Diurnal patterns of cocaine and heroin self-administration in rhesus monkeys responding under a schedule of multiple daily sessions

A number of non-pharmacological factors have been shown to influence drug self-administration in experimental animals. This report examines diurnal changes in drug self-administration by rhesus monkeys trained to self-administer food (1gm fruit-flavored pellets) and cocaine (0.01 or 0.032mg/kg/injection) under a second order FR4 (VR16:S) schedule during four daily food and drug self-administration sessions. Saline, different unit doses of cocaine (0.001-0.1mg/kg/injection) or different unit doses of heroin (0.0001-0.01mg/kg/injection) were substituted for the maintenance dose of cocaine during drug sessions. Dose-effect curves relating unit dose of cocaine or heroin to the number of injections per session displayed an inverted U-shape during each of the four daily drug sessions. When 0.032mg/kg/injection cocaine or 0.0032mg/kg/injection heroin were available, monkeys usually self-administered the maximum number of injections during all four drug sessions. Substitution of saline or lower unit doses of cocaine (0.001-0.01mg/kg/injection) or heroin (0.0001-0.001mg/kg/injection) decreased the number of injections/session; however, these decreases were consistently greater during the evening (20.00-21.00h) and morning (07.00-08.00h) sessions than during the afternoon sessions (12.00-13.00h and 16.00-17.00h). As a result, the ascending limbs of the cocaine and heroin dose-effect curves for the evening and morning sessions were shifted to the right of the ascending limbs of the dose-effect curves for the afternoon sessions. Moreover, when saline was substituted for cocaine for only two sessions per day, drug self-administration decreased more during the evening and morning sessions even when the cocaine was available during those sessions. These findings suggest a diurnal variation in cocaine and heroin self-administration. Specifically, drug self-administration during the evening and morning sessions appears to be more sensitive to a decrease in reinforcer magnitude than responding during the afternoon sessions. These findings confirm and extend previous reports of the influence of non-pharmacological factors on drug self-administration.     

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.     

Heroin self-administration by rats: influence of dose and physical dependence

Lever-pressing behavior reinforced by intravenous infusion of various concentrations of heroin, and consequent development of physical dependence, were examined in rats. In addition, the influence of opiate dependence, and of its disappearance following withdrawal, on heroin self-administration were investigated. It was found that intravenous self-administration of heroin at 0.03 mg/kg/infusion maintained self-administration behavior without producing physical dependence. Total responses per session decreased with increasing unit dose of heroin, whereas the total amount of drug self-administered was directly related to unit dose. Significantly greater numbers of withdrawal signs and percentage body weight losses in response to naloxone injections were observed following self-administration of heroin at 0.1, 0.3 or 0.6 mg/kg/infusion. Intake of heroin at 0.03 mg/kg/infusion, but not at 0.1, 0.3 or 0.6 mg/kg/infusion, was found to increase significantly in opiate-dependent and postdependent animals. These findings support the previous use of 0.03 mg/kg/infusion as a suitable dose for illustrating the reinforcing effect of heroin without the influence of physical dependence.     

Pharmacological regulation of intravenous cocaine and heroin self-administration in rats: a variable dose paradigm

Rats were trained to intravenously self-administer unit doses of cocaine or heroin. Constant supplemental infusion of a portion of each rat's mean hourly intake increased the mean time between successive infusions, but the effect was not statistically reliable from the data of a small sample of animals. A variable dose per infusion (VDI) paradigm was developed which enabled testing of several unit doses of cocaine or heroin within single test sessions. Unit doses of 0.5, 1.0, and 2.0 mg/kg of cocaine or 0.025, 0.05, and 0.1 mg/kg of heroin were made available with equal frequency but in unpredictable sequence to independent groups of rats. The mean time between successive infusions was linearly related to the log dose of the preceding infusion in each case. Pimozide, a drug thought to attenuate the reinforcing effects of both cocaine and heroin, shifted the functions without disturbing the dose-response relations; pimozide reliably decreased the time between successive cocaine infusions across a 4-fold range of pimozide doses. The effect of pimozide on heroin self-administration was not statistically significant and disrupted responding at the highest dose tested. This paradigm thus offers a within-session assessment of the dose-dependent duration of reinforcing actions of cocaine and heroin, and this assessment is sensitive to at least one challenge of intravenous drug reinforcement.     

The effects of chronic buprenorphine on intake of heroin and cocaine in rats and its effects on nucleus accumbens dopamine levels during self-administration

Rationale Buprenorphine reduces both heroin and cocaine intake in opioid addicts, but the mechanisms remain unclear.Objectives To determine the effects of chronic buprenorphine treatment on intake of heroin and/or cocaine and measure nucleus accumbens (NAc) dopamine (DA) levels during self-administration.Methods In experiment 1, plasma levels of buprenorphine were determined in rats with buprenorphine osmotic minipumps (3.0 mg/kg/day) using an ELISA. In experiment 2, rats self-administered (FR1) one dose of heroin [(0.025, 0.05, or 0.1 mg/kg/infusion (inf)] and one dose of cocaine (0.25, 0.5, or 1.0 mg/kg/inf) before and under sham or chronic buprenorphine treatment (1.5 or 3.0 mg/kg/day). In experiment 3, the effect of sham or chronic buprenorphine treatment (3.0) on heroin (0.05 mg/kg/inf) or cocaine (0.5 mg/kg/inf) self-administration under FR5 and progressive ratio (PR) schedules was evaluated. In experiment 4, in vivo microdialysis sampling from the NAc was carried out during heroin (0.05 mg/kg/inf) or cocaine (0.5 mg/kg/inf) self-administration (FR1) under sham or buprenorphine treatment (3.0).Results Buprenorphine levels in plasma were stable over time. Buprenorphine treatment had no effect on total heroin intake at any dose or under any schedule, whereas it suppressed cocaine intake at all doses and under all schedules. Buprenorphine enhanced basal levels of DA, attenuated the NAc DA response to heroin, and enhanced the DA response to cocaine. It is interesting to note that buprenorphine increased the latency to respond to drug-associated cues at the start of self-administration sessions.Conclusions Chronic buprenorphine reduces cocaine, but not heroin, intake and possibly reduces drug seeking by reducing the salience of the drug-associated cues.     

'Nicotine deprivation effect' in rats with intermittent 23-hour access to intravenous nicotine self-administration

Our previous work demonstrates that rats allowed extended 23-hour access to intravenous nicotine self-administration (IVSA) display voluntary, dose-related levels of nicotine intake (i.e., higher doses result in higher intake) that remain stable across 40 days. This study examined whether an escalating dose regimen with intermittent abstinence periods produces different levels of nicotine intake relative to those observed during continuous access to a fixed unit dose. Rats were trained to nose-poke for food and water in 23-hour sessions prior to and after recovery from surgical implantation of jugular catheters. Animals (n=12) then were given access to nicotine IVSA in 4-day cycles, each separated by three intervening days of abstinence in their home cage. The unit dose available for nicotine IVSA was increased between cycles as follows: 0.015, 0.03, 0.06, 0.09 mg/kg/0.1 ml infusion/1 s, fixed ratio 1. Control rats (n=6) were given access to saline for five 4-day IVSA periods. Nicotine dependence was assessed by examining physical signs of withdrawal following an injection of the nicotinic antagonist mecamylamine (1.5 mg/kg, i.p.). Nicotine intake dose-dependently increased between cycles. Within each cycle, nicotine intake was highest on the first day after abstinence and decreased over the next 3 days of continuous access. Mecamylamine produced a significant increase in overt signs of withdrawal in the 23-hour access animals comparable to that observed in previous studies of nicotine dependence. Our findings suggest that abstinence from nicotine may produce a "deprivation effect" in nicotine-dependent rats. In addition, intermittent access to increasing unit doses appears to produce higher levels of nicotine intake than continuous access to a constant unit nicotine dose.     

Olanzapine-induced suppression of cocaine self-administration in rhesus monkeys.

The neuropharmacological profile of the atypical antipsychotic, olanzapine, is consistent with a potentially useful medication for cocaine abuse. The present study utilized an i.v. drug self-administration paradigm in nonhuman primates to obtain definitive evidence regarding the effectiveness of olanzapine to modulate the reinforcing effects of cocaine. The effects of olanzapine were compared directly to those of the neuroleptic, haloperidol. Rhesus monkeys (n=7) were trained to self-administer cocaine (0.03-0.3 mg/kg/injection) under a second-order, fixed-interval 600-s schedule with fixed ratio 20 components. Experimental sessions comprised five consecutive fixed intervals, each followed by a 1-min timeout. In drug-interaction experiments, a single dose of olanzapine (0.03-0.3 mg/kg) or haloperidol (0.01-0.03 mg/kg) was administered i.v. 15 min presession for at least three consecutive sessions. In drug-substitution experiments, different doses of olanzapine (0.01-0.1 mg/kg/injection) were substituted for cocaine until responding stabilized. Olanzapine caused dose-related decreases in cocaine self-administration at pretreatment doses that had no overt behavioral effects indicative of sedation. A dose of 0.1 mg/kg eliminated cocaine self-administration in all subjects. In contrast, doses of haloperidol that suppressed cocaine self-administration induced marked sedation and catalepsy. Olanzapine failed to maintain self-administration behavior above saline extinction levels over a range of unit doses. In vivo microdialysis experiments in a second group of awake rhesus monkeys (n=3) confirmed previous reports in rodents that olanzapine effectively increases extracellular dopamine in ventral striatum. The dose of olanzapine that markedly suppressed cocaine self-administration behavior increased dopamine to approximately 190% of control values. Lastly, pretreatment with fluoxetine had no systematic effect on olanzapine-induced increases in striatal dopamine. The results indicate that olanzapine can effectively suppress cocaine self-administration behavior in nonhuman primates at doses that enhance dopamine release but do not maintain drug self-administration.     

Motivation of heroin-seeking elicited by drug-associated cues is related to total amount of heroin exposure during self-administration in rats

Conditioned stimuli (CSs) previously associated with heroin are critically involved in activating long-lasting relapse and compulsive drug seeking. This study examined the magnitude of heroin seeking induced by drug-related cues in relation to the total amount of drug exposure during training. Five groups of male Sprague-Dawley rats (n=6/group) were trained by the nose-poking response to self-administer different doses of heroin (0, 0.01, 0.025, 0.05, and 0.1 mg/kg per infusion respectively, one 4-h session daily, limited to 25 infusions per session) under an identical progressive ratio schedule with gradual incremental response requirements. All the rats established stable heroin self-administration within 14 days of self-administration training, and the time needed to obtain all the 25 heroin infusions decreased across sessions. After 14 days of abstinence, heroin seeking elicited by contextual cues (self-administration chamber) or discrete contingent CSs previously associated with heroin infusions was measured in two consecutive 1-h test phases. During both test phases, the rats trained with heroin even at the lowest dose (0.01 mg/kg) showed higher active responses than saline controls, and the active responses were also higher in rats trained with doses of 0.025, 0.05, and 0.10 mg/kg in comparison with those trained with a dose of 0.01 mg/kg. There was no observable dose-dependence increase of responses at doses above 0.025 mg/kg. The results suggested that an increased motivation to seek heroin induced by drug-related cues is associated with the total amount of heroin intake.     

Intraventricular self-administration of heroin in the rat: reward seems dissociated from analgesia and physical dependence

Experimentally naive rats were implanted with a cannula in the lateral ventricle of the brain and were allowed to self-administer heroin in doses of 0.125, 0.25, 0.5, 1 or 2 micrograms/infusion or placebo for five daily sessions of 3 h. The number of self-injections was related to the unit dose in an inverted U-shaped manner: the 0.5 microgram/infusion dose induced the highest infusion rate. The total heroin intake was proportionally related to the unit dose. A hot-plate test performed immediately after the fourth session revealed no analgesic effects in any of the groups that self-administered heroin. A naloxone (10 mg/kg) challenge given immediately after the fifth session induced very mild withdrawal signs only in the group that administered the highest dose of heroin. The results indicate that rats readily acquire intraventricular heroin self-administration behaviour and suggest that the rewarding effects of heroin can be dissociated from its analgesic and physical dependence-inducing effects.     

Intracerebral self-administration of the cannabinoid receptor agonist CP 55,940 in the rat: interaction with the opioid system

The effect of CP 55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclo-hesanol], heroin and etonitazene on intracerebroventricular (i.c.v.) self-administration in a free-choice procedure was evaluated in rats. Animals were trained in 1-h daily sessions with a continuous reinforcement schedule to press two active levers to obtain the vehicle of each drug. Then, when a stable baseline was reached, each drug could be self-administered by pressing the lever found to be less preferred during training, while the vehicle came from the other. The number of bar pressings associated with the delivery of increasing unit doses of CP 55,940 (0.1, 0.2, 0.4, 0.8, 1.6 microg/2 microl/infusion), heroin (0.125, 0.25, 0.5, 1, 2 microg/2 microl/infusion) or etonitazene (0.1--0.2--0.5--1 microg/ 2 microl/infusion) and with the delivery of the corresponding vehicle was fitted by symmetrical parabolas. The mean drug intake was linearly related to the log of self-administered drugs. Pretreatment with SR141716A [N-piperidino-5-(4-chlorophenyl)1-(2,4-dichloro-phenyl)-4-methylpyrazole-3-carboxamide] (0.5 mg/kg) or naloxone HCl (2 mg/kg/i.p.) 15 min before each daily session reduced the self-administration of both CP 55,940 and heroin. The combination of CP 55,940 with heroin or etonitazene reduced the number of drug-associated lever pressings compared to that obtained with the maximal reinforcing unit dose of each drug alone. These findings suggest there may be a strong interaction between opioids and the cannabinoid system.     

Influence of 5-HT3 receptor antagonists and the indirect 5-HT agonist,dexfenfluramine, on heroin self-administration in rats

The purpose of the present study was to examine the effects of the 5-HT₃ antagonists ondansetron and MDL72222, and the 5-HT releaser and reuptake inhibitor dexfenfluramine, on intravenous heroin self-administration by Wistar rats. Using separate squads of animals, two separate schedules of heroin reinforcement were used; a relatively low dose (0.03 mg/kg per infusion) made available under a FR5 schedule for 1 h each day, and a moderate heroin dose (0.1 mg/kg per infusion) available under a FR1 schedule for 2 h each day. Following the acquisition of stable levels of responding across days, both naloxone pretreatment (0.25 mg/kg SC) and halving the heroin infusion dose produced increases in operant responding for heroin at each concentration. Neither ondansetron (0.01–1 mg/kg SC) nor MDL72222 (0.1–3 mg/kg SC) pretreatment influenced heroin self-administration. Chronic treatment (5 day) of ondansetron (0.01–0.1 mg/kg) was similarly ineffective. However, dexfenfluramine (0.5–2.5 mg/kg IP) consistently reduced heroin self-administration at doses producing only modest decreases in food responding. These findings are in contrast to place conditioning studies, which show that 5-HT₃ antagonists but not indirect 5-HT agonists block a morphine-induced place preference. Reasons for such discrepancies remain to be determined.     

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.     

Ketoconazole reduces low dose cocaine self-administration in rats

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

Heroin self-administration under a second-order schedule of reinforcement: acquisition and maintenance of heroin-seeking behaviour in rats

RATIONALE: Second-order schedules of heroin self-administration provide a method of measuring heroin-seeking behaviour independently of the effects of the drug on motor behaviour and of investigating the role of heroin-associated stimuli in such heroin-seeking behaviour. OBJECTIVES: These experiments aimed to establish a second-order schedule of heroin self-administration in rats, similar to that already established in this laboratory for cocaine self-administration and to investigate the role of discrete heroin-associated stimuli in the maintenance of heroin-seeking behaviour under a second-order schedule of reinforcement. METHODS: Heroin i.v. self-administration (0.04 mg/infusion) was initially contingent upon a lever press, and each infusion was paired with presentation of a 20-s light-conditioned stimulus (CS). Following acquisition of heroin self-administration, the response requirement was progressively increased so that, ultimately, responding was maintained under a fixed interval (FI) 15 min [fixed ratio (FR)5:S] second-order schedule. The effects of varying the dose of heroin (0.01 mg and 0.08 mg/infusion) and pre-treatment with the mu-opiate receptor antagonist, naloxone, on responding under a FI15(FR5:S) schedule were investigated. In addition, the role of the heroin-associated CS on responding was assessed by measuring the effects of omitting the CS during heroin-seeking behaviour and during extinction of responding, as well as the effect of CS presentation on the reinstatement of heroin-seeking behaviour following extinction. RESULTS: A second-order schedule of heroin self-administration was established. There were no clear effects on heroin-seeking behaviour of increasing or decreasing the dose of heroin. Although no effect of naloxone pre-treatment was seen on heroin-seeking behaviour during the first, drug-free interval of responding, an extinction-like pattern of responding was seen in that interval during subsequent sessions. Omission of the light CS resulted in a reduction in levels of responding for i.v. heroin, indicating its role in maintaining heroin-seeking behaviour. However, under extinction conditions, response-contingent CS presentations did not affect the rate of extinction, nor did non-contingent presentations of the CS following extinction reinstate heroin-seeking behaviour. CONCLUSIONS: These experiments have established a method of measuring heroin-seeking behaviour in rats by adopting a second-order schedule of i.v. heroin self-administration. The results indicate a relatively weak impact of discrete, heroin-associated cues on heroin-seeking behaviour relative to cocaine-seeking behaviour studied under similar conditions.     

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.     

Unlimited access to heroin self-administration: independent motivational markers of opiate dependence.

The goal of the present study was to develop and validate an animal model of unlimited access to intravenous heroin self-administration combined with responding for food and water to characterize the transition to drug dependence. Male Wistar rats were allowed to lever press for heroin (60 microg/kg/0.1 ml infusion/s; fixed ratio 1; 20-s time out) and nosepoke for food and water in consecutive, daily 23-h sessions. Daily heroin intake increased over days, reaching significance by Day 14. Drug-taking increased across the circadian cycle, reflected as increases in both the nocturnal peak and diurnal nadir of heroin intake. Changes in the circadian pattern of food intake and meal patterning preceded and paralleled the changes in heroin intake. By Day 7, the circadian amplitude of feeding was blunted. Nocturnal intake decreased because rats consumed smaller and briefer meals. Diurnal intake increased due to increased meal frequency, whereas total daily food intake decreased. To control for time or experience in the self-administration boxes as a possible confound, rats with saline (no drug) tethers were tested and did not display significant changes in food intake pattern. Body weight gain slowed slightly in heroin rats relative to saline controls. Separate groups of rats revealed that significant physical dependence as measured by physical signs of opiate withdrawal following a naloxone injection (1.0 mg/kg, subcutaneous (s.c.)) was reached by Day 14. Significant increases in heroin intake could be produced using low doses of naloxone (0.003-0.03 mg/kg, s.c.) on days 28-31 of heroin access. After 6 weeks of heroin self-administration, rats injected with buprenorphine (0, 0.01, 0.04, and 0.2 mg/kg, s.c.) showed a dose-dependent reduction in heroin intake. Changes in the pattern of drug and food intake in the present unlimited heroin access model may serve as independent motivational markers for the transition to a drug-dependent state.     

Self-administration of remifentanil, an ultra-short acting opioid, under continuous and progressive-ratio schedules of reinforcement in rats

RATIONALE: Remifentanil is a mu-opioid agonist with an exceptionally short duration of action. Evaluating remifentanil's effects within the self-administration model of drug abuse may provide insight into the relationship between a drug's duration of action and its effectiveness as a reinforcer. OBJECTIVES: This study was conducted to establish a dose-effect function for intravenous remifentanil self-administration in rats and to assess the drug's ability to maintain responding under intermittent schedules of reinforcement. METHODS: Inter-infusion intervals were recorded under two continuous-reinforcement schedules of remifentanil self-administration. In the fixed-dose schedule, the unit dose (0.25-32 micrograms/kg) was held constant within sessions but varied across sessions. In the variable-dose schedule, four different doses were self-administered in random order within each session. For comparison, heroin (6.25-125 micrograms/kg) was studied with the variable-dose schedule. Remifentanil and heroin were also compared under a progressive-ratio schedule of reinforcement in which the response requirements increased exponentially with each successive infusion until responding ceased within each session. RESULTS: Under the continuous-reinforcement schedules, inter-infusion intervals for both drugs increased monotonically as a function of dose, with the remifentanil curve being considerably flatter. Under the progressive-ratio schedule, breaking points varied as an inverted-U shaped function, and the highest breaking points maintained by remifentanil and heroin were similar. At the doses that maintained the highest breaking points under the progressive-ratio schedule, post-infusion pauses under the continuous-reinforcement schedule were about three times shorter with remifentanil than with heroin. CONCLUSIONS: Although rates of self-administration are clearly influenced by a drug's duration of action, the ability to maintain responding under intermittent schedules of reinforcement may be independent of duration of action.     

Influence of a conditioned light stimulus on cocaine self-administration in rats

RATIONALE: A number of studies have suggested that the continued presentation of stimuli associated with cocaine may contribute to drug-seeking and drug-taking. The influence of conditioned stimuli on the maintenance of self-administration has not, however, been systematically investigated. OBJECTIVES: This study was designed to determine whether omission of a stimulus that had been paired with self-administered cocaine would influence the maintenance of cocaine self-administration and whether the effect was dependent on cocaine dose or session length. METHODS: During self-administration training, self-administered cocaine infusions were always paired with the illumination of a light. On test days, self-administered cocaine was delivered either with or without the cocaine-associated cue. For one group of rats, responding maintained by cocaine (0.50 mg/kg per infusion) was measured during daily 18-h sessions. For other groups, responding maintained by additional doses of cocaine (0.125, 0.25, or 1.0 mg/kg per infusion) was measured during daily 8-h sessions. For a final group, daily test sessions (4-5 h) produced the dose-effect curve (0.015-1.0 mg/kg per infusion) by repeatedly reducing the cocaine dose from a starting dose of 1.0 mg/kg per infusion. RESULTS: Removal of the light cue decreased cocaine self-administration. The magnitude of this effect was dependent on the dose of self-administered cocaine and on the test session duration. Greater decrements in responding were produced as session length increased or when low doses of cocaine were self-administered. CONCLUSIONS: These findings demonstrate that in the absence of a cocaine-associated stimulus, cocaine self-administration is attenuated and that maintenance of cocaine self-administration is maximally affected by the presence or absence of the conditioned stimulus when the self-administered dose is low and/or when session duration is long.     

The serotonin/noradrenaline reuptake inhibitor venlafaxine attenuates acquisition, but not maintenance, of intravenous self-administration of heroin in rats

Opioids and antidepressants are frequently used for the treatment of various pain conditions. A combination of both drug classes may be more effective than either treatment alone, and combined treatment with an antidepressant may result in an opiate-sparing effect. Although it has been shown that antidepressants can attenuate self-administration of psychomotor stimulant and depressant drugs, it is not known whether they also attenuate self-administration of opiates. To determine whether venlafaxine, a serotonin/noradrenaline reuptake inhibitor with antidepressive and analgesic properties, affects acquisition and maintenance of intravenous heroin self-administration in rats, male Long-Evans rats were trained to press a lever in order to receive heroin (0.05 mg/kg/infusion) under a fixed ratio or a progressive ratio schedule. A control group was trained in a fixed ratio food-reinforced operant procedure. The effect of venlafaxine on operant responding for heroin and food was assessed both during acquisition and, in separate groups of rats, during maintenance (i.e., after acquisition) of self-administration behaviour. Daily treatment with venlafaxine (10 mg/kg i.p.) before the operant session attenuated the acquisition of responding for heroin, but not for food. However, when tested during the maintenance phase in rats showing stable responding, acute treatment with venlafaxine only marginally affected operant responding for heroin under a fixed ratio:10 schedule of reinforcement, and neither acute nor subchronic (once daily during 4 weeks) venlafaxine treatment affected responding under a progressive ratio schedule. Thus, daily treatment with an antidepressant attenuates the acquisition of heroin self-administration in a behaviourally specific manner, while having only marginal effects on maintenance of heroin self-administration.     

The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice

Rationale. Nicotine increases glutamate release in the ventral tegmental area and the nucleus accumbens, and thus enhances dopamine neurotransmission in the mesolimbic system that has been implicated in mediating the rewarding effects of drugs. Metabotropic glutamate receptors 5 (mGluR5) are found in the nucleus accumbens and may play a role in modulating the post-synaptic response to both glutamate and dopamine. Objectives. The present study investigated the effects of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on intravenous nicotine self-administration in Wistar rats and DBA/2J mice. Methods. Rats were allowed to self-administer nicotine (0.01, 0.03 mg/kg per infusion) or respond for food on one of two fixed-ratio 5 schedules of reinforcement. Drug-naive mice were acutely exposed, in pairs, to nicotine (0, 0.016, 0.048, 0.16, 0.48 μg per infusion) self-administration under a fixed ratio 1 schedule of reinforcement, with one subject controlling the delivery of nicotine to both subjects in each pair. Results. MPEP (1–9 mg/kg) dose-dependently reduced nicotine self-administration with no effect on food-maintained responding in the rats. Self-administration of nicotine was obtained only at the 0.048 μg per infusion dose by the mice, and administration of MPEP (5–20 mg/kg) decreased nicotine self-administration response rates in the mice. Conclusions. These results indicate that blockade of mGluR5 decreased nicotine self-administration in both rats and mice, and are consistent with findings showing a role of mGluR5 in cocaine self-administration. It is postulated that mGluR5 plays an essential role in mediating the reinforcing effects of nicotine, possibly but not exclusively, via modulation of mesolimbic dopaminergic neurotransmission. Electronic Publication