Patterns of cocaine self-administration in rats produced by various access conditions under a discrete trials procedure

Frequency of drug access greatly affects the pattern and stability of cocaine self-administration. Previous research has shown that restricted drug availability produces remarkably consistent levels of daily cocaine intake, whereas increased or unlimited access produces more variable patterns of self-administration that may change over time. In the present study we used a discrete trials (DT) procedure to document how levels of access affect the pattern of cocaine intake. Rats that had been implanted with a chronically indwelling jugular cannula and trained to self-administer cocaine on an FR1 schedule were given access to cocaine during 10-min DT that were initiated throughout the day/night cycle for 21 days. Frequency of access (2, 3, 4 or 5 trials/h; 1.5 mg/kg/inj) and dose (1.0, 1.5, 2.0 and 2.5 mg/kg/inj, 3 trials/h) were investigated in separate groups of rats. When rats were presented with two or three trials an hour (1.5 mg/kg/inj), a highly regular and circadian pattern of intake was observed across weeks. Increasing the number of trials or increasing the unit dose resulted in a significant increase in average daily cocaine intake. Access to higher dose or higher frequency conditions produced a sustained drug-taking binge during the first few days on the schedule. Rats given access to five trials per hour typically responded at every opportunity for more than 48 h, then stabilized within a range of 80-100 mg/kg/day for the remainder of the experiment. To assess whether such high levels of cocaine intake had altered the motivation to respond, cocaine reinforced break-points were assessed on a progressive ratio schedule (0.32, 1.5 and 3.0 mg/kg/inj) in separate groups of animals before and 24 h after 5 days access on the DT procedure (5 trial/h). Sustained exposure to high levels of cocaine produced a shift in the dose-response curve to the right indicating tolerance to the reinforcing effects. This DT procedure provides a method to examine the behavioral and neurochemical effects of high cocaine intake over extended periods without toxicity.     

Effects of positive allosteric modulators of the GABAB receptor on cocaine self-administration in rats

Rationale Previous studies have strongly implicated a role for GABA_B receptors in modulating the reinforcing effects of cocaine.Objective The purpose of the present study was to examine the efficacy of two novel positive allosteric modulators of the GABA_B receptor, CGP7930 and GS39783, to decrease cocaine self-administration in rats responding under various schedules of reinforcement.Methods Rats were trained to self-administer cocaine under progressive ratio (PR), fixed ratio (FR) and discrete trials (DT) schedules of reinforcement, and the ability of CGP7930 and GS39783 to decrease cocaine-maintained responding was examined.Results On a PR schedule, CGP7930 markedly decreased break points maintained by 1.5 mg/kg per injection cocaine in a dose-dependent manner. GS39783 produced only modest decreases in cocaine-reinforced break points, with only the highest dose decreasing break points relative to baseline. On an FR1 schedule of reinforcement, both drugs decreased responding for a threshold dose of cocaine, but did not alter responding for higher doses of cocaine. In a DT procedure, 1.5 mg/kg per injection cocaine was made available during three 10-min trials each hour during 24-h sessions (DT3), engendering a circadian pattern of responding characterized by high numbers of infusions during the dark phase and low numbers of infusions during the light phase. Doses of 30 mg/kg CGP7930, 3.0 mg/kg GS39783 and 2.5 mg/kg baclofen significantly decreased cocaine-maintained responding when administered at the beginning of the dark phase of the cycle. Across all schedules, CGP7930 was more effective at decreasing cocaine self-administration than GS39783, a finding that may be due to differences in bioavailability between the two drugs.Conclusions These findings suggest that positive allosteric modulators of the GABA_B receptor may hold promise as potential pharmacotherapies for cocaine abuse and dependence.     

Effects of extended-access self-administration and deprivation on breakpoints maintained by cocaine in rats

Rationale Animal models that identify the effects of self-administration histories on subsequent patterns, levels of intake, and other aspects of reinforcement will help clarify the controlling variables of human drug use.Objective Identify the effects of extended-access to cocaine and 1 or 7 days of deprivation on cocaine-maintained breakpoints on a progressive ratio (PR) schedule of reinforcement.Methods Male, Sprague–Dawley rats were trained to self-administer intravenous cocaine (expt 1: 1.5 mg/kg per infusion; expt 2: 0.75 mg/kg per infusion), and then given various histories of self-administration and deprivation. Breakpoints, the number of infusions self-administered on a PR schedule, were assessed following the deprivation period.Results Rates of cocaine intake increased when access to cocaine was extended to 6 h/day. From day 1 to day 14, daily intake increased from 92 (±2.5) to 101 (±2.8) mg/kg in expt 1, and from 55 (±4) to 78 (±2.2) mg/kg in expt 2. Total intake across this 2-week period was approximately 1260 and 970 mg/kg in expts 1 and 2. Breakpoints were not different following this escalation period. The introduction of a 7-day deprivation period failed to alter breakpoints.Conclusions There is dissociation between changes in rate of cocaine intake (or consumption) and breakpoints maintained on a PR schedule. Extended-access to cocaine produced increases in rate of intake without altering breakpoints. Depending on the experimental question, extended-access conditions may prove useful for studying changes in certain aspects of reinforcement, such as consumption, but not others, such as the strength of a drug as a reinforcer.     

Sex differences in the behavioral effects of 24-h/day access to cocaine under a discrete trial procedure.

Although more men than women are addicted to cocaine, it has been suggested that women may have an accelerated transition to addiction, and that once addicted they may be more vulnerable to relapse. Here we investigate the effects of extended access to cocaine under a 24-h/day discrete trial procedure on patterns of intake and subsequent motivation to use cocaine as assessed by responding under a progressive-ratio schedule in male and female rats. Rats were initially trained to self-administer cocaine (1.5 mg/kg/infusion) under a fixed-ratio 1 schedule until acquisition occurred, and then responding was assessed under a progressive schedule for three sessions. Subsequently, rats had 24-h access to intravenous cocaine infusions (1.5 mg/kg) that were available in discrete trials (4, 10 min trials/h) for 7 consecutive days. At 10 days after the last discrete trial session, responding was reassessed under a progressive-ratio schedule for three additional sessions to investigate changes in motivation to obtain cocaine. Prior to cocaine self-administration under the 24-h access discrete trial procedure, males and females did not differ on cocaine self-administration under the fixed-ratio or progressive-ratio schedules. However, sex differences emerged under the 24-h access discrete trial procedure with females self-administering higher levels of cocaine, for longer initial periods of time, and showing a greater disruption in the diurnal control over intake than did males. Additionally, following a 10-day forced abstinence period, females responded at higher levels under the progressive-ratio schedule to obtain cocaine infusions than did males. These findings suggest that extended access to cocaine under the discrete trial cocaine self-administration procedure produces sex-dependent patterns of intake and sex-specific changes in motivation to obtain cocaine as measured by progressive-ratio responding.     

Cross-sensitization of the reinforcing effects of cocaine and amphetamine in rats

Rationale Cross-sensitization between cocaine and amphetamine has been demonstrated in different behavioral paradigms. There is a relative paucity of studies examining whether cross-sensitization occurs between amphetamine and cocaine when both are self-administered. Objective The current study was designed to test whether animals sensitized to the reinforcing effects of cocaine would show cross-sensitization of the reinforcing effects of amphetamine, using a self-administration paradigm. Materials and methods Male, Sprague–Dawley rats were trained to self-administer cocaine and given limited or high exposure to cocaine under a fixed ratio (FR) 1 procedure. After the initial exposure to cocaine, animals self-administered cocaine (1.5 mg/kg per injection) under a progressive ratio (PR) procedure. Subsequently, breakpoints on a PR schedule and rates of intake on an FR schedule maintained by different doses of amphetamine were assessed. Results Animals with high initial exposure to cocaine (40 injections of 1.5 mg/kg per injection per day for 5 days) showed stable breakpoints throughout testing. Animals given limited initial cocaine exposure (20 injections of 0.75 mg/kg per injection for 1 day) produced a gradual increase in breakpoints maintained by cocaine over time (i.e., sensitization of the reinforcing effects of cocaine). When subsequently tested with amphetamine, the dose–effect curve was shifted upward in the limited-exposure group relative to the high-exposure group, suggesting cross-sensitization of the reinforcing effects of amphetamine. Conclusions Sensitization of the reinforcing effects of cocaine resulted in cross-sensitization of the reinforcing effects of amphetamine. This phenomenon occurs even when both drugs are self-administered.     

Self-administration of GBR 12909 on a fixed ratio and progressive ratio schedule in rats

Intravenous self-administration of GBR 12909, an indirect dopamine agonist, was examined on a Fixed Ratio (FR 1) and a Progressive Ratio (PR) schedule of reinforcement in rats. Subjects were first trained to self-administer cocaine (1.5 mg/kg/inj) during daily 5 h sessions, after which GBR 12909 (0.187–1.5 mg/kg/inj) was substituted. On the FR 1 schedule, the inter-infusion interval for GBR 12909 self-administration was directly related to dose and was approximately three times longer than that established for equivalent doses of cocaine. Breaking points on the PR schedule were comparable for GBR 12909 and cocaine self-administration. The data indicate that, compared to cocaine, GBR 12909 has a longer duration of action and a similar reinforcing efficacy.     

Systemic pretreatment with MK-801 (dizocilpine) increases breaking points for self-administration of cocaine on a progressive-ratio schedule in rats

 The effects of the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, on cocaine self-administration were investigated. Forty-six male Wistar rats were trained to intravenously self-administer four unit doses of cocaine (0.19, 0.38, 0.75 and 1.5 mg/kg per injection) on a progressive-ratio schedule of reinforcement. The effects of increasing doses of MK-801 (0.05, 0.1, 0.15 and 0.2 mg/kg, IP, 30 min before test sessions) on breaking point (BP) for cocaine self-administration were investigated. The results showed that pretreatment with MK-801 produced effects on cocaine BPs that fit on an inverted-U function. That is, the 0.05 and 0.1 mg/kg doses of MK-801 produced no effect or a small enhancement of BPs across all doses of cocaine, respectively. The 0.15 mg/kg dose of MK-801 produced a significant treatment effect characterized by increased BPs, relative to baseline BPs, across all doses of cocaine. The 0.2 mg/kg dose of MK-801 produced a nonsignificant decrease in BPs across most doses of cocaine. The dose-dependent effects on cocaine BPs after pretreatment with MK-801 suggest that MK-801 can potentiate, and at higher doses attenuate, the rewarding effects of self-administered cocaine. Received: 3 January 1996 / Final version: 12 June 1996     

Escalation of intravenous cocaine self-administration,progressive-ratio performance,and reinstatement in rats selectively bred for high (HiS) and low (LoS) saccharin intake

Rationale Rats selectively bred for high saccharin (HiS) intake consume more alcohol and acquire intravenous (IV) cocaine self-administration more rapidly than their low saccharin (LoS) consuming counterparts.Objectives The purpose of the present study was to determine whether HiS and LoS rats also differ in the escalation, maintenance, and reinstatement of IV cocaine self-administration.Methods LoS and HiS female rats were allowed to self-administer cocaine [0.4 mg/kg; fixed ratio (FR) 1] under short (ShA, 2 h per day) or long (LgA, 12 h per day) access conditions for 21 days. Session lengths were subsequently equated (2 h) and (1) FR1-maintained cocaine (0.4 mg/kg) self-administration, (2) progressive ratio (PR)-maintained cocaine (0.2–1.6 mg/kg) self-administration, and (3) saline-induced and cocaine (10 mg/kg, IP)-induced reinstatement of drug-seeking behavior were examined.Results HiS LgA rats escalated their cocaine intake more rapidly and self-administered more cocaine (mg/kg) than LoS LgA rats; however, there was no LoS versus HiS phenotype difference in the number of infusions self-administered by Day 21. Post-escalation cocaine self-administration under an FR1 schedule did not differ as a function of phenotype (LoS versus HiS) or access condition (ShA versus LgA); however, LoS rats responded more for cocaine under the PR schedule than HiS rats, and they showed a greater reinstatement of cocaine-seeking behavior than HiS rats. In contrast, ShA versus LgA did not affect PR or reinstatement performance in the LoS and HiS groups.Conclusions These results suggest that LoS and HiS rats have distinct drug-seeking and drug-taking profiles that differ as a function of the experimental phase and access condition. The LoS and HiS rats differ along a wide range of behavioral dimensions and represent an important model to study the interactions of feeding, emotionality, and other factors related to vulnerability to drug abuse.An erratum to this article can be found at     

Self-administration of two long-acting monoamine transport blockers in rhesus monkeys

RATIONALE: 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) is a cocaine analog with high affinity at and selectivity for the dopamine transporter (DAT). 2beta-propanoyl-3beta-(2-naphthyl)-tropane (HD-23), like cocaine, binds with approximately equal affinity to the DAT, the serotonin transporter, and the norepinephrine transporter but has over a 100-fold higher affinity for these monoamine transporters than cocaine. The reinforcing effects of these drugs have not been evaluated in cocaine-na nonhuman primates. OBJECTIVE: The primary goal of the present study was to examine the reinforcing effects of PTT and HD-23 in rhesus monkeys before and after a history of intravenous cocaine self-administration. METHODS: Monkeys (n=4) were initially trained to respond under a fixed-ratio 30 schedule of food presentation. When responding was stable, saline, PTT (0.001-0.03 mg/kg per injection), and HD-23 (0.0003-0.0056 mg/kg per injection) were made available for self-administration for least five sessions per dose. Next, a cocaine dose-effect function (0.0003-0.3 mg/kg per injection) was determined and then     

Effects of chronic<Emphasis Type="Italic"> d</Emphasis>-amphetamine treatment on cocaine- and food-maintained responding under a progressive-ratio schedule in rhesus monkeys

Rationale. d-Amphetamine is a candidate agonist medication for the treatment of cocaine dependence, and evaluation of d-amphetamine effects on abuse-related effects of cocaine in preclinical assays is warranted. Objective. This study was designed to assess the effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a progressive-ratio schedule in rhesus monkeys. The effects of schedule manipulations on cocaine and food-maintained responding were also examined for comparison with d-amphetamine effects. Methods. Key-press responding under a progressive-ratio schedule resulted in the delivery of cocaine (0.032 mg/kg per injection) or 1 g food pellets. The effect of manipulating cocaine dose (saline, 0.001–0.1 mg/kg per injection) or the number of food pellets delivered (0, 1 and 4 pellets) was determined. Subsequently, three schedule parameters were manipulated: (1) starting ratio value, (2) increments of the ratio progression, and (3) duration of post-reinforcer time-outs when the ratio value was constant. Finally, the effects of 10-day treatment with d-amphetamine (0.01–0.1 mg/kg per hour) were examined. Results. Break points increased as a function of cocaine dose or the number of food pellets, and similar break points were maintained by delivery of 0.032 mg/kg per injection cocaine and 1 food pellet. Manipulation of schedule parameters produced similar effects on responding maintained by cocaine (0.032 mg/kg per injection) or food (1 pellet). In contrast, d-amphetamine produced a dose-dependent decrease in cocaine-maintained responding and had less consistent effects on food-maintained responding. Conclusions. These results are consistent with the hypothesis that chronic treatment with d-amphetamine decreases cocaine self-administration in rhesus monkeys, possibly by attenuating the reinforcing effects of cocaine. Electronic Publication     

Initiation,maintenance and extinction of cocaine self-administration with and without conditioned reward

 Relapse prevention in abstinent cocaine addicts remains a major focus of drug addiction therapy. We used a rat model of cocaine addiction that focused on cocaine-seeking behavior elicited interoceptively and by conditioned stimuli. Each of 18 rats could self-administer a maximum of 20 intravenous cocaine injections (1.5 mg/kg) per session per day. To prevent initiation of responding by cocaine itself priming injections were never administered. Although cocaine was available beginning every session the rats displayed a self-imposed period of abstinence followed by a period of rapid consumption. The abstinence period was variable among rats but consistent for individual rats. In experiment 1 we studied the contribution of a CS⁺ (stimulus light and lever retraction) to the motivation to initiate and maintain a cocaine self-administration episode. We compared the number of responses the rats emitted to receive the first and subsequent injections of the day between a group responding on a fixed-ratio (FR) schedule (n=6) and a group responding on a second-order (SO) schedule (n=5) of reinforcement. For all rats the number of responses per injection was raised daily until a rat failed to consume more than four injections. The SO group was able to emit approximately four times as many responses as the FR group to obtain their first and subsequent injections. In experiment 2 (n=7) responses during extinction were counted with and without the CS⁺. Responding was greater in the presence of the CS⁺ than in its absence. The present model demonstrates that the motivation to self-administer cocaine is variable and greatly enhanced by conditioned stimuli. Received: 25 January 1996 / Final version: 23 May 1996     

Long-term cocaine self-administration under fixed–ratio and second-order schedules in monkeys

Rationale Studies in rodents have demonstrated that increased access to cocaine can result in increases in drug intake per unit time. Objectives The present studies characterized long-term changes in cocaine self-administration associated with quantitatively and qualitatively different conditions of cocaine availability in monkeys. Materials and methods Separate groups of rhesus monkeys (n = 6/group) self-administered cocaine (0.2 mg/kg per injection) under a fixed ratio (FR) 30 schedule for 3 h twice daily for two consecutive days each week for 1 year, or responded under a second-order FR 10 (fixed interval 3-min:S) schedule of 0.2 mg/kg per injection cocaine during daily sessions. After 18 weeks, probe sessions were conducted once per week, in which responding was maintained under a fixed interval (FI) 30-min schedule in the presence of distinct stimuli. Results Weekly cocaine intakes under the FR schedule were stable in three subjects, but increased progressively in three monkeys over 1 year. In contrast, response rates under the second-order schedule were low and stable over time. Responding under the FI 30-min schedule was higher for monkeys in the FR group and pattern of responding was not indicative of FI performance, perhaps due to experimental history. Conclusions These data suggest that increases in cocaine intake can be observed under ratio schedules in monkeys. The use of an FI 30-min “probe” to assess changes in “drug seeking” appeared to be influenced by experimental history. These data may aid in the development of behavioral models of cocaine abuse, which focus on the compulsive nature of drug taking.     

Sucrose intake predicts rate of acquisition of cocaine self-administration

Rationale: A number of studies have indicated a relationship between the intake of palatable foods or fluids and drug self-administration. Objectives: Two experiments were conducted to determine whether the intake of sucrose or fat was related to subsequent cocaine self-administration. Methods: In separate groups of rats, sucrose or fat was presented for 60 min daily for 7 days. On day 8, a mild stressor (saline injection) was given just prior to sucrose or fat presentation. Rats were then catheterized and tested for cocaine self-administration on a fixed ratio schedule at doses from 0.2 mg/kg to 1.0 mg/kg per infusion and on a progressive ratio schedule at doses from 0.2 mg/kg to 1.5 mg/kg per infusion. Results: Sucrose intake after a mild stressor was significantly related to time to acquisition, with those rats consuming the most sucrose meeting the acquisition criterion sooner than those rats consuming lower amounts of sucrose. Subsequent to acquisition, however, low and high sucrose feeders did not consistently differ in the amount of cocaine self-administered. No relationship was observed between fat intake and rate of acquisition. Conclusion: These results provide additional evidence of a relationship between sucrose intake and drug reward, and suggest that stress reactivity may be an important component of this relationship. Received: 4 October 1999 / Final version: 21 December 1999     

The GABA(B) agonist CGP 44532 decreases cocaine self-administration in rats: demonstration using a progressive ratio and a discrete trials procedure

Previous self-administration experiments have shown that baclofen, the prototypical GABA(B) agonist, produces an apparent attenuation in the reinforcing effects of cocaine in rats. The present experiments examined the effects of CPG 44532, a novel and highly specific GABA(B) agonist, on cocaine self-administration using two distinctly different procedures. CGP 44532 (0.063-0.5 mg/kg) produced a dose dependent decrease in break point on a progressive-ratio (PR) schedule. A low dose of CGP 44532 (0.125 mg/kg) produced an apparent shift of the cocaine dose-response curve to the right. In contrast there was comparatively little effect on food-reinforced responding on the same PR schedule. Using a discrete-trials procedure that engendered a circadian pattern of self-administration, CPG 44532 (0.063-0.5 mg/kg) produced a dose-dependent suppression of cocaine intake in the 4 h period following treatment. When a concurrently available food reinforced lever was added to the discrete trials paradigm CGP 44532 failed to disrupt responding for food at any of the doses tested. Data from the PR and discrete-trials procedures taken together indicate that CGP 44532 produced a specific decrease in the motivation to self-administer cocaine.     

Baclofen suppression of cocaine self-administration: demonstration using a discrete trials procedure

 We have previously reported that rats display a circadian pattern of cocaine self-administration if access to drug is limited to 10-min discrete trials that are separated by at least 20 min. In the present study, the pattern of cocaine intake (1.5 mg/kg per injection) was studied in two large groups of animals that were maintained on different 12-h light/dark cycles (3 a.m. to 3 p.m. versus 10 a.m. to 10 p.m.). Regardless of the time of light onset, a circadian pattern of cocaine self-administration was observed. Maximum cocaine intake occurred during the final 6 h of the dark period and was followed by a relative abstinence period during the light phase. This highly predictable pattern of drug taking behavior provided an opportunity to explore the effect of baclofen, a GABA_B agonist, on the initiation of self-administration behavior. In two separate studies, acute treatment with baclofen (1.25–5.0 mg/kg) was shown to suppress cocaine intake for at least 4 h. Baclofen had no significant effect on responding for food reinforcement. Previous results have indicated that baclofen appears to reduce specifically the motivation to respond for cocaine. Together, these data suggest that baclofen should be considered as a possible pharmacotherapeutic agent in cocaine addiction. Received: 30 July 1996 / Final version: 8 February 1997     

Oral caffeine pretreatment produced modest increases in smoked cocaine self-administration in rhesus monkeys

Several recent studies have shown that caffeine potentiates the reinforcing, discriminative stimulus, and motor activating effects of cocaine in rats. The present study was designed to determine whether oral caffeine pretreatment would enhance the reinforcing effects of cocaine in rhesus monkeys trained to self-administer smoked cocaine base. The effects of oral caffeine pretreatment (0, 100, or 200 mg) and fixed-ratio (FR) value on cocaine-base smoking were evaluated in four male rhesus monkeys. Monkeys responded on a lever under a fixed-ratio (FR) schedule (FR 128, 256, 512, 1024, 2048, or 4096) and then made five inhalations on a smoking spout to gain access to volatilized cocaine base (0.25 or 1.0 mg/kg per delivery) during daily experimental sessions. Twenty pellets [20 non-caffeinated (0 mg caffeine), ten non-caffeinated+ten caffeinated (100 mg caffeine), or 20 caffeinated (200 mg caffeine) pellets] were administered 30 min prior to experimental sessions. The lever FR value was held constant within each experimental session, but was increased after 3 consecutive days of stable responding. Although the number of smoke deliveries that was self-administered significantly decreased from FR 128 to FR 4096, it did not change as a function of cocaine dose across the range of FR values tested. However, the interaction between cocaine dose and caffeine pretreatment was statistically significant. Compared to 0 mg caffeine, three of four monkeys pretreated with 200 mg caffeine responded for a greater number of smoke deliveries when they were maintained on a cocaine dose of 1.0 mg/kg per delivery, but not 0.25 mg/kg per delivery. Thus, caffeine pretreatment can produce small, but statistically significant increases in smoked cocaine self-administration in rhesus monkeys.     

Effect of (−)-DS 121 and (+)-UH 232 on cocaine self-administration in rats

The novel dopamine autoreceptor antagonists (–)-DS 121 and (+)-UH 232 were tested for their ability to alter cocaine self-administration behavior in rats reinforced on a progressive ratio (PR) schedule. (–)-DS 121 (15 mg/kg) and (+)-UH 232 (30 mg/kg) produced significant decreases in breaking point. (–)-DS 121 produced variable results on rate of cocaine intake on an FR1 schedule, indicating that rate may on occasion be insensitive to changes in cocaine reinforcement. In animals previously trained to self-administer cocaine, (–)-DS 121 failed to maintain responding when substituted for cocaine. This profile suggests that (–)-DS 121 is a promising new candidate for the treatment of cocaine abuse.     

Effect of baclofen on cocaine self-administration in rats reinforced under fixed-ratio 1 and progressive-ratio schedules

Rationale: Recent reports have indicated that the γ-aminobutyric acid (GABA)_B agonist baclofen attenuates the reinforcing effects of cocaine. Objectives: To further evaluate the effect of baclofen on cocaine self-administration under a fixed ratio (FR) and progressive ratio (PR) schedule of reinforcement. Methods: In the first series of experiments, three dose–response curves were generated that examined the effect of three doses of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) against four unit-injection doses of cocaine (0.19, 0.38, 0.75, and 1.5 mg/kg per injection) reinforced under a FR1 schedule. For comparison, an additional group of rats was pretreated with haloperidol (32, 56, or 100 μg/kg, i.p.). A separate experiment examined the effect of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) on responding for concurrently available cocaine or food reinforcement. Results: Under the FR1 schedule, baclofen suppressed intake of low but not high unit injection doses of cocaine. In contrast to haloperidol, baclofen had no effect on the distribution of inter-injection intervals and, instead, produced long pauses in cocaine self-administration. Baclofen dose dependently reduced cocaine- reinforced responding on a PR schedule; concurrent access to a food-reinforced lever demonstrated that the animals retained the capacity to respond at high rates. Conclusion: The effect of baclofen pretreatment on cocaine self-administration is dependent on the unit injection dose of cocaine and on the response requirements of the schedule. Received: 22 July 1999 / Final version: 23 September 1999     

Environmental enrichment decreases intravenous amphetamine self-administration in rats: dose-response functions for fixed- and progressive-ratio schedules

Rationale: Recent case series suggest that chromium picolinate in doses of 400 μg daily may have antidepressant properties, perhaps through increasing the peripheral availability of tryptophan for brain serotonin (5-HT) synthesis. Objectives: To determine the effects of chromium treatment on plasma tryptophan availability and on brain 5-HT function in human and animal models. Methods: We studied the effects of short-term chromium supplementation on plasma concentrations of tryptophan and other large neutral amino acids. Brain 5-HT function was assessed by measuring the corticosterone/cortisol response to the 5-HT precursor, 5-hydroxytryptophan (5-HTP), a response believed to be mediated via indirect activation of 5-HT_2A receptors. Results: In rats, chromium increased peripheral and central tryptophan availability and elevated brain 5-HT content. Changes in peripheral tryptophan availability were not seen in humans but in both rats and humans, chromium lowered the cortisol response to challenge with 5-HTP. Conclusions: Chromium can modify brain 5-HT function in humans and animals, perhaps by altering the sensitivity of central 5-HT_2A receptors. Electronic Publication     

The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats

Rationale

There is a focus on developing D3 receptor antagonists as cocaine addiction treatments.

Objective

We investigated the effects of a novel selective D3 receptor antagonist, SR 21502, on cocaine reward, cocaine-seeking, food reward, spontaneous locomotor activity and cocaine-induced locomotor activity in rats.

Methods

In Experiment 1, rats were trained to self-administer cocaine under a progressive ratio (PR) schedule of reinforcement and tested with vehicle or one of three doses of SR 21502. In Experiment 2, animals were trained to self-administer cocaine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with vehicle or one of the SR 21502 doses on cue-induced reinstatement of responding. In Experiment 3, animals were trained to lever press for food under a PR schedule and tested with vehicle or one dose of the compound. In Experiments 4 and 5, in separate groups of animals, the vehicle and three doses of SR 21502 were tested on spontaneous or cocaine (10 mg/kg, IP)-induced locomotor activity, respectively.

Results

SR 21502 produced significant, dose-related (3.75, 7.5 and 15 mg/kg) reductions in breakpoint for cocaine self-administration, cue-induced reinstatement (3.75, 7.5 and 15 mg/kg) and cocaine-induced locomotor activity (3.75, 7.5 and 15 mg/kg) but failed to reduce food self-administration and spontaneous locomotor activity.

Conclusions

SR 21502 decreases cocaine reward, cocaine-seeking and locomotor activity at doses that have no effect on food reward or spontaneous locomotor activity. These data suggest SR 21502 may selectively inhibit cocaine’s rewarding, incentive motivational and stimulant effects.