at h 4 after BUTR injection, they consumed significantly more food than controls. In the second part of the experiment, an autoshaping procedure was used to quantitatively evaluate the rate of acquisition of cocaine self-administration. By day 30, 86% of the DEPR and 69% of the control groups had acquired cocaine self-administration.