Absence of reinforcement with low dose intravenous ethanol self-administration in rats

Male hooded rats were implanted with intravenous cannulas and housed in operant chambers supplied with 2 levers and enclosed in sound-attenuating cubicles. In Experiment 1, seven rats received a 1.0 mg/kg infusion of ethanol for each press on the previously determined non-preferred lever. The other lever served to count "activity lever presses." An additional 7 rats served as controls and were treated identically except that each press on the non-preferred lever led to an infusion of saline, isovolumetric to the ethanol infused in the experimental subjects. The rats were tested under these conditions of continuous reinforcement for 9 days. Throughout this period, self-infusions and "activity lever presses" did not differ between the groups, suggesting that ethanol was not reinforcing at a dose of 1.0 mg/kg. These results were replicated, and extended to other low doses of ethanol in Experiment 2. Here, we employed a design where depression of either lever, under conditions of continuous reinforcement, led to the infusion of a solution. Fifteen rats were randomly assigned to one of three groups (5 rats/group). In one group, depression of the previously determined non-preferred lever led to an infusion of 16.0 mg/kg of ethanol, while depression of the other lever led to an infusion of isocaloric glucose. For the other two groups, depression of the non-preferred level led to an infusion of 4.0 and 1.0 mg/kg ethanol respectively, and depression of the other lever led to a glucose infusion. The animals were tested for 9 days, and in each case, ethanol self-infusions did not differ significantly from glucose self-infusions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intravenous self-administration of pentobarbital and ethanol in rats

Rats provided with unlimited access to intravenous doses of ethanol (30, 60, 90, 180, and 360 mg/kg/infusion) failed to initiate and maintain lever pressing that resulted in ethanol delivery. When pentobarbital (0.5 mg/kg/infusion) was substituted for ethanol, lever pressing increased. There were three indications of the positive reinforcing effects of pentobarbital: (1) a greater number of lever presses occurred when pentobarbital was response-contingent than when saline was available; (2) a greater number of responses were made on the pentobarbital lever than on a control "activity" lever; and (3) systematic changes in lever pressing were a function of pentobarbital dose (0.125, 0.25, 0.5, 1.0, and 2.0 mg/kg/infusion). Sequential substitution of ethanol (30, 90, 360 mg/kg/infusion) for pentobarbital failed to maintain lever pressing. However, access to combinations of ethanol (1, 3, 10, 30, 60 mg/kg/infusion) and a nonreinforcing dose of pentobarbital (0.125 or 0.25 mg/kg/infusion) did maintain lever pressing. As the dose of ethanol increased, the daily number of infusions first increased then decreased. Following a history of self-administration of ethanol-pentobarbital combinations, a retest of ethanol alone (10 or 30 mg/kg/infusions) followed by pentobarbital alone (0.125 or 0.25 mg/kg/infusion) failed to maintain lever pressing.     

The effects of quipazine and fluoxetine on extinction of a previously-reinforced operant response in rats

Previous studies have shown that treatments that reduce serotonergic neurotransmission lead to enhanced responding during extinction. To evaluate the generality of this effect, the present study examined the effects of the serotonin agonists, quipazine and fluoxetine on responding in extinction. In Experiment 1, 72 rats were trained to lever press on a continuous reinforcement schedule for 5 30-min sessions. Four sessions of extinction followed; 30-min prior to each, 3 groups (n = 16) received quipazine (0, 1.0, 5.0 mg/kg) and 3 groups (n = 8) received fluoxetine (0, 1.0, 5.0 mg/kg). The 5.0 mg/kg dose of quipazine resulted in a significant reduction in responding on day 1; the lower dose of quipazine and both doses of fluoxetine were without significant effect. In Experiment 2, 3 similarly trained groups (n = 8) received either saline or quipazine (5.0 mg/kg) prior to each extinction session; additionally, one quipazine group was injected twice with the 5.0 mg/kg dose in its home cage several days before the beginning of extinction. The results of the drug-naive quipazine group replicated those of that group from Experiment 1 whereas the drug-experienced group showed no significant effect of quipazine in extinction. The results suggested that prior drug experience could modify the effects of quipazine on behaviour. Apart from this drug novelty effect the lack of significant effect of either quipazine or fluoxetine suggested that the effects of manipulations believed to increase and decrease serotonin functioning on responding in extinction may not be symmetrical. These results may be understood with reference to the hypothesis that serotonin plays a role in tuning out or reducing responsiveness to nonreinforced or irrelevant stimuli.     

Bromocriptine self-administration and bromocriptine-reinstatement of cocaine-trained and heroin-trained lever pressing in rats

Rats were trained to lever press for intravenous cocaine (1.0 mg/kg/injection) and then switched to bromocriptine (0.3, 1.0, or 3.0 mg/kg/injection) on a FR-1 reinforcement schedule. Bromocriptine sustained responding at all three doses; hourly drug intake increased linearly with log-dose. In a second experiment, animals were trained to respond for cocaine (1.0 mg/kg/injection) or heroin (0.1 mg/kg/injection) reinforcement; drug was available for the first 2 h of each daily session; saline was substituted for cocaine or heroin for 5 subsequent hours. One hour into each saline substitution session, an intravenous injection of saline or bromocriptine (0.0, 0.5, 1.0, or 2.0 mg/kg) was given. Bromocriptine reinstated both cocaine-trained and herointrained lever pressing; under these conditions, the drug was most effective in the heroin-trained animals. Reinforcing doses of clonidine (0.0625 and 0.125 mg/kg), methohexital, and nicotine (0.05 and 0.1 mg/kg), and a sub-intoxicating dose of ethanol (2 g/kg) failed to reinstate cocaine-trained responding. These data indicate that bromocriptine has cocaine-like and heroin-like stimulus and reinforcing effects.     

Intravenous heroin and ethanol self-administration by alcohol-preferring AA and alcohol-avoiding ANA rats

The alcohol-preferring AA rats have previously been shown to drink more solution containing the opioid etonitazene than the alcohol-avoiding ANA rats. The present experiments were initiated to see whether the line difference in opioid and alcohol intake would persist if an intravenous (IV) route of self-administration is used. Following establishment of stable heroin responding (0.03 mg/kg per infusion), AA and ANA rats were first subjected to three within-session dose-response determinations during which they were allowed to respond for ascending heroin doses (0.0075, 0.015, 0.03, and 0.06 mg/kg per infusion) and then to one progressive-ratio schedule session. AA rats obtained more heroin infusions than ANAs during the first acquisition sessions but there were no significant differences between the lines either in their baseline heroin responding, across the ascending within-session doses, or on the progressive ratio probe. When, after additional heroin baseline sessions, ethanol (1.0 mg/kg per infusion) was substituted for heroin, AA rats initially increased their responding and showed stable rates for responding across ascending ethanol doses (2.0 and 4.0 mg/kg), whereas ANAs declined below their heroin baseline. These findings give evidence for only an initial line difference in IV opiate self-administration but for a sustained difference in IV ethanol self-administration, thus suggesting that the differential alcohol drinking of the AA and ANA rats is dependent at least partly on non-oral factors.     

Antagonist treatment in nucleus accumbens or periaqueductal grey affects heroin self-administration

The role of opiate receptors in the periaqueductal grey and nucleus accumbens in maintenance of intravenous heroin self-administration was examined by means of intracranial microinjections of the quaternary opiate antagonist methyl naltrexone. Over a dose range of 0-3.0 micrograms, pre-session infusions of methyl naltrexone in either brain site produced dose-related increases in responding for heroin (0.06 mg/kg/infusion) on a CRF schedule, without causing significant changes in responding on a second activity control lever. Involvement of the periaqueductal grey was also examined in animals administering a lower heroin dose (0.03 mg/kg/infusion) in shorter sessions in order to minimize drug exposure prior to treatment. In this experiment, infusion of methyl naltrexone produced selective increases in responding for heroin, whereas treatment with the identical dose of methyl naltrexone had no effect on cocaine self-administration (1.0 mg/kg/infusion) in the same animals. With respect to the nucleus accumbens, these data confirm its involvement in opiate self-administration. Data for the periaqueductal grey provide the first evidence that opiate receptors in the vicinity of this brain region may play a role in intravenous opiate self-administration.     

Discriminative stimulus properties of cocaine,norcocaine, and N-allylnorcocaine

A discriminative stimulus paradigm was employed to train eight male and female Wistar rats to discriminate 5.0 mg/kg cocaine HCl from 2.0 ml/kg saline. Subjects responded in a two bar operant chamber on an FR 30 schedule for food reinforcement. All sessions followed a 10 minute pretreatment with either saline, the training dose of cocaine, four probe doses of cocaine HCl (1.0, 2.5, 7.5, 10 mg/kg), four probe doses of norcocaine (1.0, 2.5, 5.0, 7.5 mg/kg) or four probe doses of N-allylnorcocaine (5.0, 7.5, 10, 20 mg/kg). All probe doses were tested using an extinction procedure. The three highest doses of cocaine generalized to cocaine while the 1.0 mg/kg dose of cocaine generalized to saline. The two highest doses of norcocaine generalized to cocaine while the 2.5 mg/kg dose of norcocaine resulted in 57% responding on the cocaine lever with the 1.0 mg/kg dose generalizing to saline. Only the highest dose of N-allylnorcocaine was found to generalize to cocaine with the intermediate doses resulting in an intermediate level of responding occurring on the cocaine lever. The 5.0 mg/kg dose of N-allylnorcocaine generalized to saline.     

Ro 15-4513 selectively attenuates ethanol,but not sucrose,reinforced responding in a concurrent access procedure: comparison to other drugs

The experiments described in this report used a concurrent access procedure to study ethanol reinforcement. Rats were trained to lever press for a 10% sucrose solution and a 10% ethanol/10% sucrose mixture, and both reinforcers were available on variable-interval 5-s schedules. In baseline and vehicle injection sessions, the animals distributed their responding between both solutions. When injected with the partial inverse benzodiazepine agonist Ro 15-4513 (3, 9, and 18 mg/kg), responding for the ethanol solution decreased while responding for sucrose remained intact. Ethanol injections (0.5 and 1.0 g/kg) engendered a similar profile. Chlordiazepoxide led to an increase in ethanol mix responding at 2 mg/kg and a decrease in ethanol mix responding at higher doses; no dose affected sucrose responding. Morphine (0.5–16 mg/kg) decreased responding for both the ethanol mix and sucrose solutions, more or less simultaneously. Naloxone (0.125–20 mg/kg) selectively reduced ethanol mix responding at low doses, and decreased responding for both reinforcers at high doses. In another group of animals, isocaloric alternatives were concurrently available: 10% ethanol/0.25% saccharin versus 14% sucrose. Injections of Ro 15-4513 and chlordiazepoxide produced similar results as in the first group of rats: an increase in ethanol mix responding with low dose chlordiazepoxide, and a decrease in ethanol mix responding with Ro 15-4513. However, naloxone injections did not selectively affect responding for either of the reinforcers when they were isocaloric. These results are discussed in terms of ethanol's neuropharmacological actions.     

The effects of opiate antagonists on the discriminative stimulus properties of ethanol

The effects of naloxone HCl (1.0 mg/kg, 10.0 mg/kg) and naltrexone HCl (1.0 mg/kg, 10.0 mg/kg) on the discriminative stimulus properties of ethanol were measured in order to assess the role of opiate pathways in that behavioral property of ethanol. Forty-eight Sprague-Dawley rats were trained to perform ethanol: saline discriminations on a DRL 10″ schedule of reinforcement in a double lever operant paradigm. Discrimination training for 170 days established 0.6 mg/kg IP ethanol doses as a discriminative stimulus producing at least 80% of all responses as drug appropriate lever choices during 10 min test sessions. After that performance criterion was achieved the effects of the opiate antagonists on the discrimination were assessed by administering naloxone (1.0 mg/kg, IM, 10.0 mg/kg IM) or naltrexone (1.0 mg/kg, IM, 10.0 mg/kg, IM) 15–30 min before the ethanol test dose. Neither antagonist produced significant changes in the performance of the ethanol-saline discrimination. These data demonstrate that the discriminative stimulus properties of ethanol do not require intact opiate pathways. That result implies that the neuropharmacological mechanisms mediating ethanol's stimulus properties in rodents are different from the mechanisms mediating many other behavioral actions of ethanol, including its reinforcing properties.     

Nicotine reinstatement of nicotine self-administration after long-term extinction

The effect of non-contingent priming injections of nicotine on the reinstatement of drug-seeking behaviour was studied in rats following the long-term extinction of nicotine self-administration. Male rats were trained to lever press for 0.03 mg/kg per infusion of intravenous nicotine. Nicotine maintained a robust self-administration behaviour (11.5±1.2; mean±SEM infusions/1-h session). When nicotine availability was discontinued, and only a non-contingent saline infusion was presented to the experimental subjects at the beginning of each daily session, responding for the drug-paired lever decreased to low values. After 4–13 sessions, responding extinguished. During this “extinction” period, non-contingent priming infusions of nicotine 0.001, 0.003, 0.01 or 0.03 mg/kg per infusion induced reinstatement of responsing for the drug-paired lever. The increased responding, compared with the corresponding previous day on saline, was observed at all four nicotine doses but was not statistically significant for the higher priming dose (0.03 mg/kg per infusion). These preliminary results indicate that nicotine priming is able to induce reinstatement of drug-seeking behaviour in rats similarly to other reinforcing drugs. The present findings show analogies with similar phenomena described in ex-smokers and support the addictive role of nicotine in tobacco smoking.     

Drug-induced reinstatement to heroin and cocaine seeking: a rodent model of relapse in polydrug use

The authors investigated several features of polydrug use in rats. Heroin and cocaine were self-administered following responses on different levers, with only 1 drug and 1 lever available on alternate days of training. Four doses of each drug (heroin: 25, 50, 100, and 200 microg/kg/infusion; cocaine: 0.25, 0.5, 1, and 2 mg/kg/infusion) were tested, and each rat was exposed to a single dose combination. Rats readily developed drug-specific and dose-related responding. During extinction, rats displayed a significant bias for responding on the cocaine- associated lever. Priming injections of either cocaine (20 mg/kg) or heroin (0.25 mg/kg) reinstated responding that was selective for the lever previously associated with each drug. These results suggest that in this type of polydrug use, drugs have the capacity to activate drug-seeking behavior selectively oriented toward stimuli previously associated with their administration.     

Acamprosate attenuates cue-induced reinstatement of nicotine-seeking behavior in rats

Acamprosate is used in the treatment of alcoholism; however, there is little information on its effects on nicotine addiction. The objective of this study was to determine whether acamprosate inhibits cue-induced relapse to nicotine self-administration in the rat. Rats were trained to press a lever to obtain intravenous infusions of nicotine (0.03 mg/kg/infusion) that were associated with the illumination of a cue light. After 29 days of nicotine self-administration sessions, extinction sessions were run during which responses on the active lever did not result in the infusion of nicotine or the illumination of the cue light. After 14 days of extinction sessions the rats received twice-daily injections of saline or acamprosate (50, 100, or 200 mg/kg/intraperitoneally). Seven days later the response to the previously conditioned cue was tested, but only saline infusions were delivered. Pretreatment with all doses of acamprosate reduced responding to a cue previously associated with nicotine. The lowest dose of acamprosate (50 mg/kg) reduced responding for the cue previously associated with nicotine infusions, but had no effect on food-rewarded behavior. These results show that acamprosate reduced cue-induced nicotine-seeking behavior and suggest that acamprosate might be efficacious in treating nicotine addiction in humans.     

A reliable model of intravenous MDMA self-administration in naïve mice

Rationale

MDMA is one of the most widely consumed recreational drugs in Europe. However, the mechanisms involved in the reinforcing properties of MDMA are still unclear. In this sense, the establishment of a reliable model of MDMA self-administration in mice could represent an important approach to study the neuronal substrates associated with MDMA reward by using genetically modified mice.

Objectives

To develop a reliable model of operant intravenous MDMA self-administration in drug-naïve mice.

Materials and methods

Mice were trained to acquire intravenous self-administration of MDMA at different doses (0, 0.06, 0.125, 0.25, 0.5 and 1.0 mg/kg/infusion) on a FR1 schedule of reinforcement for 15 consecutive days. The motivational value of different doses of MDMA (0.125, 0.25 and 0.5 mg/kg/infusion) was then tested using a progressive ratio paradigm. Finally, [³H]-mazindol autoradiographic studies were carried out in order to quantitatively assess presynaptic dopamine transporter (DAT) binding sites in the striatum of mice trained to self-administer MDMA (0 and 1.0 mg/kg/infusion) during 15 days.

Results

The latency for discrimination between the active and inactive holes, as well as the number of animals acquiring stability criteria, varied as a function of the dose of MDMA. The mice responding for intermediate doses (0.125, 0.25 and 0.5 mg/kg/infusion) discriminated earlier than those responding for low (0.06 mg/kg/infusion) or high (1.0 mg/kg/infusion) doses. The percentage of animals achieving stability criteria increased with days of testing and was inversely proportional to the dose of MDMA. The breaking points achieved for doses of 0.125 and 0.25 mg/kg/infusion were significantly higher than for a dose of 0.5 mg/kg/infusion. No significant DAT neurotoxicity was observed in the striatum of animals self-administering MDMA at a dose of 1 mg/kg/infusion.

Conclusions

The present results show that MDMA can be reliably self-administered by drug-naïve mice.     

Blockade of the acquisition of cocaine self-administration by the NMDA antagonist MK-801 (dizocilpine)

In an attempt to assess the contribution of the NMDA receptor system to the development of cocaine self-administration, acquisition of intravenous self-administration (0.25mg/kg/infusion) was assessed in rats that received pretreatment with MK-801 (0.0, 0.1 or 0.25mg/kg). For control rats, reliable self-administration was obtained in 3-8 days of testing. These rats rapidly discriminated between depression of a lever that resulted in the delivery of cocaine and an inactive lever. Within the initial 10 day test period, most of the rats pretreated with MK-801 failed to acquire a preference for an active lever which, when depressed, resulted in a cocaine infusion: responding was generally high on both the cocaine reinforced and inactive lever. For six rats, MK-801 treatment was discontinued after 10 days. Although some of these rats had received substantial exposure to cocaine during the initial 10 days, self-administration subsequent to the termination of treatment progressed either with a time course comparable to cocaine-naive rats, or not at all. For rats that continued to receive MK-801 treatment, most failed to acquire reliable self-administration within the 18 day test period. These data suggest that the glutamatergic NMDA receptor system plays an important role in the establishment of cocaine as an effective reinforcer.     

Discriminative stimulus effects of cocaine and amphetamine in rats following developmental exposure to polychlorinated biphenyls (PCBs)

Polychlorinated biphenyls (PCBs) are environmental neurotoxicants known to affect the brain dopaminergic (DA) system. This project investigated whether developmental exposure to PCBs would alter the discriminative stimulus effects of psychostimulant drugs known to act on the DA system. Female Long-Evans rats were orally exposed to 0, 3, or 6 mg/kg/day of an environmentally relevant PCB mixture from four weeks prior to breeding through weaning of their litters on PND 21. When they reached adulthood one male and female/litter were trained to discriminate cocaine (10.0 mg/kg, IP) from saline by repeatedly pairing cocaine injections with reinforcement on one operant response lever, and saline injections with reinforcement on the other lever. After response training, generalization tests to four lower doses of cocaine (7.5, 5.0, 2.5, and 1.25 mg/kg, IP) and to amphetamine (1.0, 0.5, 0.25, and 0.125 mg/kg, IP) were given two days/week, with additional training dose days in-between. Percent responding of the PCB-exposed rats on the cocaine-paired lever was significantly higher than that of controls for the highest generalization dose of cocaine, and lower than that of controls for the highest dose of amphetamine. Response rate and percent responding on the cocaine lever did not differ among the exposure groups on the days when the training dose of cocaine was given, suggesting that the generalization test results were not due to pre-existing differences in discrimination ability or rate of responding. These findings suggest that developmental PCB exposure can alter the interoceptive cues of psychostimulants.     

The effects of Ro 15-4513 on the behavioral actions of ethanol in an operant reaction time task and a conflict test

Ro 15-4513, an analogue of the benzodiazepine receptor antagonist Ro 15-1788, has been reported to selectively block the anxiolytic and intoxicating properties of ethanol in rats. To examine the specificity and selectivity of this ethanol antagonism, the effects of Ro 15-4513 were tested on the actions of ethanol in an operant reaction time and conflict test in rats. The operant reaction time task involved holding down a lever for 0.25-2.0 seconds to obtain food, and animals treated with 1 g/kg of ethanol showed a significant disruption in performance. This disruptive effect was reversed by Ro 15-4513 in doses of 1.5-5.0 mg/kg. Ro 15-4513 was also tested in an operant conflict paradigm sensitive to alcohol effects. Ro 15-4513 (0, 1.5, 3.0, 6.0 mg/kg) produced a significant decrease in both punished and unpunished responding in the conflict test. Ethanol (0.75 g/kg), pentobarbital (5 mg/kg) and chlordiazepoxide (5 mg/kg) all produced a significant release of punished responding that was blocked by pretreatment with 6.0 mg/kg Ro 15-4513, but again Ro 15-4513 suppressed responding on its own at this dose. These results suggest that Ro 15-4513 has inverse agonist properties that may explain its ethanol-antagonist action.     

The effects of amphetamine, apomorphine, SKF 38393, quinpirole and bromocriptine on responding for conditioned reward in rats

The present study investigated the effects of the dopamine (DA) D1 selective agonist, SKF 38393, and the D2 selective agonists, quinpirole and bromocriptine, on responding for conditioned reward. The nonselective DA agonist apomorphine and the indirect agonist amphetamine, were also evaluated. Male rats (n = 302) were tested in a procedure consisting of three distinct phases. During the pre-exposure phase the rats were exposed to an operant chamber containing two levers; one lever produced a lights-off stimulus (3s) and the other a tone stimulus (3s). This was followed by 4 conditioning sessions during which the levers were removed and rats received pairings of the lights-off stimulus (80 per day) and food, presented according to a variable time 45s schedule. Two test sessions followed during which the levers were present and the number of responses made on each lever was calculated as a ratio of the number of responses made during pre-exposure. Drugs were administered prior to each test session. A saline group showed a higher ratio of responding for the lights-off stimulus than the tone stimulus, indicating that the lights-off stimulus had become a conditioned reward. Amphetamine (0.01-2.0mg/kg) and to a lesser extent, quinpirole (0.01-5.0mg/kg) and bromocriptine (0.05-10.0mg/kg) dose-dependently increased responding and specifically enhanced responding on the lever producing the conditioned reward. Apomorphine (0.1-5.0mg/kg) increased responding on both levers at higher doses but the conditioned reward effect was lost. SKF 38393 (0.1-10.0mg/kg) appeared to impair the acquisition of responding for conditioned reward. The results were interpreted as indicating that responding for conditioned reward may be dependent on a D1 receptor-mediated reward signal.     

Bromocriptine enhancement of responding for conditioned reward depends on intact D1 receptor function

It has been suggested that reward-related learning may require intact functioning at the dopamine D₁ receptor. The present experiment tested this hypothesis by challenging the reward-enhancing effects of the D₂ agonist, bromocriptine, with a D₁ antagonist, SCH 23390. For comparison, the effects of the D₂ antagonist, pimozide, were also evaluated. Male rats (n=240) were pre-exposed to a chamber with two levers, one producing a 3-s lights-off stimulus and the other a 3-s tone stimulus. Four conditioning sessions followed, during which levers were absent and presentations of the lights-off stimulus were paired with food. Testing consisted of comparing presses on each lever after conditioning to before conditioning for each rat. Control groups showed a significantly greater increase in responding for lights-off than tone, indicating that the lights-off stimulus had become a conditioned reward. Results showed that bromocriptine (0.25–10.0 mg/kg, IP, 60 min before test session) enhanced responding at doses of 2.5 and 5.0 mg/kg significantly more on the conditioned reward lever than on the other lever. The lowest dose of SCH 23390 (1.0 µg/kg, SC, 2 h before testing) eliminated the bromocriptine-produced enhancement at 2.5 mg/kg and a significant enhancement was seen at 10.0 mg/kg. The higher doses of SCH 23390 (5.0 and 10.0 µg/kg) eliminated the bromocriptine effect and the conditioned reward effect itself, respectively. The low dose of pimozide (0.1 mg/kg, IP, 4 h before test session) eliminated the bromocriptine-produced enhancement at 2.5 and 5.0 mg/kg and a significant enhancement was now seen at 10.0 mg/kg; the higher dose (0.2 mg/kg) appeared to block the conditioned reward effect itself. These results suggest that both SCH 23390 and pimozide interfered with the reward-enhancing effects of bromocriptine. Thus, the present results suggest that reward-related learning can be enhanced through D₂ receptor stimulation with bromocriptine and that this effect appears to depend on intact D₁ receptor function.     

Access to a running wheel inhibits the acquisition of cocaine self-administration

Physical activity decreases cocaine self-administration in laboratory animals and is associated with positive outcomes in substance abuse treatment programs; however, less is known about its efficacy in preventing the establishment of regular patterns of substance use in drug-naive individuals. The purpose of the present study was to examine the effects of access to a running wheel on the acquisition of cocaine self-administration in experimentally naive rats. Male, Long-Evans rats were obtained at weaning and assigned to sedentary (no wheel) or exercising (access to wheel) conditions immediately upon arrival. After six weeks, rats were surgically implanted with intravenous catheters and placed in operant conditioning chambers for 2 h/day for 15 consecutive days. Each session began with a noncontingent priming infusion of cocaine, followed by a free-operant period in which each response on the active lever produced an infusion of cocaine on a fixed ratio (FR1) schedule of reinforcement. For days 1-5, responding was reinforced with 0.25 mg/kg/infusion cocaine; for days 6-15, responding was reinforced with 0.75 mg/kg/infusion cocaine. In addition, all rats were calorically restricted during days 11-15 to 85% to 95% of their free-feeding body weight. Compared to sedentary rats, exercising rats acquired cocaine self-administration at a significantly slower rate and emitted significantly fewer active lever presses during the 15 days of behavioral testing. These data indicate that access to a running wheel inhibits the acquisition of cocaine self-administration, and that physical activity may be an effective intervention in substance abuse prevention programs.     

Diazepam self-administration and resistance to extinction

Self-administration behavior was maintained by a unit dose of 0.03 mg/kg diazepam in 4 of 5 monkeys trained to respond on a lever by successive approximation using diazepam or saline. A dose-response function was determined using diazepam doses ranging between 0.01 and 0.3 mg/kg/infusion. Peak rates of responding occurred at doses of 0.01 or 0.03 mg/kg/infusion and drug intake was directly related to dose. When saline was substituted for diazepam either before or again after the dose-response function was determined, levels of responding remained unexpectedly high, even after as many as 16 consecutive sessions. The rates of responding maintained under extinction conditions appeared to be directly related to the amount of diazepam previously self-administered. For instance, monkeys which did not initially have high rates of responding for saline showed increases in responding after additional exposure to diazepam. Furthermore, the one monkey with low diazepam self-administration rates also had low rates of responding for saline. However, following a period of cocaine self-administration, responding declined in all monkeys when saline was substituted for cocaine. The data suggest that diazepam self-administration affects responding under extinction conditions, an effect which makes the interpretation of diazepam's reinforcing properties difficult.