Observing responses maintained by stimuli associated with cocaine or remifentanil reinforcement in rhesus monkeys

Abstract Rationale. The stimuli associated with drug reinforcement may be particularly relevant to drug abuse and relapse. Objectives. The study measured behavior maintained by conditioned reinforcing stimuli in an observing response procedure. Methods. The experiment was conducted with rhesus monkeys in three stages: 1) discriminative control was established by reinforcing responding on one lever with either intravenous cocaine or remifentanil in the presence of one stimulus and extinguishing the response in the presence of another stimulus, 2) discriminative control was suspended by not presenting the stimuli, and 3) a final stage was implemented wherein the stimuli from the first stage were presented only when one or more responses were made on a second (observing) lever. Results. Under FR1 conditions, observing responses were maintained at low rates, but increased markedly when the response requirement was increased. Conclusions. The procedure maintained observing responses quite well and may be useful to an analysis of conditioned reinforcement based on drug reinforcement. Electronic Publication     

Self-administration of GBR 12909 on a fixed ratio and progressive ratio schedule in rats

Intravenous self-administration of GBR 12909, an indirect dopamine agonist, was examined on a Fixed Ratio (FR 1) and a Progressive Ratio (PR) schedule of reinforcement in rats. Subjects were first trained to self-administer cocaine (1.5 mg/kg/inj) during daily 5 h sessions, after which GBR 12909 (0.187–1.5 mg/kg/inj) was substituted. On the FR 1 schedule, the inter-infusion interval for GBR 12909 self-administration was directly related to dose and was approximately three times longer than that established for equivalent doses of cocaine. Breaking points on the PR schedule were comparable for GBR 12909 and cocaine self-administration. The data indicate that, compared to cocaine, GBR 12909 has a longer duration of action and a similar reinforcing efficacy.     

Effects of dose and infusion delay on cocaine self-administration choice in rhesus monkeys

Rationale. Drug abuse is often considered a problem related to impulse-control disorders, but little is known about the factors that determine the choice to self-administer a drug in a self-control/impulsivity paradigm. Objective. The objective of the present study was to evaluate choice between a low dose of cocaine administered after a relatively short delay (impulsive option) and a high dose of cocaine following a relatively longer delay (self-control option). Methods. Rhesus monkeys self-administered intravenous cocaine in a discrete-trials choice procedure. First, choice was between different 3:1 doses (0.3/0.1 and 0.1/0.03 mg/kg per injection) following equal 30-s delays to infusion. Second, choice was between equal doses (0.1 mg/kg per injection) following 3:1 delays (30 s/10 s, 90 s/30 s, 270 s/90 s, 810 s/270 s). Third, choice was between 0.1 or 0.03 mg/kg per injection after the same 3:1 delays with the larger dose following the longer delay and the smaller dose following the shorter delay. Fourth, the same 3:1 delays were used to study choice between 0.3 and 0.1 mg/kg per injection. Results. With equal delays, the larger dose of cocaine was chosen almost exclusively, and with equal doses, the shorter delay was chosen almost exclusively. When both dose and delay were manipulated, mean large-dose (0.1 mg/kg per injection) choices for three of four subjects was 98% when the delays were the shortest (30 s/10 s), but this preference reversed as the delays increased, so that 74% of choices were for the smaller dose (0.03 mg/kg per injection) at the longest delays (810 s/270 s). This systematic decrease in large-dose choices as the absolute, but not relative, values of the delays were increased, was also observed with the higher dose combination. Conclusion. Delay discounting was supported by the present findings in that the value of a large reinforcer (higher cocaine dose) was decreased as its delay to presentation was increased. The importance of not only relative, but absolute, values of delays to drug reinforcement in determining drug choice was also demonstrated. Thus, a self-control/impulsivity paradigm can be extended to conditions with non-human subjects and drug reinforcers. Electronic Publication     

Similar enhancement of the discriminative stimulus effects of cocaine and GBR 12909 by heroin in squirrel monkeys

RATIONALE AND OBJECTIVES: Heroin previously was shown to engender partial cocaine-like discriminative stimulus (DS) effects in squirrel monkeys. The present study assessed the degree to which heroin modified the DS effects of cocaine and the cocaine-like DS effects of the selective dopamine transport blocker GBR 12909. METHODS AND RESULTS: In squirrel monkeys discriminating cocaine (0.3 mg/kg) from saline, cocaine and GBR 12909 dose-dependently engendered levels of responding on the cocaine-associated lever greater than or equal to 90% (full substitution). Heroin engendered full substitution for cocaine in two monkeys, partial substitution (75%) in a third monkey, and no substitution in the fourth monkey. When administered as a pretreatment, heroin shifted the dose-response function for cocaine to the left in the three monkeys for which heroin engendered cocaine-lever responding, but did not alter the DS effects of cocaine in the fourth monkey. Heroin pretreatment also shifted the dose-response function for the cocaine-like DS effects of GBR 12909 to the left in the former three monkeys, and did not alter the effects of GBR 12909 in the fourth monkey. Isobolographic analysis of the DS effects of cocaine-heroin and GBR 12909-heroin combinations in the former three monkeys revealed that the potencies of the combinations were not different from predicted values based on dose-additive effects. CONCLUSIONS: These findings show that heroin can enhance similarly the DS effects of cocaine and GBR 12909, suggesting that activation of dopaminergic systems underlies enhancement of the interoceptive effects of cocaine by heroin.     

Naltrexone effects on food- and codeine-maintained responding in rhesus monkeys

The delivery of food or the i.v. injection of codeine maintained lever pressing in rhesus monkeys during alternating periods of daily experimental sessions. Responding was maintained by food or codeine under a chain differential reinforcement of other behavior 30 sec (DRO 30), fixed-ratio 30 response (FR 30) schedule of reinforcement. Maximum FR rates of codeine-reinforced responding were maintained by 25–47 μg/kg per injection codeine. Both lower (8 μg/kg per injection) and higher (80–800 μg/kg per injection) doses of codeine maintained lower FR response rates. FR rates of food-maintained responding only decreased as a function of codeine dose. Response rates during the DRO component of the schedule, when either food or codeine maintained responding, were extremely low (<0.01 responses/sec) and these rates were generally unaffected by the codeine dose. Naltrexone (0.003–0.32 mg/kg i.m.), administered before experimental sessions, produced a dose-related shift to the right in the rate-decreasing effects of codeine on FR responding maintained by food. In contrast, the dose-effect curve relating the FR rate of codeine-maintained responding to codeine dose was shifted consistently to the right only by the lowest dose of naltrexone (0.003 mg/kg). Although a 10-fold higher dose of naltrexone, 0.03 mg/kg, initially shifted the codeine self-injection curve to the right in one monkey, these higher naltrexone doses (0.03–0.32 mg/kg) generally resulted in response rates as low as or lower than those maintained by saline,e across a wide range of codeine doses (25–800 μg/kg per injection). These data suggest that naltrexone may decrease codeine-reinforced responding by mechanisms other than, or in addition to, a competitive antagonism of codeine's reinforcing effects.     

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. Compared to the initial FI baselines, cocaine intake (mg/kg per session) was significantly higher following an FR-history and significantly lower following training under an IRT schedule, for 60 consecutive sessions. In addition, there was a significant effect of behavioral history on the cocaine dose-response curve, such that descending limb was shifted farther to the right in FR-history subjects compared to IRT-history monkeys. Results from the present study indicate that previously established drug-seeking behavior can be modified by training under different reinforcement schedules. Knowledge of such historical variables may be important in understanding the determinants of drug self-administration.     

Effects of bromocriptine and desipramine on behavior maintained by cocaine or food presentation in rhesus monkeys

This experiment tested whether bromocriptine or desmethylimipramine (DMI), both agents used clinically to treat cocaine abuse, could specifically alter behavior maintained by cocaine injections. Rhesus monkeys were trained to press a lever in daily experimental sessions under a three-component multiple schedule of reinforcement. In the first and third components, food was available under a fixed-ratio (FR) 30 schedule. In the second component cocaine (0.025 or 0.050 mg/kg/injection, IV) was available under a FR 30 schedule. Monkeys received continuous (24 h/day) IV infusions of several doses of bromocriptine or DMI. Bromocriptine (0.8–6.4 mg/kg/day) was infused for at least the same number of sessions as was required for responding to decline to low levels when the monkeys were allowed to self-administer saline. DMI (0.8–12.8 mg/kg/day) was infused for a minimum of 3 weeks. In some instances, low doses of bromocriptine decreased responding maintained by cocaine without reducing food-maintained responding, while higher doses of bromocriptine decreased responding maintained by either food or cocaine. However, bromocriptine doses that reduced cocaine intake also caused overt stimulation of locomotor activity. In contrast, DMI, at doses as much as 10 times higher than those used clinically to treat cocaine abuse did not affect responding maintained by cocaine or food. These results indicate that bromocriptine can selectively reduce behavior maintained by cocaine, although apparently by a mechanism other than blockade of reinforcing effects. On the other hand, DMI did not alter the reinforcing effects of either cocaine or food under these conditions.     

Cocaine,d-amphetamine,and pentobarbital effects on responding maintained by food or cocaine in rhesus monkeys

The effects of IM injections of cocaine, d-amphetamine, and pentobarbital were studied in rhesus monkeys whose lever-press responding was maintained under a second-order fixed-interval, fixed ratio schedule of reinforcement. Within each session, fixed-interval components, ending with the IV injection of 30 g/kg cocaine (one group of monkeys) or the delivery of a 300 mg food pellet (second group of monkeys), alternated with fixed-interval components ending without an injection of cocaine or the delivery of food (extinction). Drug pretreatments generally caused comparable dose-related decreases in the overall rates of responding reinforced either by cocaine or by food. Response rates during extinction usually increased and then decreased as the dose of each drug increased. An analysis of the drug effects on response rates in different temporal segments of the fixed intervals showed that in both the reinforcement and extinction components, the normally low control rates of responding which occurred earlier in the intervals were usually increased, while higher control rates which occurred later in the intervals were increased less or decreased. Thus, the effects of these drugs were relatively independent of the reinforcing event (food or cocaine) and tended to depend more on the ongoing rate of responding under these conditions.     

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). Response rates were higher in this latter group compared to rates generated by either group of monkeys after food-reinforcement histories. Furthermore, a significant interaction between behavioral history and cocaine dose on response rates was observed. Results from the present study indicate that a history of responding maintained by a nondrug reinforcer can have significant and long-lasting effects on response rates and total cocaine intake under an FI schedule. Furthermore, these results indicate that prior experiences may produce different effects on acquisition and maintenance of cocaine self-administration.     

Cocaine-induced reinstatement during limited and extended drug access conditions in rhesus monkeys

Rationale  The progression of addiction from controlled to compulsive drug use leads to serious adverse consequences, including a greater propensity to relapse to drug use after sustained periods of abstinence. Objective  The present study assessed the potential effects of cocaine self-administration history on the magnitude and persistence of cocaine-induced reinstatement in rhesus monkeys (n = 6). Methods  During a 3-month period of limited access to cocaine self-administration under a second-order schedule, subjects could take a maximum of 0.5 mg/kg per session 5 days per week. During a subsequent 3-month period of extended access to cocaine self-administration, subjects could take an additional 3.0 mg/kg under a fixed-ratio 20 schedule 3 days per week. Reinstatement effects were evaluated on six separate occasions that included limited and extended access conditions. Saline was substituted for cocaine, and once extinction criteria were met (response rates <20% of cocaine-maintained rates), response-independent cocaine (0.1 mg/kg) was administered i.v. prior to extinction sessions. Reinstatement was defined as a restoration of drug-appropriate responding above extinction criteria. Reinstatement experiments were conducted repeatedly on a daily basis until response rates returned to extinction levels. Peak response rates provided a measure of reinstatement magnitude whereas number of sessions required to meet extinction levels provided a measure of reinstatement persistence. Results  Both the magnitude and persistence of reinstatement were consistent across all determinations regardless of drug history. Conclusions  The results indicate that reinstatement under the second-order schedule is remarkably stable even when supplemental drug intake is provided over several months.     

A comparison of d-amphetamine, l-amphetamine, and methamphetamine self-administration in rhesus monkeys

Rhesus monkeys were trained to self-administer cocaine on a fixed-ratio 10 schedule of reinforcement during a daily 3 hr session. d-amphetamine, l-amphetamine, and methamphetamine, at various dosages, were substituted for the cocaine for six consecutive sessions. The animals were returned to cocaine baseline between each test series. All three drugs were self-administered at rates higher than saline control levels. d-Amphetamine and metamphetamine were equipotent in maintaining self-administration behavior and both were approximately 4 times more potent than l-amphetamine.     

Effects of drugs on food- and cocaine-maintained responding III: Dopaminergic antagonists

 The effects of three dopamine (DA) antagonists (SCH23390, pimozide, and chlorpromazine), with various degrees of selectivity for D₁ and D₂ receptors, and an agonist (the cocaine analog, CFT) were studied on responding maintained under a multiple fixed-ratio (FR) 30 food, FR30 cocaine (1–100 μg/kg per injection) delivery, with an interposed 10-min time-out (TO), schedule in rhesus monkeys. The effects of each drug depended upon the unit dose of cocaine. With an intermediate (10 μg/kg per injection) unit dose of cocaine, each antagonist decreased rates of responding maintained by either event in a dose-related manner. At higher (56–100 μg/kg per injection) unit doses of cocaine, antagonists generally increased and then decreased both food- and cocaine-maintained responding in a dose-related manner. These increases appeared to result from the blockade of non-specific rate-decreasing effects of self-administered cocaine, questioning their relevance to the reinforcing effects of cocaine. The results failed to support a role for pharmacological selectivity in this rate-decreasing effect of cocaine, as both D₁ and D₂ antagonists were able to reverse the effect. In contrast, CFT decreased cocaine-maintained responding at doses less than those that decreased food-maintained responding, and failed to shift the cocaine dose-effect function to the left. These results, together with previous work, suggest that agonists can selectively decrease drug-seeking behavior. Received: 5 January 1996 / Final version: 5 August 1996     

The effect of second-order schedule history on fixed-ratio performance maintained by orally-delivered phencyclidine in rhesus monkeys

Thirteen monkeys were trained to self-administer orally-delivered phencyclidine (0.25 mg/ml) and water under a concurrent fixed ratio (FR) 16 schedule. Phencyclidine was available from one lip-operated drinking device and water was available from another drinking device during daily 3-hr sessions. Seven monkeys were trained to respond under a second-order FR 240 (FR 20: brief stimulus) schedule. Upon completion of 4800 responses, the monkeys were allowed to self-administer 300 phencyclidine deliveries under an FR 1 schedule. After a mean of 33.3 sessions of second order schedule training, including 10 sessions at the terminal parameter, the monkeys were returned to the concurrent FR 16 schedule. Phencyclidine-maintained responding persisted at rates that were 42 percent higher than before second-order schedule training; however, concurrent water-maintained behavior increased only slightly. A second group of three monkeys were treated in an identical manner except that during second-order schedule training they received a saccharin solution (0.05%, wt/vol) instead of phencyclidine. After a mean of 30 sessions of second-order schedule training, including 10 sessions at the terminal parameter, the monkeys were returned to the concurrent FR 16 schedule, and there was no consistent change in phencyclidine or water deliveries. A third group of three monkeys received 300 phencyclidine deliveries at the same time after session onset and for the same total number of sessions as the monkeys that received second-order schedule training with phencyclidine; however, this group was not required to respond under the second-order schedule to gain access to the phencyclidine deliveries.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reinforcing properties of intravenous procaine in rhesus monkeys.

The lever pressing behavior of rhesus monkeys was maintained by a fixed ratio 10 schedule of intravenous cocaine (3 monkeys) or codeine (2 monkeys) injections during 2 hour sessions. Saline or various doses of procaine hydrochloride were substituted for the baseline reinforcer for 6 consecutive sessions. Each substitution was separated by 3 or more days of cocaine or codeine reinforced responding. At one or more doses, procaine substitution resulted in response rates higher than saline control in all 5 animals. High response rates (greater than 30 injections per session) were obtained in 4 of the 5 monkeys. In addition, procaine self-administration was studied in two naive monkeys given 23 hour per day access to procaine following an initial 10 days of saline contingent operant level responding. At a dose of 0.3 mg/kg/injection, both animals initiated responding for procaine reinforcement. Drug intake varied widely from day to day, however each animal took over 1200 injections per day (over 360 mg/kg) at least once during the 30 days of access. With the exception of decreased food intake, there was little evidence for behavioral toxicity from these doses. Following a second 10 days of saline self-administration, both animals were given access to 3.0 mg/kg/injection procaine. A substantially greater intake of procaine was observed which was associated with marked toxicity.     

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.     

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 the dopamine reuptake inhibitor PTT on reinstatement and on food- and cocaine-maintained responding in rhesus monkeys

Rationale High-affinity, slow-onset, long-acting dopamine transporter (DAT) inhibitors are being considered as potential agonist replacement therapies for cocaine addiction, and therefore the ability of these drugs to reinstate cocaine seeking and to selectively decrease cocaine-maintained responding should be assessed.Objectives The purpose of these experiments was to evaluate the effects of the active enantiomer of a high-affinity, slow-onset, long-acting DAT inhibitor, (–)2-propanoyl-3-(4-tolyl)-tropane (PTT), and cocaine on food- and cocaine-maintained responding and on extinguished responding previously maintained by cocaine in non-human primates using a within-subjects design.Methods Rhesus monkeys (n=3) responded under a multiple fixed-ratio schedule of food (1 g) and drug reinforcement, and cocaine dose-response curves (saline, 0.003–0.3 mg/kg per injection) were determined. The effects of pretreatment with (–)PTT (0.001–0.056 mg/kg, IV) and cocaine (0.03–0.3 mg/kg, IV) were determined when the dose of cocaine that maintained peak response rates (0.03 mg/kg per injection) or saline was available.Results (–)PTT and cocaine reduced cocaine intake; (–)PTT affected cocaine self-administration only at doses that also decreased food-maintained responding. (–)PTT and cocaine reinstated responding that was previously reinforced by cocaine at lower doses than were necessary to decrease cocaine-maintained responding. For all studies, PTT was at least 1.0 log-unit more potent than cocaine. Compared to cocaine, PTT had a longer duration of action in all behavioral measures.Conclusions These results suggest that PTT would decrease cocaine use, but only at doses that disrupted other behaviors. It appears that the potency of this class of drugs to reinstate cocaine-seeking is substantially greater than their potency at decreasing cocaine self-administration.     

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.     

Effects of the monoamine uptake inhibitors RTI-112 and RTI-113 on cocaine- and food-maintained responding in rhesus monkeys

Cocaine blocks uptake of the monoamines dopamine, serotonin and norepinephrine, and monoamine uptake inhibitors constitute one class of drugs under consideration as candidate “agonist” medications for the treatment of cocaine abuse and dependence. The pharmacological selectivity of monoamine uptake inhibitors to block uptake of dopamine, serotonin and norepinephrine is one factor that may influence the efficacy and/or safety of these compounds as drug abuse treatment medications. To address this issue, the present study compared the effects of 7-day treatment with a non-selective monoamine uptake inhibitor (RTI-112) and a dopamine-selective uptake inhibitor (RTI-113) on cocaine- and food-maintained responding in rhesus monkeys. Monkeys (N = 3) were trained to respond for cocaine injections (0.01 mg/kg/inj) and food pellets under a second-order schedule [FR2(VR16:S)] during alternating daily components of cocaine and food availability. Both RTI-112 (0.0032-0.01 mg/kg/hr) and RTI-113 (0.01-0.056 mg/kg/h) produced dose-dependent, sustained and nearly complete elimination of cocaine self-administration. However, for both drugs, the potency to reduce cocaine self-administration was similar to the potency to reduce food-maintained responding. These findings do not support the hypothesis that pharmacological selectivity to block dopamine uptake is associated with behavioral selectivity to decrease cocaine- vs. food-maintained responding in rhesus monkeys.     

Effects of repeated methamphetamine administration on methamphetamine self-administration in rhesus monkeys

The effects of prolonged exposure to high doses of stimulants on stimulant self-administration in rhesus monkeys have not been established. In the present experiment, rates of methamphetamine self-administration as well as the effects of methamphetamine on food-maintained responding were determined before and after a regimen of repeated methamphetamine injections. Increases in self-administration of some doses of methamphetamine as well as tolerance to the rate-decreasing effects of the drug on food-maintained responding were observed following the repeated injection regimen. The results suggest that while tolerance may develop to the rate-decreasing effects of the drug, there may be an increased sensitivity to its reinforcing properties. In addition, since this injection regimen has been shown in previous studies to deplete central monoamines, especially dopamine, the results suggest a role for these monoamines in these behavioral effects of methamphetamine.