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

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

Food deprivation and cocaine self-administration

The effects of food deprivation on the self-administration of cocaine were assessed in three rhesus monkeys under different schedules of reinforcement. In one subject, decreasing body weight to 80% of free-feeding weight (ffw) resulted in increased response rates and number of cocaine infusions taken. The same effects were observed in a second subject when restricted food intake resulted in 88% ffw. When schedule contingencies limited the number of infusions available, reduction to 90% ffw in the third subject resulted in increased response rates. These data suggest that food deprivation can be a potent variable in responding maintained by cocaine self-administration.     

Effects of concurrent saccharin availability and buprenorphine pretreatment on demand for smoked cocaine base in rhesus monkeys

The effects of saccharin and the opioid partial agonist buprenorphine on cocaine base smoking were evaluated in five male rhesus monkeys. Monkeys completed a sequence of responding consisting of lever-press responses maintained under a fixed-ratio (FR) schedule followed by inhalation responses (FR5) on a smoking spout to gain access to a single delivery of volatilized cocaine base (1.0 mg/kg per delivery). Monkeys could receive a maximum of ten smoke deliveries per session. In the first experiment, either saccharin (0.03% wt/vol) or water was concurrently available under an FR1 schedule through a lip-operated drinking device. As lever FR values increased from 128 to 256, 512, 1024 and 2048, the number of cocaine smoke deliveries decreased. Cocaine intake was not statistically different when water versus saccharin was concurrently available. However, as cocaine consumption decreased, saccharin intake increased demonstrating that under these conditions, saccharin was substituting for cocaine as a reinforcer. On the first day that lidocaine replaced cocaine, all of the monkeys received the maximum number of smoke deliveries (ten) and saccharin intake increased. Lever-press responding gradually extinguished over days when lidocaine (1.0 mg/kg per delivery) was available with concurrent saccharin. In the second experiment, water was concurrently available with cocaine and buprenorphine (0.01 or 0.1 mg/kg) was administered intramuscularly (IM) 30 min before the start of the session. Although pretreatment with the lower dose of buprenorphine (0.01 mg/kg) had little effect on cocaine intake overall, individual differences in cocaine intake occurred. The higher dose of buprenorphine (0.1 mg/kg) decreased the amount of cocaine consumed at all lever FR values tested.     

Self-administration of orally-delivered methohexital in rhesus monkeys with phencyclidine or pentobarbital histories: effects of food deprivation and satiation

Orally-delivered methohexital was demonstrated to function as a reinforcer for rhesus monkeys with either phencyclidine or pentobarbital self-administration histories. The effects of food deprivation and food satiation were compared across a wide range of methohexital concentrations. Initially, three monkeys were trained to orally self-administer phencyclidine (0.25 mg/ml) and water, and three were trained to orally self-administer pentobarbital (0.5 mg/ml) and water under concurrent fixed-ratio (FR) schedules during daily 3-hr sessions. Liquid deliveries during the session (drug and water) and intersession (water) were contingent upon lip contact responses on solenoid-operated drinking spouts. The monkeys were first tested while food deprived by maintaining them at 85% of their free-feeding body weights. Methohexital concentrations were presented in the following order, and each concentration was held constant until at least five or six sessions of stable behavior were obtained: 2, 2.8, 4, 2 (retest), 1, 0.5, (plus 0.25 and 0.125 in monkey M-W) and 2 (retest) mg/ml. The monkeys were then food satiated by allowing them unlimited access to food, and the methohexital concentration series was repeated. During food deprivation, the concentration-response functions generally resembled an inverted U. Concurrent water-maintained responding was generally low, but it increased in some monkeys as methohexital concentrations increased in some monkeys. During food satiation, methohexital-maintained responding was not different from water-maintained responding in some monkeys, but in others it was substantially higher than water-maintained responding. Maximum drug intake ranged from 20.4 to 93.8 mg/kg during food deprivation and from 6.4 to 64.2 during food satiation among the six monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of food deprivation and satiation on oral pentobarbital self-administration in rhesus monkeys

The effects of food deprivation and satiation on oral pentobarbital self-administration were studied in four rhesus monkeys. Pentobarbital (1.0 mg/ml) or water was available during alternate daily 3-hr session; between sessions, water was freely available. Lip contacts on a drinking spout activated a solenoid operated liquid delivery system. Liquid deliveries (0.56 ml) occurred after a fixed number of lip contact responses were emitted; that is, liquids were delivered according to fixed-ratio (FR) schedules. Under food deprivation conditions, pentobarbital-maintained behavior exceeded water-maintained behavior. Thus, pentobarbital functioned as a reinforcer. Abrupt unlimited access to food resulted in decreased pentobarbital intake. Pentobarbital-maintained behavior increased to previous levels when food intake was again restricted. In a second experiment, the effects of pentobarbital availability on water-maintained behavior were studied. Access to pentobarbital during alternate sessions produced elevated levels of water drinking during intervening sessions. Water drinking decreased to low levels when pentobarbital access was terminated and water was present for consecutive sessions. When pentobarbital was again available during alternate sessions, high levels of water drinking recurred. In the third experiment, water and pentobarbital (1.0 mg/ml) were concurrently available via separate drinking spouts. All three monkeys drank much more pentobarbital solution than water.     

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.     

Ethanol effects on self-administration of alfentanil, cocaine, and nomifensine in rhesus monkeys

 A common form of polydrug use is that of cocaine and ethanol. The identification of an ethanol-cocaine combination product, cocaethylene, with properties in common with cocaine, has led to speculation that this metabolite may contribute to the co-abuse of cocaine and ethanol. In order to determine whether ethanol pretreatments selectively altered cocaine’s reinforcing potency, ethanol pretreatments were given to monkeys trained to press levers and receive IV infusions of several doses of cocaine or alfentanil. In addition, nomifensine, a drug which has a mechanism of action similar to cocaine’s, was evaluated in the presence and absence of ethanol in monkeys with the cocaine baseline history. Ethanol, in doses ranging from 100 to 1780 mg/kg, given 10 min before the 130-min session, had no effect on responding maintained by alfentanil. These doses also had no significant effect on cocaine-maintained responding, although the potency of cocaine as a reinforcer was increased following administration of 1000 mg/kg ethanol in two of the four subjects. The potency of nomifensine as a reinforcer was significantly increased by 1000 mg/kg ethanol, but again, this enhancement was limited to the same two subjects. These data indicate that, in this paradigm, cocaethylene did not selectively modify cocaine’s reinforcing potency, but there appear to be individual differences with respect to ethanol’s ability to stimulate rates of drug-maintained responding. Received: 24 April 1996 / Final version: 7 November 1996     

Effects of body weight reduction and food deprivation on cocaine self-administration

The present experiments attempted to study the effects of food deprivation and body weight reduction on cocaine self-administration. Rats whose body weight was reduced to 80% free feeding weight (FFW) with 23 hours' food deprivation increased cocaine intake by 30-fold compared to 100% FFW animals. The results demonstrated that, in rats, body weight reduction and the state of food deprivation interact to further enhance self-administration of cocaine. From the practical point of view, the results suggest that there may be an increased risk of drug dependence with patients taking stimulants to control body weight.     

Parametric analysis of cocaine self-administration under a progressive-ratio schedule in rhesus monkeys

The present study was designed to investigate parameters and quantitative analysis of cocaine self-administration under a progressive-ratio (PR) schedule of reinforcement, with the goal of enhancing the resolution of PR schedules for measuring reinforcing efficacy. Six rhesus monkeys were prepared with chronic intravenous catheters and trained to self-administer cocaine under a PR schedule. The schedule consisted of five components, each made up of four trials (i.e., 20 trials total). Each trial within a component had the same response requirement. Three initial response requirements were tested: fixed-ratio (FR) 60, FR 120 and FR 240. The response requirements doubled in successive components to a maximum of FR 960, FR 1920 or FR 3840, respectively, in the fifth component. A trial ended with an injection or the expiration of a 12- or 24-min limited hold (LH). The inter-trial interval (ITI) was 15 or 30 min. Four dependent measures were assessed: break point (last FR completed), injections/session, responses/session and response rate (responses/s). For the three initial FRs, the break point, number of injections/session, responses/session and rate increased with dose of cocaine (0.013–0.1 mg/kg per injection) at both ITI/LH values. At the ITI15/LH12, responding decreased at higher doses, i.e., the dose-response functions were biphasic. In contrast, at the ITI30/LH24, responding reached an asymptote at higher doses. In general, cocaine maintained significantly higher break points, injections/session, responses/session and rate at ITI30/LH24 than at ITI15/LH12. However, at both ITI/LHs, as initial FR was increased, injections/session at the higher doses decreased while break point, total responses/session and rate did not change. A ceiling on performance, as assessed by break point, total responses/session and response rate, may have limited the number of cocaine injections an animal could take in a session. The results of this study indicate that optimal conditions for measuring the reinforcing efficacy of cocaine were obtained at the longer ITI/LH and at initial FRs above 60.     

A within-subject assessment of the discriminative stimulus and reinforcing effects of self-administered cocaine in rhesus monkeys

Rationale

Drug discrimination (DD) and drug self-administration (SA) are frequently used preclinical assays. All preclinical studies with cocaine have examined the discriminative stimulus (S^D) and reinforcing (S^R) effects in separate groups of subjects.

Objective

The objective of the study is to train drug-naïve rhesus macaques to discriminate self-administered cocaine from saline and to assess S^D and S^R effects using a within-subjects design.

Materials and methods

Adult male rhesus monkeys (n?=?4) were trained to self-administer cocaine (0.1 mg/kg per injection) under a progressive-ratio (PR) reinforcement schedule. Next, they were trained to discriminate self-administered cocaine (0.45 or 0.56 mg/kg) or saline under a fixed-ratio (FR) 50 schedule of food presentation. The final schedule combined DD and SA into a multiple [chained FR 50 SA (cocaine or saline), food-reinforced DD] and PR SA schedule.

Results

Each subject acquired SA under a PR schedule with significant differences in breakpoint between saline and cocaine evident by session 5. Self-administered cocaine was established as an S^D, such that 80% of responding before delivery of the first reinforcer and 90% of all responding occurred on the injection-appropriate lever. In all monkeys, there was at least one cocaine dose that did not engender cocaine-appropriate responding during DD (i.e., <20% cocaine-appropriate responding) yet functioned as a reinforcer during PR SA, suggesting that cocaine-like S^D effects are not necessary for cocaine reinforcement.

Conclusions

This within-subject model may provide new information related to the behavioral mechanisms of action leading to the high abuse potential of cocaine; such information may lead to novel pharmacological treatment strategies for addiction.     

Comparison of the reinforcing efficacy of cocaine and procaine in rhesus monkeys responding under a progressive-ratio schedule

Rhesus monkeys (n=5) were prepared with chronic IV catheters and trained to lever press under a PR schedule of drug injection. The schedule consisted of five components, each made up of four trials (i.e., 20 trials total). Each trial within a component had the same response requirement. The response requirement in the first component was 120/trial and doubled in successive components to a maximum of 1920 in the fifth. A trial ended with an injection or the expiration of a 12-min limited hold (LH). The inter-trial interval (ITI) was 15 or 30 min. Following an injection or expiration of the LH, all stimulus lights were extinguished and responding had no consequence for the remainder of the trial. A session ended when either all 20 injections were self-administered or the response requirement was not met within the LH for two consecutive trials. The number of injections/session and responses/session increased with dose for cocaine (0.012–0.1 mg/kg per injection) and procaine (0.12–2.0 mg/kg per injection) at both ITI values. At the 15-min ITI, responding decreased again at higher doses in some monkeys with cocaine and in all monkeys with procaine. At maximum, cocaine maintained significantly more injections and responses/session when the ITI was 30 min than when it was 15 min. In contrast, the increase in ITI did not increase the maximum maintained by procaine. Cocaine was approximately 10-fold more potent than procaine and maintained at maximum significantly more injections and responses than procaine when the ITI was 30 min but not when the ITI was 15 min. These results are consistent with previous studies demonstrating that cocaine is a more efficacious positive reinforcer than procaine. Moreover, they extend recent findings suggesting that number of injections/session provides a measure of PR performance that is amenable to statistical analysis and may, therefore, be useful in establishing reliable differences among drugs in terms of relative reinforcing efficacy. Reliable quantification of between-drug differences in reinforcing efficacy can enhance not only estimates of relative abuse liability but also pharmacological analysis of central mechanisms mediating reinforcing effects.     

Effects of dopamine receptor antagonists (D1 and D2) on the demand for smoked cocaine base in rhesus monkeys

Rationale: Previous studies suggest that dopamine antagonists may reduce the reinforcing effects of cocaine. However, the effects of these antagonists on the demand for smoked cocaine base have not been quantified. Objectives: To evaluate the effects of selective D₁ (SCH 23390) and D₂ (raclopride) dopamine receptor antagonists on the demand for smoked cocaine base in rhesus monkeys using a behavioral economic analysis. Methods: Six rhesus monkeys were trained to self-administer smoked cocaine base (1.0 mg/kg/delivery) under chained fixed-ratio (FR) schedules (FR64, 128, 256, 512, 1024 or 2048 for lever presses and FR5 for inhalations) during daily 4-h sessions. A maximum of ten smoke deliveries were available. After 5 days of stable behavior at each FR, SCH 23390 (0.01 and 0.056 mg/kg) or raclopride (0.03 and 0.056 mg/kg) were injected intramuscularly, before each session, for 3 consecutive days. Results: Pretreatment with both antagonists dose-dependently reduced cocaine intake across most FR values tested; however, the decrease in consumption was greater at the higher unit prices than at the lower unit prices. A statistical estimate of the price (FR) at which maximum responding occurred (P_max) was decreased during drug pretreatment, indicating weakened reinforcing effectiveness of cocaine. Conclusions: These data suggest that both antagonists reduce the reinforcing effectiveness of smoked cocaine base, and they have a greater effect on cocaine consumption at higher FR values. Received: 19 October 1998 / Final version: 1 March 1999     

Comparison of plasma cocaine levels during a "binge" pattern of cocaine administration in male and female rhesus monkeys

Abstract Rationale. Cocaine is often abused in a "binge" pattern, but little is known about changes in plasma cocaine concentrations or cocaine pharmacokinetics during administration of multiple cocaine doses. Moreover, the extent to which gender may influence plasma cocaine levels during a cocaine binge has not been studied in rhesus monkeys. Objectives. To compare the effects of repeated injections of the same dose of cocaine (0.4 mg/kg or 0.8 mg/kg, i.v.) on plasma cocaine concentrations, cocaine pharmacokinetics and behavioral responses in male and female rhesus monkeys. Methods. Four injections of cocaine (0.4 mg/kg or 0.8 mg/kg, i.v.) were administered at 30-min intervals to five or six male and five or six female rhesus monkeys. Samples for plasma cocaine analysis were collected at 2, 4, 8, 16 and 24 min after the first three injections. After the fourth cocaine injection, additional samples were collected at 10-min intervals over 150 min. Results. Plasma cocaine peaks and nadirs increased monotonically after successive cocaine injections (P<0.0001). Peak plasma cocaine levels measured at 2 min after cocaine administration were higher after 0.8 mg/kg cocaine than after 0.4 mg/kg cocaine (P<0.006). There were no significant gender differences in time to peak plasma cocaine levels (t_max), peak cocaine concentrations (C_max) or half-life (t_1/2; min) at either dose of cocaine. Group average behavioral ratings were similar in males and females after each dose of cocaine. Conclusions. Peak plasma cocaine concentrations increased progressively during low and high dose cocaine binge episodes, and there were no significant gender differences in cocaine pharmacokinetics. These findings demonstrate the feasibility of simulating "binge" patterns of cocaine administration in rhesus monkeys. Electronic Publication     

Effects of dose on increased etonitazene self-administration by rats due to food deprivation

Rats were trained to self-administer IV-delivered etonitazene while food satiated. A wide range of etonitazene doses (5–80 g/kg) and saline were tested under food satiation and food deprivation conditions. Food deprivation produced a parallel increase in the dose-response function under FR 1 and FR 16 schedule conditions.     

Relationship between the discriminative stimulus effects and plasma concentrations of intramuscular cocaine in rhesus monkeys

The relationship between the discriminative stimulus effects and plasma pharmacokinetics of cocaine was evaluated in six rhesus monkeys trained to discriminate cocaine (0.4 mg/kg, IM) from saline under a FR30 schedule of food presentation. The same monkeys were tested in two procedures. In a cumulative dosing procedure, five cumulative doses of cocaine (0.013–1.3 mg/kg) were administered and discriminative stimulus effects were evaluated 10 min after the administration of each dose. Cocaine plasma concentrations were measured in separate sessions using the same doses and interdose intervals. In a single dosing procedure, the time-courses of the discriminative stimulus effects and plasma concentrations of cocaine were assessed after the administration of cocaine (0.4 mg/kg). A close correspondence between cocaine's discriminative stimulus effects and plasma concentrations was obtained in both procedures. Cocaine was virtually undetectable in plasma at doses that produced saline-appropriate responding (0.013 and 0.04 mg/kg), whereas increasing plasma concentrations were measured at doses that produced primarily cocaine-appropriate responding (0.13 mg/kg or higher). The time-course of the discriminative stimulus effects of cocaine was characterized by a rapid onset (within 1–3 min post-cocaine) and offset (within 20–60 min post-cocaine). Peak plasma levels were obtained at 10 min post-cocaine. No differences in plasma concentrations were found 10 min after the administration of a cumulative versus a single dose of cocaine 0.4 mg/kg (mean, 75.8 and 74.0 ng/ml, respectively). Cocaine plasma concentrations lasted longer than its discriminative stimulus effects. The results of the present study confirm that the cumulative dosing procedure used yields plasma concentrations of cocaine that are similar to the concentrations obtained after single cocaine dosing.In Memoriam: Xavier Lamas, MD, phD; August 26, 1995; Mt. EverestThis work was supported by in part by grants DA 02159, DA 04059, DA 07252 and KO award DA 00101 from the National Institute on Drug Abuse, NIH. Xavier Lamas was supported by a grant from the Ministry of Education and Science of Spain (Formación del Personal Investigador, Subprograma de Perfeccionamiento para Doctores y Tecnólogos). Animals used in this study were maintained in accordance with guidelines of the Committee on Care and Use of Laboratory Animal Resources, National Research Council (Department of Health, Education and Welfare, Publication No. (NIH) 85–23, revised 1985), and the McLean Hospital Institutional Animal Care and Use Committee.     

Effects of pentobarbital and d-amphetamine on oral phencyclidine self-administration in rhesus monkeys

The purpose of this study was to examine the benzodiazepine-like activity of fominoben-HCl, a compound with prominent antitussive and respiratory stimulant actions. Towards this end we examined the anticonvulsant actions of fominoben as well as its ability to displace benzodiazepine (BDZ) binding from brain membranes. Scatchard analysis of binding data demonstrated that fominoben displaced 3H-flunitrazepam binding from rat cortical membrane preparations. Furthermore when tested against 3H-ethyl-beta-carboline-3-carboxylate, the addition of GABA resulted in a mean (+/- SE) shift of the IC50 from 4.05 +/- 0.10 microM to 2.2 +/- 0.05 microM, a characteristic of benzodiazepine agonists. Seizures were induced in male, Swiss Webster mice with pentylenetetrazol (PTZ) or 3-mercaptoproprionic acid (3-MP). Fominoben (50 and 100 mg/kg) completely protected mice from seizures induced by 50 mg/kg PTZ and elevated the seizure latency against 75 mg/kg of PTZ. The anticonvulsant effects of fominoben were less pronounced against 3-MP-induced seizures. The benzodiazepine antagonist Ro 15-1788 antagonized the anticonvulsant action of fominoben against both convulsants. Taken together, these data suggest that the anticonvulsant action of fominoben may be mediated by agonistic actions at benzodiazepine binding sites.     

Rapid acquisition of oral phencyclidine self-administration in food-deprived and food-satiated rhesus monkeys: Concurrent phencyclidine and water choice

Eight rhesus monkeys were trained to self-administer orally-delivered phencyclidine, with water concurrently available, under a fixed ratio (FR) schedule during daily 3-hr sessions. Liquid deliveries (0.55 ml) were contingent upon lip-contact responses on solenoid-operated drinking spouts. During the sessions, phencyclidine and water were available under FRs ranging from 1 to 16. Water was always available between sessions (FR 1), and food initially was available 24 hr/day. In Experiment 1 the monkeys initially were given access to water (FR 1) during the 3-hr sessions. Subsequently, phencyclidine (0.25 mg/ml) was substituted for water, and the monkeys were reduced to 85 percent of their free-feeding weights. The FR value was then increased from 1 to 8. Next, the monkeys received concurrent access to water from one spout and phencyclidine from the other (each under the FR 8 schedule), then the FR value was increased to 16 for both drug and water. Orally-delivered phencyclidine was rapidly demonstrated to function as a reinforcer (37.2 sessions) without using food to induce drinking. In Experiment 2 a similar procedure was used for another group of monkeys, except the monkeys remained food satiated throughout the acquisition phase. Phencyclidine was rapidly demonstrated to function as a reinforcer (25.9 sessions), although intakes were lower than in Experiment 1. After concurrent phencyclidine- and water-maintained performance stabilized at FR 16, the monkeys were food deprived, and phencyclidine intake increased to the levels reported in Experiment 1. Food deprivation greatly enhanced the reinforcing effect of phencyclidine and changed the temporal pattern of responding, but neither food deprivation nor food-induced drinking were necessary conditions to demonstrate the drug's reinforcing effects.     

Orally delivered pentobarbital as a reinforcer for rhesus monkeys with concurrent access to water: Effects of concentration,fixed-ratio size,and liquid positions

The number of liquid deliveries and pattern of concurrent pentobarbital and water drinking were studied in three food deprived rhesus monkeys during daily 3-hr sessions. During the daily sessions, deliveries of approximately 0.6 ml of each liquid occured under fixed-ratio (FR) schedules of lip contact responses. Between sessions water was freely available. Session drinking was studied as a function of pentobarbital concentration (1.0, 1.41, 2.0, and 4.0 mg/ml) and FR size (4, 8, 16 and 32 lip contacts per delivery). The number of drug deliveries decreased with increases in drug concentration. Drug intake ranged from 21 to 52 mg/kg of body wt./3-hr session. At all concentrations and FR values tested, the number of pentobarbital deliveries substantially exceeded the number of water deliveries. The positive reinforcing effect of the pentobarbital was indicated by a consistent choice of drug over water irrespective of the side position of pentobarbital and by higher rates of drug responding. Pentobarbital drinking occured in a negatively accelerated pattern whereas water drinking did not have any consistent pattern. Marked intoxication followed bouts of drug drinking.     

Cocaine reinforced progressive ratio performance in the rhesus monkey.

A series of experiments were conducted to determine the effectiveness of a progressive ratio (PR) procedure in measuring the relative reinforcing efficacy of several intravenous doses of cocaine. In Experiment 1, utilizing much smaller increases in the ratio requirement than previously reported, the animals generally displayed increases in breaking point with increases in the cocaine unit dose up to 0.4 mg/kg/inj. The highest dose studied (0.8 mg/kg/inj.) engendered breaking points lower than the 0.4 mg/kg dose but higher than the remaining lower doses. Experiment 2 was conducted utilizing the same reinforcement schedule as in Experiment 1 but with liquid Tang as the reward. The results demonstrated that this procedure would function to discriminate reinforcing strength with a more traditional reward. Experiment 3 examined a more expedient procedure to see if results similar to those seen in Experiment 1 could be obtained in a shorter period of time. However, the shorter procedure engendered excessive intrasubject variability, suggesting that some intermediate level of baseline experience between the 5-7 days used in Experiment 1 and the 50 reinforced responses used in Experiment 3 would be necessary to obtain consistent breaking point-unit dose functions.     

Effects of delay to reinforcement on the choice between cocaine and food in rhesus monkeys

Rationale Although a delay between behavior and reinforcer has been shown to weaken behavior, little is known about the effects of delay on drug choice.Objectives The present study examined effects of delay between lever press and reinforcer presentation on the choice between a drug and non-drug reinforcer and between different drug doses.Materials and methods Monkeys (n=4) were allowed to choose 32 times/day between cocaine and four food pellets. The delay between lever press and a preferred dose of cocaine (0.05 mg/kg/injection) was increased systematically from 0 to 240 s, while the delay to food remained at 0 s. A second group of monkeys (n=4) was allowed to choose between 0.05 mg/kg/injection and a lower dose of cocaine (0.025 mg/kg/injection). Next, a delay that resulted in less than 20% choice of 0.05 mg/kg/injection cocaine was selected and delay to the alternative was varied.Results Results were similar across groups. The choice of 0.05 mg/kg/injection approximated 100% at 0 delay and decreased to near 0 as delay increased. As the delay to alternative was subsequently increased from 0 to 240 s, choice of 0.05 mg/kg/injection increased, though full cocaine choice was not generally restored. The delay estimated to maintain 50% choice (indifference point) was lower for the cocaine-food choice (mean=64 s) than for the cocaine–cocaine choice (mean=207 s).Conclusions This experiment demonstrates that the choice between cocaine and a non-drug or drug alternative can be modified by increasing the interval between behavior and drug injection. Overall, the results are consistent with a temporal discounting model of drug choice.