Fixed-interval 5-min Schedule Research Articles

Regional elevations in microglial activation and cerebral glucose utilization in frontal white matter tracts of rhesus monkeys following prolonged cocaine self-administration.

It has been shown that exposure to cocaine can result in neuroinflammatory responses. Microglia, the resident CNS immune cells, undergo a transition to an activated state when challenged. In rodents, and possibly humans, cocaine exposure activates microglia. The goal of this study was to assess the extent and magnitude of microglial activation in rhesus monkeys with an extensive history of cocaine self-administration. Male rhesus monkeys (N = 4/group) were trained to respond on a fixed-interval 3-min schedule of food or 0.3mg/kg/injection cocaine presentation (30 reinforcers/session) for 300 sessions. At the end of the final session, monkeys were administered 2-[14C]deoxyglucose intravenously and 45min later euthanized. Brain sections were used for autoradiographic assessments of glucose utilization and for microglia activation with [3H]PK11195, a marker for the microglial 18-kDa translocator protein. There were no group differences in gray matter [3H]PK11195 binding, while binding was significantly greater in cocaine self-administration animals as compared to food controls in 8 of the 11 white matter tracts measured at the striatal level. Binding did not differ from control at other levels. There were also significant increases in white matter local cerebral glucose utilization at the striatal level, which were positively correlated with [3H]PK11195 binding. The present findings demonstrate an elevation in [3H]PK11195 binding in forebrain white matter tracts of nonhuman primates with a prolonged history of cocaine self-administration. These elevations were also associated with greater cerebral metabolic rates. These data suggest that white matter deficits may contribute to behavioral, motivational, and cognitive impairments observed in cocaine abusers.

Influence of experimental history on nicotine self-administration in squirrel monkeys.

Methods for establishing robust long-term self-administration of intravenous (i.v.) nicotine, the primary psychoactive agent in tobacco, are not well-established in laboratory animals. Here, we examine the use of a fading procedure to establish robust and consistent i.v. nicotine self-administration under second-order schedule conditions in squirrel monkeys. First, self-administration behavior was developed in two groups of male squirrel monkeys using a second-order fixed-interval 5-min schedule with fixed-ratio 5 units (FI 5-min (FR5: S)). Comparable performances were maintained by i.v. cocaine (0.032mg/kg/injection (inj); group A, n = 3) and the combination of food delivery (20-30% condensed milk) and 0.01mg/kg/inj i.v. nicotine (group B, n = 3). Subsequently, the concentration of condensed milk was gradually reduced to zero in the second group and self-administration behavior was maintained by i.v. nicotine alone. Next, self-administration of a range of doses of i.v. nicotine (0.001-0.032mg/kg/inj) and, in additional experiments, the minor tobacco alkaloid anatabine (0.01-0.18mg/kg/inj) was studied in both groups. Results show that nicotine and anatabine had reinforcing effects in both groups. However, optimal doses of nicotine and anatabine maintained significantly higher rates of i.v. self-administration behavior in subjects trained with the fading procedure than in subjects provided with a history of cocaine-maintained responding. These results illustrate conditions under which robust i.v. nicotine self-administration can be established in squirrel monkeys and the influence of prior experimental history in the expression of reinforcing effects of nicotine and anatabine.

Effects of abstinence from chronic cocaine self-administration on nonhuman primate dorsal and ventral noradrenergic bundle terminal field structures.

Repeated exposure to cocaine is known to dysregulate the norepinephrine system, and norepinephrine has also been implicated as having a role in abstinence and withdrawal. The goal of this study was to determine the effects of exposure to cocaine self-administration and subsequent abstinence on regulatory elements of the norepinephrine system in the nonhuman primate brain. Rhesus monkeys self-administered cocaine (0.3mg/kg/injection, 30 reinforcers/session) under a fixed-interval 3-min schedule of reinforcement for 100 sessions. Animals in the abstinence group then underwent a 30-day period during which no operant responding was conducted, followed by a final session of operant responding. Control animals underwent identical schedules of food reinforcement and abstinence. This duration of cocaine self-administration has been shown previously to increase levels of norepinephrine transporters (NET) in the ventral noradrenergic bundle terminal fields. In contrast, in the current study, abstinence from chronic cocaine self-administration resulted in elevated levels of [(3)H]nisoxetine binding to the NET primarily in dorsal noradrenergic bundle terminal field structures. As compared to food reinforcement, chronic cocaine self-administration resulted in decreased binding of [(3)H]RX821002 to α2-adrenoceptors primarily in limbic-related structures innervated by both dorsal and ventral bundles, as well as elevated binding in the striatum. However, following abstinence from responding for cocaine binding to α2-adrenoceptors was not different than in control animals. These data demonstrate the dynamic nature of the regulation of norepinephrine during cocaine use and abstinence, and provide further evidence that the norepinephrine system should not be overlooked in the search for effective pharmacotherapies for cocaine dependence.

Functional consequences of cocaine re-exposure after discontinuation of cocaine availability

Cocaine users exhibit a wide range of behavioral impairments accompanied by brain structural, neurochemical and functional abnormalities. Metabolic mapping studies in cocaine users and animal models have shown extensive functional alterations throughout the striatum, limbic system, and cortex. Few studies, however, have evaluated the persistence of these effects following cessation of cocaine availability. The purpose of this study, therefore, was to assess the functional effects of re-exposure to cocaine in nonhuman primates after the discontinuation of cocaine self-administration for 30 or 90 days, using the quantitative autoradiographic 2-[14C]deoxyglucose (2DG) method. Rhesus monkeys self-administered cocaine (fixed interval 3-min schedule, 30 infusions per session, 0.3 mg/kg/infusion) for 100 sessions followed by 30 (n = 4) or 90 days (n = 3) during which experimental sessions were not conducted. Food-reinforced control animals (n = 5) underwent identical schedules of reinforcement. Animals were then re-exposed to cocaine or food for one final session and the 2DG method applied immediately after session completion. Compared to controls, re-exposure to cocaine after 30 or 90 day drug-free periods resulted in lower rates of glucose utilization in ventral and dorsal striatum, prefrontal and temporal cortex, limbic system, thalamus, and midbrain. These data demonstrate that vulnerability to the effects of cocaine persists for as long as 90 days after cessation of drug use. While there was some evidence for recovery (fewer brain areas were affected by cocaine re-exposure at 90 days as compared to 30 days), this was not uniform across regions, thus suggesting that recovery occurs at different rates in different brain systems.

DEVELOPMENT OF KEY‐PECKING, PAUSE, AND AMBULATION DURING EXTENDED EXPOSURE TO A FIXED‐INTERVAL SCHEDULE OF REINFORCEMENT

Six pigeons key-pecked under a fixed-interval (FI) 3-min schedule of food presentation. Each pigeon was studied for 200 daily sessions with 15 intervals per session (3,000 total food presentations). Analyses included the examination of latency to first peck (pause), mean rate of key pecking, and ambulation. Characterizations of stable performance were assessed across measures of behavior and evaluated using commonly employed stability criteria. Stability of response rate and pause was identified better by assessments that evaluated variability and trend, rather than just variability. Between-subject differences in rate of acquisition and terminal values of steady-state performance of pause were observed, and stable pause durations took longer to develop than did stable key-pecking rates. Relative variability in response rate and pause duration decreased as the means increased. A temporally organized pattern of key-pecking (the so-called FI scallop) developed within 50 sessions of exposure to the schedule. Overall ambulation decreased during the early sessions of exposure and further analyses showed greater rates of ambulation during the pause than after it for 4 of the 6 pigeons. Performance under the FI 3-min schedule developed relatively slowly, and key-pecking, pause, and ambulation developed at different rates.

Abstinence from Chronic Cocaine Self-Administration Alters Striatal Dopamine Systems in Rhesus Monkeys

Although dysregulation within the dopamine (DA) system is a hallmark feature of chronic cocaine exposure, the question of whether these alterations persist into abstinence remains largely unanswered. Nonhuman primates represent an ideal model in which to assess the effects of abstinence on the DA system following chronic cocaine exposure. In this study, male rhesus monkeys self-administered cocaine (0.3 mg/kg per injection, 30 reinforcers per session) under a fixed-interval 3-min schedule for 100 days followed by either 30 or 90 days abstinence. This duration of cocaine self-administration has been previously shown to decrease DA D2-like receptor densities and increase levels of D1-like receptors and DA transporters (DAT). Responding by control monkeys was maintained by food presentation under an identical protocol and the same abstinence periods. [(3)H]SCH 23390 binding to DA D1 receptors following 30 days of abstinence was significantly higher in all portions of the striatum, compared to control animals, whereas [(3)H]raclopride binding to DA D2 receptors was not different between groups. [(3)H]WIN 35 428 binding to DAT was also significantly higher throughout virtually all portions of the dorsal and ventral striatum following 30 days of abstinence. Following 90 days of abstinence, however, levels of DA D1 receptors and DAT were not different from control values. Although these results indicate that there is eventual recovery of the separate elements of the DA system, they also highlight the dynamic nature of these components during the initial phases of abstinence from chronic cocaine self-administration.

The effects of eticlopride and the selective D 3-antagonist PNU 99194-A on food- and cocaine-maintained responding in rhesus monkeys

The dopamine D 3 receptor is mainly expressed in regions of the brain associated with the limbic system. D 3 receptor blockade may antagonize cocaine reinforcement while producing less severe extrapyramidal side effects than blockade of D 2 receptors. The purpose of the present studies was to evaluate the effects of a selective D 3 receptor antagonist and a non-selective D 2/D 3 receptor antagonist on food- and cocaine-maintained responding under two schedules of cocaine self-administration. Adult male rhesus monkeys were trained to respond under multiple schedules of food (1.0 g pellets) and cocaine (0.01–0.3 mg/kg/injection) presentation. In one experiment ( n = 4), the schedule was a fixed-interval (FI) 3-min and a second study ( n = 6) was conducted using a second-order fixed-ratio 5 (FI 6-min : S) schedule. The D 3 antagonist PNU 99194-A (0.3–3.0 mg/kg), which is 14-fold selective for D 3 relative to D 2 receptors, or the D 2/D 3 antagonist eticlopride (0.001–0.03 mg/kg) was administered immediately prior to the experimental session for at least 5 consecutive sessions. Under the multiple FI 3-min schedule of food and cocaine presentation, PNU 99194-A and eticlopride decreased food- and cocaine-maintained responding in a dose-dependent manner and irrespective of cocaine dose. Under the multiple second-order schedule of food and cocaine presentation, at least one dose of PNU 99194-A and eticlopride decreased cocaine- and food-maintained responding. These findings indicate that PNU 99194-A can decrease operant responding in monkeys, but not in a manner that would suggest selectivity of cocaine- over food-maintained responding. Future studies with more selective D 3 antagonists are needed to better address the role of this receptor subtype in cocaine addiction.

Discriminative stimulus and reinforcing effects of p-fluoro-l-deprenyl in monkeys

para-Fluoro-L-deprenyl (Fludepryl), a halogenated derivative of L-deprenyl, shares structural similarities with amphetamine and may have potential as a medication for psychostimulant abuse. p-Fluoro-L-deprenyl was evaluated for psychomotor stimulant, discriminative stimulus, and reinforcing effects in squirrel monkeys. One group of monkeys was trained under a ten-response fixed-ratio (FR10) schedule of stimulus termination to discriminate between methamphetamine (0.32 mg/kg, i.m.) and saline. Other monkeys were trained to self-administer i.v. cocaine under either a simple FR10 schedule or a second-order fixed-interval 5-min schedule with FR10 components. Full generalization to the methamphetamine-training stimulus was produced by an i.m. dose of 10.0 mg/kg p-fluoro-L-deprenyl. L-Deprenyl and the metabolites of p-fluoro-L-deprenyl, p-fluoro-L-amphetamine, and p-fluoro-L-methylamphetamine were more potent, producing full generalization at doses of 1.0-3.2 mg/kg. Under the FR10 schedule of drug injection, persistent self-administration behavior was maintained by i.v. cocaine injections but not by injections of vehicle or injection doses of p-fluoro-L-deprenyl up to 1.0 mg/kg. However, p-fluoro-L-deprenyl did maintain moderate levels of i.v. self-administration responding under the second-order schedule of drug injection. Peak response rates maintained by 0.1-mg/kg injections of p-fluoro-L-deprenyl were significantly greater than those associated with saline substitution, yet significantly lower than those maintained by cocaine or D-amphetamine. p-Fluoro-L-deprenyl has methamphetamine-like discriminative-stimulus properties in squirrel monkeys that appear at higher doses than for its parent compound, L-deprenyl. It also appears to function as a relatively limited reinforcer of intravenous self-administration behavior in monkeys trained to self-administer i.v. cocaine.

Cocaine- and food-maintained responding under a multiple schedule in rhesus monkeys: environmental context and the effects of a dopamine antagonist.

Environmental context has been shown to influence responding under multiple schedules of food reinforcement and to modify the behavioral effects of drugs. However, no systematic study has been conducted under conditions of cocaine self-administration. The hypothesis was that changes in the magnitude of food reinforcement would affect cocaine-maintained response rates and influence the behavioral potency of a dopamine antagonist to decrease cocaine self-administration. A multiple schedule was used to evaluate the effects of changes in the magnitude of food reinforcement on the self-administration cocaine dose-response curve and on the behavioral potency of a dopamine receptor antagonist to decrease food- and cocaine-maintained responding. Rhesus monkeys (n=3) were trained to self-administer intravenous cocaine under a multiple fixed-interval (FI) 5-min schedule of food and cocaine presentation. Food (one or four pellets) was available in the first and third components and cocaine (saline, 0.01-0.3 mg/kg per injection) was available in the second and fourth components. After completion of cocaine dose-response curves, the effects of the dopamine D(2)/D(3) receptor antagonist 2,3-dimethoxy-N-(9-p-fluorobenzyl)-azabicyclo[3.3.1]nonan-3beta-yl benzamide (MABN) were examined. Cocaine- and food-maintained responding varied as a function of dose and were characterized as inverted U-shaped functions; cocaine-maintained response rates were significantly influenced by the magnitude of food in the other component. The behavioral potency of MABN on food- and cocaine-maintained responding was not influenced by the magnitude of food reinforcement. These results suggest that cocaine self-administration under a multiple schedule with food reinforcement is influenced by the environmental context. These schedule interactions, however, did not alter the behavioral effects of a dopamine D(2)/D(3) receptor antagonist.

The effects of benzamide analogues on cocaine self-administration in rhesus monkeys.

Based on the differential distribution of dopamine (DA) D(3) receptors in mesolimbic regions relative to nigrostriatal regions, the hypothesis was that D(3)-selective antagonists (i.e., higher affinity at D(3)- than D(2)-receptors) would be more potent than D(2)-selective antagonists at decreasing total cocaine intake relative to disrupting rates of responding. To evaluate the effects of acute administration of seven DA antagonists with varying affinities for D(2) and D(3) receptors in monkeys self-administering cocaine. Rhesus monkeys were trained to self-administer intravenous cocaine (0.01-0.3 mg/kg per injection) under a fixed-interval (FI) 5-min schedule during daily 4-h sessions. The use of a FI schedule allowed for independent assessment of rate effects and changes in reinforcement frequency as a consequence of drug pretreatments. The compounds examined, in order of D(3) binding affinity, were: 2,3-dimethoxy-N-(9-p-fluorobenzyl)-azabicyclo[3.3. 1]nonan-3beta-yl benzamide (MABN) = eticlopride = 5-bromo- 2, 3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin-4-yl]benz-amide (BBP) > spiperone > fluoroclebopride (FCP) > 2, 3-dimethoxy-N-(p-fluorobenzyl)piperdin-4-yl benzamide (MBP) > haloperidol. In the absence of any pretreatments, cocaine-maintained responding varied as a function of dose and was characterized as an inverted U-shaped function, while cocaine intake increased in a dose-related fashion. When the dose of cocaine that maintained peak rates was available, all DA antagonists decreased response rates and cocaine intake in a dose- dependent manner. Increases in cocaine dose attenuated the effects of the DA antagonists, resulting in rightward shifts of the cocaine dose-response curves. Based on the ratio of behavioral potency at decreasing response rates relative to intake (ED(50) rate/ED(50) intake) when the highest cocaine dose was available, the order of potency and ED(50) ratio values were: MABN (2.5) > eticlopride (1. 63) > BBP = spiperone (1.5) > FCP (1.35) > MBP = haloperidol (0.89). This order parallels each compound's affinity at D(3) receptors (r(2)=0.84) to a greater degree than D(2) receptor affinity (r(2)=0. 34). These results, using a FI schedule of cocaine self-administration, suggest that D(3) receptor antagonists are more likely to selectively decrease intake relative to response rates than D(2) receptor antagonists.

The effects of morphine on clocked fixed-interval performance: stimulus function or strength of stimulus control?

The present experiment was conducted to determine whether the modification of the effects of morphine by food deprivation would occur under conditions of strong stimulus control. Four pigeons pecked response keys under a multiple fixed-interval (FI) 5-min and clocked fixed-interval (CFI) 5-min schedule of food presentation. During the FI component, the key was lit green and the house light was on throughout. During the CFI component, the key light and house light settings changed in a regular manner as the interval elapsed. In all conditions, pigeons received a range of doses of morphine (1.0-10.0 mg/kg) and saline. In the first condition, pigeons were maintained at 80% of their free-feeding weights. When calculated over entire 5-min intervals, morphine produced dose-dependent decreases in the index of curvature (a measure of temporal patterning) during the FI component, but did not affect the index of curvature during the CFI component. A more detailed analysis revealed that the index of curvature during the last stimulus in the CFI sequence was reduced in a dose-dependent manner, similar to the effects obtained for the entire FI component. When the pigeons were maintained at 70% and 90% of their free-feeding weights, measures of the effects of morphine on temporal patterning did not differ as a function of body weight. The effects of morphine on rates of key-pecking, however, were related to body weight. For three of four pigeons, rates of key-pecking were not suppressed until higher doses, and increases in rates of key-pecking were more common at lower doses, when the pigeons were maintained at 70% of their free-feeding weights, than when they were maintained at 90% of their free-feeding weights. It is suggested that the effects of morphine on CFI performance can be understood in terms of the function of the stimuli that comprise the schedule, rather than the strength of the stimulus control engendered.

Dopamine D 2/D 3 receptors modulate cocaine’s reinforcing and discriminative stimulus effects in rhesus monkeys

Numerous studies have suggested that dopamine (DA) D 2 and D 3 receptors are involved in the behavioral effects of cocaine. The present experiments evaluated the reinforcing and cocaine-like discriminative stimulus effects of several D 2/D 3 agonists in rhesus monkeys. In the first experiment, animals ( n=4) were trained to self-administer 0.03 mg/kg/inj cocaine under a fixed-interval (FI) 5-min schedule. When substituted for cocaine, the D 2/D 3 agonist quinpirole (0.003–0.03 mg/kg/inj) functioned as a reinforcer in all monkeys. In two cocaine-naive monkeys trained to respond under an FI 3-min schedule of food presentation, quinpirole maintained low rates of responding in one subject, while at the highest dose (0.03 mg/kg/inj) it functioned as a reinforcer in the second monkey. In this animal, increased activity was observed at this dose, which may have contributed to the overall rate of responding. In the second experiment, monkeys ( n=4) were trained to discriminate cocaine from saline using a two-lever, food-reinforced, drug discrimination procedure. The D 2/D 3 agonists quinpirole, (±)-7-OH-DPAT, and R-(+)-7-OH-DPAT fully substituted for cocaine. However, the time-course of substitution differed between quinpirole, which substituted for cocaine 10 min after administration, and (±)- and R-(+)-7-OH-DPAT, which required 60-min pretreatments. The behavioral potencies, as determined from ED 50 values, correlated with previously reported in vitro binding affinity and functional activity at the D 3 receptor [R-(+)-7-OH-DPAT>(±)-7-OH-DPAT>quinpirole]. These results further indicate that direct-acting D 2/D 3 agonists can function as reinforcers and produce cocaine-like discriminative stimulus effects, and support the idea that D 3 receptors should continue to be a valuable target for future behavioral studies evaluating cocaine’s mechanisms of action.

Food-deprivation level alters the effects of morphine on pigeons' key pecking.

Four pigeons pecked response keys under a multiple fixed-ratio 30 fixed-interval 5-min schedule of food presentation. Components alternated separated by 15-s timeouts; each was presented six times. Pigeons were maintained at 70%, 85%, and greater than 90% of their free-feeding weights across experimental conditions. When response rates were stable, the effects of morphine (0.56 to 10.0 mg/kg) and saline were investigated. Morphine reduced response rates in a dose-dependent manner under the fixed-ratio schedule and at high doses under the fixed-interval schedule. In some cases, low doses of morphine increased rates under the fixed-interval schedule. When pigeons were less food deprived, reductions in pecking rates occurred at lower doses under both schedules for 3 of 4 birds compared to when they were more food deprived. When pigeons were more food deprived, low doses of morphine increased rates of pecking in the initial portions of fixed intervals by a greater magnitude. Thus, food-deprivation levels altered both the rate-decreasing and rate-increasing effects of morphine. These effects may share a common mechanism with increased locomotor activity produced by drugs and with increased drug self-administration under conditions of more severe food deprivation.

Self-administration of the dopamine D3 agonist 7-OH-DPAT in rhesus monkeys is modified by prior cocaine exposure.

Cocaine self-administration was compared with responding maintained by the dopamine D3 agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) in rhesus monkeys. In the first experiment, monkeys (n = 3) with an extensive cocaine history responded under a fixed-interval (FI) 5-min schedule of IV cocaine (0.03 mg/kg per injection) presentation, during daily 4-h sessions. When responding was stable, dose-response curves were determined for cocaine (0.01-0.3 mg/kg per injection) and 7-OH-DPAT (0.001-0.1 mg/kg per injection); each dose was available for at least five consecutive sessions. When substituted for the baseline dose of cocaine, other doses of cocaine and 7-OH-DPAT maintained rates higher than responding maintained by saline injections, in all monkeys. 7-OH-DPAT maintained response rates equal to or higher than rates of cocaine-maintained responding in all monkeys. In a second experiment, acquisition of 7-OH-DPAT self-administration was evaluated in a group of cocaine-naive monkeys (n = 3). Various doses of 7-OH-DPAT (0.003-0.03 mg/kg per injection) were available under an FI 15-s schedule during daily 4-h sessions. After 10-13 sessions, 7-OH-DPAT self-administration could not be trained in any cocaine-naive monkey. When cocaine was made available to these monkeys, responding was reliably maintained within one to four sessions and the schedule was gradually increased to FI 5-min. After stable responding under an FI 5-min schedule of 0.03 mg/kg per injection cocaine presentation, 7-OH-DPAT (0.01 mg/kg per injection) was again made available to two of the monkeys, and maintained responding at rates higher than saline. To determine better whether a history of responding maintained by another reinforcer would result in high rates of 7-OH-DPAT self-administration, two cocaine-naive monkeys were trained to respond under an FI 5-min schedule of food presentation. Substituting 7-OH-DPAT (0.003-0.03 mg/kg per injection) for food resulted in very low rates of responding. Taken together, these results suggest that despite comparable reinforcing effects in cocaine-substitution studies, 7-OH-DPAT and cocaine differ in their rate of acquisition, perhaps indicating a lower abuse liability for 7-OH-DPAT.

Cocaine's effects on food-reinforced pecking in pigeons depend on food-deprivation level.

Four pigeons deprived to 80% of their laboratory free-feeding weights pecked keys under a multiple fixed-ratio 30 fixed-interval 5-min schedule of food presentation. Components alternated strictly with 15-s timeouts separating them; each was presented six times. When rates of pecking were stable, 2 pigeons' weights were reduced to 70%, and the other 2 pigeons' weights were increased to 82.5% to 85% of free-feeding levels. Cocaine (1.0, 3.0, 5.6, and 10.0 mg/kg and saline) was administered 5 min prior to sessions. When each dose had been tested twice, pigeons' weights were adjusted to the level that they had not yet experienced, and cocaine was tested again. Cocaine reduced response rates in a dose-dependent manner under the fixed-ratio schedule and under the fixed-interval schedule at high doses, and increased rates under the fixed-interval schedule at low low doses. Reductions in pecking rates occurred at lower doses under both schedules in 3 of 4 pigeons when they were less food deprived compared to when they were more food deprived. Low doses of cocaine increased low baseline rates of pecking in the initial portions of the fixed-interval schedules by a greater magnitude when pigeons were more food deprived. Thus, food-deprivation levels altered both the rate-decreasing and rate-increasing effects of cocaine. The implications of these results for the mechanisms by which food deprivation increases cocaine self-administration and for the dependence of cocaine's effects on the baseline strength of operant behavior are discussed.

Effects of different food-reinforcement histories on cocaine self-administration by rhesus monkeys

The purpose of the present study was to examine whether a history of responding under food reinforcement schedules that generated either high or low response rates would influence the acquisition and maintenance of cocaine self-administration. Eight experimentally naive rhesus monkeys were initially trained to respond on the right lever under either a fixed-ratio (FR) 50 or interresponse times (IRT) > 30-s schedule of food reinforcement. After 65 sessions of food-maintained responding, monkeys were surgically prepared with indwelling intravenous catheters and cocaine 0.03 mg/kg per injection (IV) was available on the left lever under a fixed-interval (FI) 5-min schedule. After at least 60 consecutive sessions at this dose, a cocaine dose-response curve (saline, 0.01-0.3 mg/kg per injection) was determined. The FR 50 schedule generated high rates of food-maintained responding (90.1 +/- 6.2 responses/min), while response rates under the IRT > 30-s schedule were low (1.9 +/- 0.1 responses/min). Across the 60 consecutive sessions under the FI 5-min schedule, linear changes in response rates and cocaine intake were significantly different between FR- and IRT-history monkeys. FR-history monkeys responded at higher rates than IRT-history subjects, while cocaine intake during the first 15 sessions was lower in FR- compared to IRT-history monkeys. Rates of cocaine-maintained responding after food-reinforcement histories were compared to response rates of monkeys initially trained to self-administer cocaine under an FI 5-min schedule (Nader and Reboussin 1994).(ABSTRACT TRUNCATED AT 250 WORDS)

TOLERANCE TO COCAINE'S RATE‐INCREASING EFFECTS UPON REPEATED ADMINISTRATION

Four squirrel monkeys responded daily under a fixed-interval 5-min or 8-min schedule of food-pellet delivery. Cocaine (0.03 to 1.7 mg/kg) and saline were injected before occasional daily sessions (acute administration). Some doses of cocaine produced substantial overall increases in response rate for 3 of the subjects; effects were less substantial for the remaining subject, who exhibited modest increases in response rate early in the session and during the middle portion of the intervals. A dose that increased response rate when administered acutely was then administered before each session (chronic administration). Chronic administration resulted in a reduction in the increases in response rate seen under acute administration for all subjects.

The effects of behavioral history on cocaine self-administration by rhesus monkeys.

The purpose of the present study was to examine whether a history of responding under schedules that generate either high or low response rates could modify previously established cocaine self-administration. Eight experimentally naive rhesus monkeys were trained to respond on one of two levers under a fixed-interval (FI) 5-min schedule of intravenous cocaine (0.03 mg/kg per injection) presentation. When responding was stable a cocaine dose-response curve (saline, 0.01-0.3 mg/kg per injection) was determined. Following completion of the dose-response curves, the monkeys were randomly assigned to one of two groups (n = 4/group) and trained to respond on the other lever under either a fixed-ratio (FR) 50 or inter-response times (IRT) > 30-s schedule of cocaine (0.03 mg/kg per injection) presentation. After 65 sessions responding was again maintained under the FI5-min schedule of 0.03 mg/kg per injection cocaine for 60 sessions, followed by redetermination of the cocaine dose-response curve. During the initial exposure to the FI schedule, the mean rate of responding was 4.02 (+/- 0.33) responses/min and the cocaine dose-response curve was characterized as an inverted-U shape function of dose, with peak responding at 0.03 mg/kg per injection. The FR50 schedule generated high rates (66.80 +/- 5.6 responses/min), while response rates under the IRT > 30-s schedule were low (2.62 +/- 0.2 responses/min). Following different behavioral histories, response rates under the FI5-min schedule were significantly higher for 60 sessions in FR-history monkeys compared to IRT-history subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Naloxone pretreatment blocks acute morphine-induced sensitization to naltrexone.

The present experiment was designed to examine whether the acute sensitization to naltrexone that is induced by a single dose of morphine could be blocked by pretreatment with naloxone. Food-deprived male Sprague-Dawley rats were trained to respond for food on a multiple-trial fixed interval 3-min schedule. Reinforcement was contingent upon a response within a 10-s limited hold period following a fixed interval of 3 min. A trial consisted of three fixed intervals separated by a 10-min timeout period during which responses were not reinforced. The rate decreasing effects of the opioid antagonist naltrexone were determined by cumulative dosing. Pretreatment with morphine (3.0 mg/kg, SC) resulted in a 70-fold increase in sensitivity to the response rate decreasing effect of naltrexone compared with saline pretreatment. The increased sensitivity was dose-dependently blocked by naloxone administration 10 min before morphine. The blockade by naloxone was overcome by increasing the pretreatment dose of morphine to 10 mg/kg. The results provide further evidence that acute agonist-induced sensitization to the rate-reducing effects of naltrexone is mediated by opioid receptors.

Behavioral effects of systemically administered mu and kappa opioid agonists in the squirrel monkey: Peptides versus alkaloids

This study compared the effects of receptor-selective peptide and nonpeptide opioid agonists administered intramuscularly to squirrel monkeys responding under a fixed-interval 3-min schedule of stimulus termination. The mu opioid receptor agonist morphine (0.1–3.0 mg/kg) increased response rate at low doses and decreased it and quarter-life at higher doses. [ D-Ala 2,N-Me-Phe 4, Gly-ol]Enkephalin (DAMGO; 0.3–3.0 mg/kg) reduced quarter-life at the highest dose. The kappa opioid receptor agonist U50,488H (0.1–1.0 mg/kg) elevated response rate transiently and dose-dependently decreased quarter-life. Dynorphin (1–13) (0.3–10 mg/kg), a purported endogenous ligand of the kappa opioid receptor, decreased response rate slightly but significantly at 3.0 mg/kg and had no effect on quarter-life. Thus, the behavior of squirrel monkeys was affected by systematically administered peptide as well as by nonpeptide opioid drugs. The two alkaloids were much more effective than the two peptides, presumably because of greater ability to penetrate the blood-brain barrier. Quarter-life was often a more sensitive measure of drug effects than was response rate.