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.     

Mecamylamine attenuates cue-induced reinstatement of nicotine-seeking behavior in rats.

Mecamylamine, a noncompetitive nicotinic cholinergic antagonist, inhibits nicotine self-administration in animals and may attenuate tobacco smoking in humans trying to quit. Our preliminary data suggested that this agent, at a dose of 2 mg/kg (subcutaneous (s.c.)), also attenuates cue-induced relapse to nicotine-seeking behavior in rats. This study determined whether mecamylamine-induced attenuation can be obtained at doses lower than the high 2 mg/kg dose used in the first study, and whether it is specific to nicotine-associated cues. Male Sprague-Dawley rats were trained to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed-ratio 5 schedule. Each infusion was accompanied by a visual cue (1 s onset of a lever light followed by offset of a house light for 20 s during which time no infusions could be obtained). After the nicotine-maintained responding was extinguished by withholding the delivery of nicotine (saline substitution) and its associated cue, reinstatement tests were conducted. Response-contingent re-presentation of the cue without further availability of nicotine significantly reinstated extinguished responding at the previously nicotine-reinforced lever. Pretreatment with mecamylamine (0.5, 1, and 2 mg/kg, s.c.) dose-dependently attenuated the cue-induced reinstatement of lever responding. Mecamylamine did not change food-taking and -seeking responses, whereas the highest dose (2 mg/kg) decreased nicotine self-administration behavior. The results confirm previous findings that stimuli conditioned to nicotine self-administration effectively elicit reinstatement of nicotine-seeking behavior after extinction and demonstrate that mecamylamine, besides suppressing self-administration of nicotine, effectively attenuates cue-induced nicotine-seeking behavior. These findings suggest that the response-reinstatement procedures used in this study may be useful for studying neurobiological mechanisms of nicotine-seeking behavior and that mecamylamine-like drugs may be potential candidates for pharmacological treatment and prevention of relapse to tobacco smoking in abstinent smokers.     

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.     

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.     

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.     

Abuse liability of the anesthetic propofol: self-administration of propofol in rats under fixed-ratio schedules of drug delivery

RATIONALE: Previous reports suggest that propofol (PPF) may have abuse potential in humans. Hence, we hypothesized that PPF could reinforce self-administration behavior in other species. Positive reinforcing effects of PPF could be interpreted as an index of abuse liability. OBJECTIVE: Acquisition and maintenance of i.v. PPF self-administration were examined in 12 rats. METHODS: Six rats were initially given access to methohexital (MHX, 2.0 mg/kg per infusion) under a fixed ratio (FR) 1 schedule, while the other six were initially given access to PPF (1.7 mg/kg per infusion). Once stable responding was established, various doses of PPF (0.56, 1.0, and 1.7 mg/kg per infusion) and vehicle (Intralipid 20%) were made available. RESULTS: The number of PPF infusions per session was an inverse function of dose, with 0.56 mg/kg and 1.0 mg/kg per infusion maintaining significantly more infusions per session than vehicle in most rats under the FR 1 schedule. For some rats, the number of vehicle infusions per session was equal to or greater than the number of PPF infusions. Increasing the response requirement to FR 5 decreased the number of vehicle infusions per session in these rats, while PPF maintained a higher number of infusions than vehicle under this FR value in six of seven rats. CONCLUSION: PPF served as a reinforcer in rats under FR schedules of i.v. drug delivery, adding to the extant evidence that it has abuse potential.     

Intravenous nicotine self-administration and cue-induced reinstatement in mice: effects of nicotine dose, rate of drug infusion and prior instrumental training

Intravenous nicotine self-administration is the most direct measure of nicotine reinforcement in laboratory animals, but this procedure has proven difficult to establish in mice. We found that stable responding for nicotine in C57BL6/J mice was facilitated by prior instrumental training for food reward, initial exposure of mice to a lower unit dose of nicotine (0.03 mg kg⁻¹ per infusion) before access to higher doses, a slower rate of drug delivery (3-s versus 1-s infusion), consistency in schedule of daily testing, and low extraneous noise during testing. Under these conditions, we found that mice lever-pressed for nicotine (0.03-0.4 mg kg⁻¹ per infusion; 60-min test sessions) under a fixed-ratio 5 time-out 20-s (FR5TO20) reinforcement schedule and consumed the drug according to an inverted ‘U’-shaped dose-response curve. Mice switched their responding onto a previously non-reinforced lever to continue earning nicotine infusions when the active/inactive lever assignment was reversed. The nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine decreased responding for nicotine, but not food rewards, verifying that nAChRs regulate nicotine self-administration in mice. The cue-light paired with nicotine delivery did not support responding when delivered independently of nicotine infusions, further verifying that mice responded selectivity for the drug. Nicotine-seeking responses extinguished when nicotine infusions and the cue-light were withheld, and exposure to the cue-light reinstated responding. Finally, mice without prior instrumental food training acquired stable responding for nicotine under the FR5TO20 schedule, but required a greater number of sessions. These data demonstrate that nicotine is an effective reinforcer in mice and establish conditions under which the drug is reliably self-administered by mice.     

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.     

Nicotine serves as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers

Rationale Although numerous studies have documented that nicotine can function as an effective reinforcer of intravenous self-administration behavior in animals, it has not been clearly shown to maintain intravenous self-administration behavior above vehicle placebo levels in humans.Objectives To compare the reinforcing effectiveness of nicotine versus saline placebo in human research volunteers responding under fixed-ratio (FR) schedules of intravenous drug self-administration while systematically increasing response requirements.Methods Eight male cigarette smokers resided in an inpatient research unit. During 3-h sessions, intravenous injections of nicotine and saline were available concurrently and were contingent on responding (pulling a lever). Nicotine dose (0.75, 1.5, 3.0 mg/injection), time out (TO) value after each injection (1–20 min) and FR response requirement (10–1600) were varied in different subjects over consecutive sessions.Results Number of nicotine injections/session significantly decreased as dose/injection increased and the number of self-administered nicotine injections was significantly greater than the number of self-administered saline injections across conditions. When FR value was progressively increased over sessions, response rates for nicotine, but not saline, injections increased, with maximal rates at the highest FR values. Rates of responding and injections/session were markedly and significantly higher for nicotine than for saline at FR values of 200 and above. Subjects rated effects of nicotine as both significantly more positive and more negative than saline placebo, with positive ratings significantly higher than negative ratings.Conclusions Nicotine functioned as a prototypic drug of abuse, serving as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers. Subjects adjusted their responding to response requirements in a way that maintained relatively constant levels of nicotine injections per session.Abstracts of these experiments previously appeared in Pharmacologist 25:219, 1983, and Neurosci Lett 14(Suppl):140, 1983.     

Nicotine self-administration, extinction responding and reinstatement in adolescent and adult male rats: evidence against a biological vulnerability to nicotine addiction during adolescence.

Initiation of smoking behavior typically occurs during adolescence and rarely occurs during adulthood. Despite this epidemiological evidence, relatively little is known about possible neurobiological differences in the response to nicotine in adolescents that might make them more vulnerable to nicotine addiction. In the current study, we assessed nicotine self-administration under fixed ratio (FR) and progressive ratio (PR) reinforcement schedules in adolescent (postnatal day (P) 33-35) and adult (P91-94) rats. We then assessed extinction and reinstatement of nicotine seeking in adulthood in rats that initiated nicotine self-administration during either adolescence or adulthood. Nicotine self-administration (0.03 mg/kg/infusion, i.v.) was higher in adult rats than in adolescent rats under FR5 and PR reinforcement schedules; no age differences in nicotine self-administration were observed under FR1 or FR2 reinforcement schedules. In contrast, saccharin self-administration under FR5 and PR reinforcement schedules was similar in both age groups, potentially ruling out age differences in general performance. Rats that initiated nicotine self-administration as adults demonstrated a greater resistance to extinction of nicotine taking behavior when saline was substituted for nicotine than rats that initiated self-administration as adolescents. Reinstatement of nicotine seeking following nicotine priming injections (0.075, 0.15, 0.3 mg/kg, s.c.) was independent of the age of onset of nicotine self-administration. The present data from established rat models of drug self-administration and drug relapse suggest that nicotine is less reinforcing in adolescent compared with adult rats and that processes other than the reinforcing effects of nicotine may be involved in the greater susceptibility to smoking during the adolescent developmental stage.     

Nicotine maintains robust self-administration in rats on a limited-access schedule

Intravenous nicotine maintained substantial responding on the drug-reinforced lever with a limited-access, fixed-ratio 5 schedule of self-administration. Responding demonstrated the expected pharmacological sensitivity; it was dose-dependently reduced by pre-session treatment with either nicotine or mecamylamine but not with hexamethonium. In addition, responding was dependent on the size of the unit dose, with maximum values occurring at 0.01 and 0.03 mg/kg/infusion. Self-administration behavior decreased at doses both above and below these, and extinction followed the substitution of saline for nicotine. Total session drug intake increased with unit dose up to a maximal value of approximately 0.5 mg/kg at 0.03 mg/kg/infusion, but did not increase further at the 0.06 mg/kg/infusion dose. A decrease in the time-out duration at the dose of 0.03 mg/kg/infusion also did not change the total session intake of nicotine. It is suggested that nicotine intake is controlled both by the total amount of drug obtained and by the magnitude of the unit dose. These results demonstrate that intravenous nicotine can maintain substantial self-administration behavior in rodents.     

Cocaine self-administration in monkeys: effects on the acquisition and performance of response sequences

A three-component multiple schedule of intravenous cocaine self-administration (0.01-0.3 mg/kg), repeated acquisition and performance was used to examine the effects of self-administered cocaine on learning in rhesus monkeys. A 0.03 mg/kg infusion of cocaine maintained reliable self-administration without markedly decreasing overall response rate or increasing the percentage of errors in the acquisition and performance components in which food was presented. When saline was substituted for 0.03 mg/kg of cocaine, there was little or no effect on responding in the acquisition or performance components while the number of infusions and response rate in the self-administration component decreased. These effects occurred to a greater extent under a FR 90 schedule (Experiment 2) as compared to a FR 30 schedule (Experiment 1) of cocaine self administration. Substitution of higher infusion doses of cocaine also decreased response rate and the number of infusions in the self-administration components, and substantially decreased responding in the acquisition components; decreases in overall accuracy of responding were evident when responding in this schedule component occurred. Taken together, these data indicate that learning is generally more sensitive than performance to the disruptive effects of self-administered cocaine.     

Smoked heroin self-administration in rhesus monkeys

The purpose of the present study was to evaluate behavioral and pharmacological determinants of smoked heroin self-administration. Eight rhesus monkeys were trained to self-administer smoked heroin under a chained fixed-ratio (FR, 64-1024) for lever presses, FR 5 for inhalations schedule during daily experimental sessions. Demand for heroin was determined by plotting consumption (smoke deliveries) as a function of price which was varied by increasing the FR lever press requirement from 64 to 1024. The heroin demand curve was compared to that obtained with smoked cocaine base. Dose-effect determinations were obtained by varying the unit dose of heroin from 0.025 to 1.6 mg/kg per delivery. Pretreatment with naloxone (0.01–1.0 mg/kg IM, 10 min presession) and substitution tests with the peripherally acting opioid loperamide (0.1 mg/kg per delivery) were also conducted. Deliveries of smoked heroin decreased, but lever responding per delivery increased as the FR increased. Demand for heroin was elastic and comparable to demand for smoked cocaine base. Varying the dose of heroin available for self-administration resulted in an asymptotic dose-effect curve. Naloxone pretreatment produced dose-dependent decreases in heroin self-administration. Substitution of loperamide for heroin produced extinction-like responding within one or two sessions, with the total smoke deliveries decreasing by 80% of heroin levels within 8–15 days. Reinstatement of heroin resulted in a rapid return to baseline levels of self-administration. These data suggest that rhesus monkeys will readily and reliably self-administer heroin via the inhalation route, and behavioral and pharmacological manipulations indicate that smoked heroin functioned as a positive reinforcer.     

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.     

Effect of bupropion on nicotine self-administration in rats

RATIONALE AND OBJECTIVE: The mechanisms underlying the therapeutic efficacy of bupropion as a smoking cessation agent are unknown. Bupropion inhibits monoamine uptake as well as neuronal nicotinic receptor (nAChR) function. The present study compared effects of bupropion on nicotine self-administration to those of other stimulant drugs (methamphetamine and apomorphine) that lack nAChR activity in order to determine its mechanism of action. To determine the specificity of bupropion-induced changes in nicotine self-administration, the ability of bupropion to alter sucrose-maintained responding or amphetamine self-administration was determined. METHODS: In nicotine and amphetamine self-administration and sucrose-maintained responding experiments, rats responded for nicotine (0.01 or 0.02 mg/kg per infusion, IV), amphetamine (0.2 mg/kg per infusion, IV) and sucrose pellets (45 mg), respectively, on a fixed ratio 5 schedule. Once responding stabilized, rats were pretreated 15 min before the session with bupropion (1-78 mg/kg) or vehicle. The ability of methamphetamine (0.3-3 mg/kg) or apomorphine (0.01-0.2 mg/kg) to alter responding for nicotine (0.02 mg/kg per infusion, IV) was determined. RESULTS: Bupropion produced a biphasic dose-response pattern at both nicotine infusion doses, increasing infusions at low bupropion doses and decreasing infusions at high bupropion doses. Methamphetamine produced a similar biphasic pattern, whereas apomorphine only decreased nicotine infusions at high doses. Bupropion dose-dependently decreased responding for sucrose and amphetamine. CONCLUSIONS: These results suggest that high bupropion doses decrease responding nonspecifically; whereas low bupropion doses selectively increase responding for nicotine. The increase in nicotine self-administration is likely due to inhibition of dopamine and norepinephrine transporters, combined with inhibition of nAChRs.     

Influence of sex, estrous cycle, and drug-onset age on cocaine self-administration in rats (Rattus norvegicus)

The influence of sex, phase of the estrous cycle, and age of drug onset on cocaine self-administration was examined. Adult male, adult female, and adolescent male rats (Rattus norvegicus) were evaluated using low fixed-ratio (FR) schedules of drug delivery with a single fixed cocaine unit dose or a range of cocaine unit doses with a single FR schedule. Sex differences in adults were observed for mg/kg consumption of the 3.0-mg/kg unit dose, with consumption being significantly less in estrus females than in males. Over the estrous cycle, mg/kg consumption of this unit dose was significantly less during estrus than during metestrus-diestrus. Differences due to age of drug onset were also observed, with mg/kg consumption of the 3.0-mg/kg unit dose being significantly less in adolescent males than adult males or adult females during metestrus-diestrus. In contrast, these various groups did not have significantly different mg/kg intakes of cocaine unit doses <3.0 mg/kg, nor did they significantly differ in the rates and patterns of responding and number of infusions earned as a function of FR schedule or unit dose of cocaine available. The role of sex, estrus cycle, and drug-onset age on cocaine self-administration appears to be minimal under these experimental conditions. Experimental conditions that favor no sex or age differences in cocaine intake (1.0-mg/kg unit dose and low FR) may be useful for evaluating potential sex or age differences in the consequences of cocaine self-administration more reliably, as cocaine intake would not be an uncontrolled factor.     

D-cycloserine selectively decreases nicotine self-administration in rats with low baseline levels of response

Expanding the variety of treatments available to aid smoking cessation will allow the treatments to be customized to particular types of smokers. The key is to understand which subpopulations of smokers respond best to which treatment. This study used adult female Sprague-Dawley rats to evaluate the efficacy of d-cycloserine, a partial NMDA glutamate receptor agonist, in reducing nicotine self-administration. Rats were trained to self-administer nicotine (0.03 mg/kg/infusion, IV) via operant lever response (FR1) with a secondary visual reinforcer. Two studies of d-cycloserine effects on nicotine self-administration were conducted: an acute dose-effect study (0, 10, 20 and 40 mg/kg, sc) and a chronic study with 40 mg/kg given before each test session for two weeks. Effects on rats with low or high pretreatment baseline levels of nicotine self-administration were assessed. In the acute study there was a significant interaction of d-cycloserine × baseline level of nicotine self-administration. In the low baseline group, 10 mg/kg d-cycloserine significantly decreased nicotine self-administration. In the high baseline group, 40 mg/kg significantly increased nicotine self-administration. In the repeated injection study, there was also a significant interaction of d-cycloserine × baseline level of nicotine self-administration. Chronic d-cycloserine significantly reduced nicotine self-administration selectively in rats with low baseline nicotine use, but was ineffective with the rats with higher levels of baseline nicotine self-administration. NMDA glutamate treatments may be particularly useful in helping lighter smokers successfully quit smoking, highlighting the need for diverse treatments for different types of smokers.     

Reinforcer interactions under concurrent schedules of food, water, and intravenous cocaine

Rats housed in three-lever, operant-conditioning chambers were trained under a concurrent, chained fixed-ratio 1, fixed-ratio 9 schedule (conc chain FR1 FR9) of food and water deliveries. After stable patterns of food and water intake were observed, the rats were prepared with intravenous catheters and a drug self-administration option was added to the schedule. Cocaine infusions (0.33 mg/infusion) were available for only 6 h (09.00 h-15.00 h), while access to food and water was available for 24 h. Addition of the cocaine option produced a minimal decrease in food and water intake and a considerable disruption ruption of food and water intake patterns. Changes in the cocaine dose (0.08-0.84 mg/infusion) did not alter responding on the levers resulting in either food or water deliveries. Cocaine self-administration, however, showed an inverted "U" shaped function as the dose of cocaine was increased. Drug extinction probes resulted in a significant increase in responding on the levers resulting in food and water deliveries and substantial decreases on the lever previously resulting in cocaine infusions. Twenty-four hour food extinction probes decreased responding on the levers resulting in food and water deliveries and produced a modest decrease in the self-administration of cocaine.     

Opiate antagonists reduce cocaine but not nicotine self-administration

Rats were trained to self-administer cocaine in 1-h sessions on a fixed ratio 5 (FR5) schedule of reinforcement. Acquisition was carried out at a unit dose of 0.3 mg/kg and responding was then stabilized at cocaine doses of 0.1, 0.3, and 1.0 mg/kg/infusion. Pretreatments with naltrexone (0.1-10 mg/kg, SC) 20 min prior to the start of self-administration sessions resulted in decreases in cocaine self-administration at doses of 0.1 and 0.3 mg/kg/infusion, but not at 1.0 mg/kg/infusion. Decreases depended on the dose of naltrexone used, with greater decreases in self-administration occurring at higher antagonist doses. In addition, treatment with the opiate antagonist naloxone also reduced cocaine self-administration at a unit dose of 0.3 mg/kg. A group of rats trained to self-administer nicotine at a dose of 0.03 mg/kg/infusion on the same schedule of reinforcement was unaffected by naltrexone treatment. These results may indicate that an endogenous opiate system plays a role in cocaine reinforcement.     

Bupropion differentially impacts acquisition of methamphetamine self-administration and sucrose-maintained behavior

Bupropion reduces the subjective effects and cue-induced craving for methamphetamine in humans. Given these effects of bupropion on methamphetamine in humans and its widespread clinical use, a preclinical model of drug-taking was used to determine if pretreatment with bupropion would alter the acquisition of methamphetamine self-administration. During acquisition, rats were given saline or bupropion (30 or 60 mg/kg, IP) 5 min before a 60-min session. For the first 8 days, each response on the active lever produced an infusion of methamphetamine (0.025 mg/kg). Responding on the inactive lever had no programmed consequence. This FR1 schedule was then increased to an FR3 for 4 more days. In a parallel study, the identical procedures were used to test the impact of bupropion on sucrose-maintained responding. Bupropion pretreatment decreased the number of methamphetamine infusions and sucrose deliveries earned on an FR1 and FR3. However, bupropion pretreatment only delayed discrimination between the active and inactive levers in the methamphetamine self-administration rats. Discrimination between active and inactive levers was acquired in all groups in the sucrose experiment regardless of pretreatment condition. Combined, these results suggest that bupropion has a more general effect within the appetitive/reward system of the brain rather than having complete specificity for methamphetamine.