Effects of altering reinforcer magnitude and reinforcement schedule on phencyclidine (PCP) self-administration in monkeys using an adjusting delay task

Compared to nondrug reinforcers, few studies have examined delay discounting for drug reinforcers. The purpose of the present study was to examine delay discounting in rhesus monkeys using orally delivered phencyclidine (PCP) as the reinforcer and to examine the effects of manipulating reinforcer magnitude and cost on delay discounting for PCP using an adjusting delay task. Monkeys could choose between a single delivery of PCP available immediately or a bundle of PCP deliveries available following a titrated delay. The average of the delays, or the mean adjusted delay (MAD), served as the quantitative measure of delay discounting. In Experiment 1, reinforcer magnitude was manipulated by varying the PCP concentration and the size of the delayed reinforcer (6 or 12 deliveries). The concentration-effect curve for PCP deliveries assumed an inverted U-shaped function, but varying PCP concentration had little effect on MAD values or the choice between immediate and delayed reinforcers. Increasing the size of the delayed reinforcer produced an upward and leftward shift in the concentration-effect curve. In Experiment 2, the cost of reinforcers was manipulated by increasing the fixed ratio (FR) requirement for each choice. Increasing the FR led to increased MAD values and decreased PCP self-administration.     

Increased impulsive choice for saccharin during PCP withdrawal in female monkeys: influence of menstrual cycle phase

Background

In previous studies with male and female rhesus monkeys, withdrawal of access to oral phencyclidine (PCP) self-administration reduced responding for food under a high fixed-ratio (FR) schedule more in males than females, and with a delay discounting (DD) task with saccharin (SACC) as the reinforcer impulsive choice for SACC increased during PCP withdrawal more in males than females.

Objectives

The goal of the present study was to examine the effect of PCP (0.25 or 0.5 mg/ml) withdrawal on impulsive choice for SACC in females during the follicular and luteal phases of the menstrual cycle.

Materials and methods

In component 1, PCP and water were available from two drinking spouts for 1.5 h sessions under concurrent FR 16 schedules. In component 2, a SACC solution was available for 45 min under a DD schedule. Monkeys had a choice of one immediate SACC delivery (0.6 ml) or six delayed SACC deliveries, and the delay was increased by 1 s after a response on the delayed lever and decreased by 1 s after a response on the immediate lever. There was then a 10-day water substitution phase, or PCP withdrawal, that occurred during the mid-follicular phase (days 7–11) or the late luteal phase (days 24–28) of the menstrual cycle. Access to PCP and concurrent water was then restored, and the PCP withdrawal procedure was repeated over several follicular and luteal menstrual phases.

Results

PCP deliveries were higher during the luteal (vs follicular) phase. Impulsive choice was greater during the luteal (vs follicular) phase during withdrawal of the higher PCP concentration.

Conclusions

PCP withdrawal was associated with elevated impulsive choice for SACC, especially in the luteal (vs follicular) phase of the menstrual cycle in female monkeys.     

Reduction of drug self-administration by an alternative non-drug reinforcer in rhesus monkeys: magnitude and temporal effects

Rationale: Recent studies have shown that non-drug alternative reinforcers reduce drug self-administration. A goal of the present study was to explore factors such as magnitude of the alternative reinforcer and inter-session access to the alternative to identify conditions that lead to optimal reductions in drug intake. Objectives: To evaluate the effects of increasing the volume/delivery (v/d) of saccharin on oral phencyclidine (PCP) self-administration in rhesus monkeys given continuous access to PCP and saccharin during daily sessions using a behavioral economic analysis. The effects of availability of a saccharin solution during the inter-session period on session PCP consumption in drug-experienced monkeys was also investigated. Methods: Subjects had access to PCP (0.25 mg/ml) and either water or saccharin (0.03%) from two drinking spouts under concurrent and independent fixed-ratio (FR) schedules during daily 3-h sessions. The FR requirements for both available liquids were simultaneously increased (FR4–64). The v/d of saccharin or water was increased (from 0.3 ml to 1.2 ml), while the v/d of PCP remained constant (0.6 ml). In a second experiment, subjects had access to water or saccharin and water during the inter-session period (17.5 h) under an FR1 schedule. PCP and water were available during daily 3-h sessions under concurrent FR schedules. The FR for both liquids was increased (FR16–128). Results: PCP intake was reduced at all FRs and magnitude conditions when saccharin (versus water) was concurrently available. Varying the v/d of saccharin only had a modest effect on the extent to which PCP intake was decreased at the higher FR values. Inter-session saccharin availability (versus water) reduced session PCP intake and the magnitude of this effect was also greater at the higher FR values. Conclusions: The magnitude of the saccharin delivery had an effect on PCP consumption at higher FRs, suggesting that economic factors such as high drug cost (FR) and low cost (responses/ml) of the alternative reinforcer (saccharin) interact to produce a maximum suppression of drug intake. Between-session availability of saccharin also effectively reduced drug intake, and it had a greater effect on the maintenance levels of drug self-administration when the unit price of drug was high. Received: 20 May 1999 / Final version: 28 July 1999     

Behavioral economics of drug self-administration

In behavioral economics, consumption of a reinforcer is determined by its price and by the price of other available reinforcers. This study examined the effects of price manipulations on the consumption of concurrently available coffee and cigarettes. During fifteen 4-h sessions, coffee and cigarettes were concurrently available according to fixed-ratio (FR) schedules of reinforcement. After consumption stabilized under a fixed ratio 100 for both reinforcers, the response requirement for each reinforcer was varied separately (i.e., FR 100, 1000 and 2500), while the response requirement for the other reinforcer was kept at 100. Increasing the FR value decreased coffee and cigarette consumption to a similar degree. Also, as the price for cigarettes increased (and consumption decreased), coffee consumption decreased; however, as the price of coffee increased, cigarette consumption did not change. These results indicate that for this setting the reinforcing effects of cigarettes and coffee were comparable but interacted asymmetrically. These findings when analyzed and quantified via economic concepts of own-price and cross-price elasticity illustrate the viability of using behavioral economics to examine drug self-administration in a choice paradigm.This study was supported by National Institute on Drug Abuse Grants DA 06626, KO1 DA 00109, DA 04545, and T32 DA 07242.     

Theory and method in the quantitative analysis of ”impulsive choice” behaviour: implications for psychopharmacology

Impulsive choice refers to the selection of small immediate gains in preference to larger delayed gains, or the selection of large delayed penalties in preference to smaller immediate penalties. Current theoretical interpretations of impulsive choice are reviewed, and a synthesis of these ideas, the ”multiplicative hyperbolic model of choice”, is presented. The model assumes that the value of a positive reinforcer increases as a hyperbolic function of its size, and decreases as a hyperbolic function of its delay and the odds against its occurrence. Each hyperbolic function contains a single discounting parameter which quantifies the organism’s sensitivity to the variable in question. The hyperbolic discounting functions combine multiplicatively to determine the overall value of the reinforcer. Equivalent functions are postulated to govern the (negative) value of aversive events, the net value of an outcome reflecting the algebraic sum of the positive and negative values. The model gives rise to a quantitative methodology for studying impulsive choice, based on a family of linear indifference (null) equations, which describe performance under conditions of indifference, when the values of the reinforcers are assumed to be equal. This methodology may be used to identify individual differences in sensitivity to the magnitude, delay and probability of reinforcement. The methodology is also suitable for the quantitative evaluation of the effects of some pharmacological interventions on discounting parameters. Recent psychopharmacological studies of impulsive choice are reviewed, and the utility of indifference equations for extending this work, and developing a quantitative psychopharmacology of impulsive choice is discussed. Received: 14 April 1999 / Final version: 6 May 1999     

Effects of lesions of the orbitofrontal cortex on sensitivity to delayed and probabilistic reinforcement

RATIONALE: Lesions of the orbital prefrontal cortex (OPFC) can cause pathologically impulsive behaviour in humans. Inter-temporal choice behaviour (choice between reinforcers differing in size, delay and/or probability) has been proposed as a model of "impulsive choice" in animals. OBJECTIVE: The effect of lesions of the OPFC on rats' inter-temporal choice behaviour was examined in two experiments: (1) rats chose between a smaller immediate reinforcer and a larger delayed reinforcer; (2) rats chose between a smaller certain reinforcer and a larger probabilistic reinforcer. METHODS: Under halothane anaesthesia, rats received injections of the excitotoxin quinolinate into the OPFC (0.1 M, 0.5 microl, two injections in each hemisphere), or sham lesions (injections of vehicle). They were trained to press two levers (A and B) for food-pellet reinforcers in discrete-trials schedules. In free-choice trials, a press on A resulted in immediate delivery of one food pellet; a press on B resulted in delivery of two pellets, either following a delay ( d) (experiment 1), or with a probability ( p) <1 (experiment 2). The values of d and p were manipulated across phases of the experiments. The locations of the lesions were verified histologically at the end of the experiment. RESULTS: In experiment 1, both groups showed declining choice of lever B as a function of d. The lesioned rats showed significantly shorter indifference delays ( D50: the value of d corresponding to 50% choice of lever B) than the sham-lesioned rats. In experiment 2, both groups showed declining choice of lever B as a function of the odds against delivery of the two-pellet reinforcer, theta ( theta =[1/ p]-1). The lesioned rats showed lower indifference odds ( theta50: the value of theta corresponding to 50% choice of lever B) than the sham-lesioned rats. In both experiments, the lesioned rats showed extensive atrophy of the OPFC, with sparing of the dorsolateral prefrontal cortex. CONCLUSIONS: The results show that lesions of the OPFC can promote preference for the smaller and more immediate, and the smaller and more certain of two reinforcers. The results are consistent with two interpretations: the lesion may have altered (i) the rates of delay and odds discounting, and/or (ii) sensitivity to the ratio of the sizes of the two reinforcers.     

Effects of quinolinic acid-induced lesions of the nucleus accumbens core on inter-temporal choice: a quantitative analysis

Rationale There is evidence that lesions of the nucleus accumbens core (AcbC) promote preference for smaller earlier reinforcers over larger delayed reinforcers in inter-temporal choice paradigms. It is not known whether this reflects an effect of the lesion on the rate of delay discounting, on sensitivity to reinforcer magnitude, or both. Aim We examined the effect of AcbC lesions on inter-temporal choice using a quantitative method that allows effects on delay discounting to be distinguished from effects on sensitivity to reinforcer size. Materials and methods Sixteen rats received bilateral quinolinic acid-induced lesions of the AcbC; 14 received sham lesions. They were trained under a discrete-trials progressive delay schedule to press two levers (A and B) for a sucrose solution. Responses on A delivered 50 μl of the solution after a delay d _A; responses on B delivered 100 μl after d _B. d _B increased across blocks of trials, while d _A was manipulated across phases of the experiment. Indifference delay d _B(50) (value of d _B corresponding to 50% choice of B) was estimated in each phase, and linear indifference functions (d _B(50) vs d _A) derived. Results d _B(50) increased linearly with d _A (r ² > 0.95 in each group). The intercept of the indifference function was lower in the lesioned than the sham-lesioned group; slope did not differ between groups. The lesioned rats had extensive neuronal loss in the AcbC. Conclusions The results confirm that lesions of the AcbC promote preference for smaller, earlier reinforcers and suggest that this reflects an effect of the lesion on the rate of delay discounting.     

Effects of a non-drug reinforcer,saccharin, on oral self-administration of phencyclidine in male and female rhesus monkeys

Rationale Previous research with male subjects has demonstrated that alternative non-drug reinforcers reduce self-administration of drugs of abuse under a wide variety of conditions. Recent findings indicate sex differences in drug self-administration, and females may be more responsive to the suppressive effects of pharmacological treatment strategies than males; however, it is not known whether or not there are similar sex differences in the effect of behavioral interventions, such as non-drug reinforcers, on drug self-administration.Objectives The goal of this research was to determine whether the suppressive effects of non-drug reinforcers vary as a function of sex using behavioral economic measures in rhesus monkeys.Methods During daily 3-h sessions, seven male and seven female adult rhesus monkeys orally self-administered concurrently available phencyclidine (PCP) and water, PCP and saccharin, or saccharin and water, from two separate spouts, under a series of fixed-ratio (FR) values. The FR value was varied from 4 to 8, 16, 32, 64, and 128, and the demand (consumption × FR) for PCP was measured in order to determine the effect of concurrent access to saccharin (versus water).Results The availability of saccharin resulted in reduced PCP self-administration compared with the condition when water was available in both males and females. Consumption of PCP and saccharin was similar between the sexes under the two conditions when water was concurrently available. When saccharin was available with PCP, PCP responses and deliveries were reduced in both sexes at low to intermediate FR values, but the amount of PCP consumed (mg/kg) was reduced significantly more in females than in males only at FR 32.Conclusions Non-drug reinforcers are an effective treatment for drug abuse in females as well as males over a range of PCP FR values. Males show elevated drug-maintained responding compared with females, but when differential body weights are considered (mg/kg) females consume more than males only under limited schedule parameters.     

Impulsivity (delay discounting) for food and cocaine in male and female rats selectively bred for high and low saccharin intake

Previous research in rats indicates that delay discounting for food, a model of impulsivity, predicted the rate of acquisition of cocaine self-administration. In other studies, rats bred for high saccharin intake (HiS) acquired cocaine self-administration at higher rates than those with low saccharin intake (LoS), and female (F) rats acquired cocaine self-administration more rapidly than males (M). The purpose of this study was to examine a possible connection between impulsivity, saccharin intake, and sex by comparing M and F rats from the HiS and LoS selectively bred lines on measures of impulsivity; i.e., their rate of delay discounting for food or i.v. cocaine infusions. The adjusting delay procedure allowed rats access to 2 response levers, and a pellet dispenser or an i.v. drug infusion pump. In 4 groups (HiS M, HiS F, LoS M, LoS F) responses under a fixed-ratio (FR) 1 schedule on one lever resulted in one 45 mg pellet immediately, and responses on the other lever resulted in 3 or 6 pellets after a delay. Four additional groups received either a small cocaine (0.2, 0.4, or 0.8 mg/kg) infusion immediately or a delayed larger infusion (3x the amount of the small infusions). The delay to the larger reinforcer began at 6 s and increased or decreased by 1 s following responses on the delay or immediate levers, respectively. A mean adjusted delay (MAD) was calculated over 30 choice trials during each daily 3-hour session, and it was used as a quantitative measure of impulsivity. In groups maintained by food, HiS rats were more impulsive (lower MADs) than LoS rats, and LoS females were more impulsive than LoS males. There were no phenotype or sex differences in delay discounting for cocaine. Understanding the relationship between impulsivity and other predictors of drug abuse (e.g., sex, saccharin intake) is important in developing prevention and treatment strategies.     

Oral self-administration of N-allylnormetazocine (SKF-10,047) stereoisomers in rhesus monkeys: substitution during phencyclidine self-administration and withdrawal

Orally-delivered N-allylnormetazocine (NANM) and its isomers were tested for their ability to function as reinforcers by substituting them for phencyclidine (PCP). Two monkeys were trained to self-administer PCP (0.25 mg/ml) and water under concurrent fixed-ratio (FR) 16 schedules during 3-hr sessions. Liquid deliveries were contingent upon lip-contact responses on solenoid-operated drinking devices. When the dextro (+)-isomer of NANM (0.062-1 mg/ml) was substituted for PCP, response rates increased and then decreased in an inverted U-shaped concentration-response function with peak response rates comparable to those maintained by PCP. Drug intake ranged from 2.8 to 25.7 mg/kg across the two monkeys and five concentrations. Water-maintained responding was considerably lower than drug-maintained behavior indicating that NANM was functioning as a reinforcer. As previously reported for PCP, almost all of the (+)-NANM was self-administered during the first half of the session. Substitution of the levo (-)-isomer of NANM resulted in an immediate decline to low response rates that were not distinguishable from those maintained by water. The racemic form (+/-) of NANM was also not self-administered in excess of concurrent water. In the second experiment concurrent PCP- and water-maintained responding were reestablished under FR 8 schedules during three 6.5-hr sessions daily. Food (6 g/pellet) was available under FR 64 and FR 80 schedules during three 1-hr sessions immediately preceding the liquid components. Water was then substituted for PCP for four days and PCP, (+)-, (-)- or (+/-)-NANM were reinstated in subsequent replications of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of amphetamine and methylphenidate on delay discounting in rats: interactions with order of delay presentation

Rationale

Drug effects on delay discounting are thought to reflect changes in sensitivity to reinforcer delay, although other behavioral mechanisms might be involved. One strategy for revealing the influence of different behavioral mechanisms is to alter features of the procedures in which they are studied.

Objective

This experiment examined whether the order of delay presentation under within-session delay discounting procedures impacts drug effects on discounting.

Methods

Rats responded under a discrete-trial choice procedure in which responses on one lever delivered one food pellet immediately and responses on the other lever delivered three food pellets either immediately or after a delay. The delay to the larger reinforcer (0, 4, 8, 16, and 32 s) was varied within session and the order of delay presentation (ascending or descending) varied between groups.

Results

Amphetamine (0.1–1.78 mg/kg) and methylphenidate (1.0–17.8 mg/kg) shifted delay functions upward in the ascending group (increasing choice of the larger reinforcer) and downward in the descending group (decreasing choice of the larger reinforcer). Morphine (1.0–10.0 mg/kg) and delta-9-tetrahydrocannabinol (0.32–5.6 mg/kg) tended to shift the delay functions downward, regardless of order of delay presentation, thereby reducing choice of the larger reinforcer, even when both reinforcers were delivered immediately.

Conclusion

The effects of amphetamine and methylphenidate under delay discounting procedures differed depending on the order of delay presentation, indicating that drug-induced changes in discounting were due, in part, to mechanisms other than altered sensitivity to reinforcer delay. Instead, amphetamine and methylphenidate altered responding in a manner consistent with increased behavioral perseveration.     

Effects of central 5-hydroxytryptamine depletion on sensitivity to delayed and probabilistic reinforcement

RATIONALE: The ascending 5-hydroxytryptaminergic (5-HTergic) pathways are believed to be involved in "impulse control". Rats whose 5-HTergic pathways have been destroyed are more liable than intact rats to select a smaller, immediate reinforcer rather than a larger, delayed reinforcer (impulsive choice), and recent evidence indicates that this effect of central 5-HT depletion reflects a change in the rate of time discounting (i.e. a change in the rate at which reinforcers become devalued as a function of delay). Delay of reinforcement and uncertainty of reinforcer delivery are believed to have equivalent effects on choice behaviour. However, it is not known whether central 5-HT depletion affects choice between probabilistic reinforcers. OBJECTIVE: We examined the effects of central 5-HT depletion on choice behaviour in two experiments: In experiment 1, rats chose between a smaller immediate reinforcer and a larger delayed reinforcer; in experiment 2, rats chose between a smaller certain reinforcer and a larger probabilistic reinforcer. METHODS: Rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei or sham lesions. They were trained to press two levers for food-pellet reinforcers in discrete-trials schedules. In free-choice trials, selection of lever A resulted in immediate delivery of one food pellet; selection of lever B resulted in delivery of 2 pellets, either following a delay (dB) (experiment 1) or with a probability (pB) less than 1 (experiment 2). RESULTS: In experiment 1, both groups showed declining choice of lever B (%B) as a function of dB. The lesioned group showed shorter indifference delays (D50: the value of dB corresponding to %B=50) than the sham-lesioned group. In experiment 2, both groups showed declining choice of lever B as a function of the odds against delivery of the two-pellet reinforcer, thetaB (thetaB=[1/pB]-1). There was no difference between the "indifference odds" (theta50: the value of thetaB corresponding to %B=50) between the two groups. In both experiments, the levels of 5-HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered. CONCLUSIONS: These results provide additional evidence that central 5-HTergic mechanisms are involved in time discounting, but provide no evidence for a similar role of 5-HT in rats' sensitivity to probabilistic reinforcement.     

Assessment of magnitude and availability of a non-drug reinforcer on preference for a drug reinforcer

This study examined choice of beer over an alternative, non-drug reinforcer (food or money), under conditions where the magnitude and availability of the non-drug reinforcer was varied. Normal volunteers participated in three sessions consisting of a computerized choice task followed by a period of relaxation and consumption of earned reinforcers. The computer task consisted of a concurrent choice schedule in which the availability of the non-drug reinforcer was varied across ‘trials’ from random ratio 1.3 to 16 (probability of reinforcement: 75 per cent to 6 per cent). Across the three sessions the magnitude of the non-drug reinforcer was varied (i.e. small, medium, large). The magnitude and availability of beer remained constant across trials at a random ratio 4 (probability of reinforcement: 25 per cent). Two experiments were conducted, one in which food was the alternative reinforcer (Experiment I) and one in which money was the alternative reinforcer (Experiment II). In both experiments, decreasing the response requirement for the non-drug reinforcer within the sessions resulted in an orderly decrease in the amount of responding to obtain alcohol. In Experiment I, changes in the magnitude of the food reinforcer did not change responding for beer. In Experiment II, however, responding for beer decreased when the magnitude of the alternative monetary reinforcer was increased. Thus, changes in the magnitude of an alternative reinforcer may have differential effects on responding for a drug reinforcer, depending on the nature of the alternative reinforcer.     

Between-session progressive ratio performance in rats responding for cocaine and water reinforcers

Rationale

A between-session progressive ratio (BtwPR) procedure was tested in rats responding for cocaine and water reinforcers.

Objectives

Experiment 1 evaluated the sensitivity of the BtwPR procedure to the magnitude of cocaine and water reinforcers. Experiment 2 compared BtwPR performance to within-session progressive ratio (WinPR) performance.

Methods

In experiment 1, rats were tested on a BtwPR procedure with three doses of cocaine (0.1, 0.3, and 1.0?mg/kg/inf) or volumes of water (0.01, 0.03, and 0.1?mL/reinforcer). BtwPR test sessions began with a seeking phase, during which the animal is required to complete a fixed ratio in order to initiate a 2-h consumption phase, where the reinforcer was available according to a fixed ratio 1 (FR1) schedule. Failure to complete the seeking ratio, which was increased after each test session, determined the breakpoint (BP). In experiment 2, the same BtwPR procedure was used except that the consumption phase was a WinPR schedule of reinforcement for cocaine (1.0?mg/kg/inf) or water (0.1?mL) reinforcers.

Results and conclusions

BtwPR BPs increased as a function of the magnitude of both cocaine and water reinforcers. The BtwPR produced smaller BPs than the WinPR for cocaine reinforcers. In contrast, the BtwPR produced larger BPs than the WinPR for water reinforcers. One possible explanation is that priming and response activating effects of the cocaine reinforcer increased the WinPR BP. BtwPR and WinPR procedures may measure different aspects of drug-seeking.     

Concurrent self-administration of ethanol and an alternative nondrug reinforcer in monkeys: effects of income (session length) on demand for drug

Eight rhesus monkeys (Macaca mulata) were trained to self-administer orally delivered ethanol (8%) and saccharin (0.03 or 0.3% wt/vol) or water under concurrent fixed-ratio (FR) schedules. The FR requirement for saccharin was fixed at 32, while the FR for ethanol was varied (4, 8, 16, 32, 64 and 128) in a nonsystematic order to assess demand for drug. Demand was defined as consumption plotted as a function of price (FR). Income was defined as the duration of access to available resources. Income was varied by allowing access to the concurrently available liquids 20, 60 or 180 min per day. Order of testing was counter-balanced across monkeys. Saccharin deliveries were much higher than ethanol deliveries under the 180-min income condition; however, they were lower than ethanol deliveries when income was reduced to 20 min and the ethanol FR was 4, 8 or 16. Thus, when the price of drug was relatively low, consumption of drug exceeded that of the nondrug reinforcer, and that relationship was reversed as income decreased. Saccharin deliveries sustained a proportionally greater reduction due to decreased income compared to ethanol deliveries. As income decreased from 180 to 20 min, saccharin deliveries were reduced by an average of 79.1% (across ethanol FR conditions) while ethanol deliveries were reduced by an average of 41.2 and 40.8% when concurrent saccharin or water were available, respectively; thus, drug self-administration was more resistant to income changes than saccharin. The demand for ethanol was shifted downward in a parallel fashion as income decreased. As ethanol cost (FR) increased, there were proportionately greater decreases in ethanol intake when saccharin was concurrently available compared to when water was available. There was a 35–50% reduction in ethanol deliveries due to concurrent saccharin (versus water) at FR 4, compared to a 55–75% reduction at FR 128. Cost of ethanol (FR), income level and the availability of a nondrug reinforcer are all variables that modify ethanol-reinforced behavior, and income alters the relative preference for a drug versus nondrug reinforcer.     

Impulsivity (delay discounting) as a predictor of acquisition of IV cocaine self-administration in female rats

Rationale Previous research in humans suggests a relationship between drug abuse and impulsivity as shown by selection of a smaller immediate reward over a larger delayed reward. However, it is not clear whether impulsivity precedes drug abuse or drug abuse influences impulsivity.Objective The hypothesis of the present experiment was that rats selected for choosing smaller, immediate over larger, delayed food would acquire IV cocaine self-administration faster than those choosing larger, delayed food rewards.Methods Female rats were screened for locomotor activity and trained on a delay discounting procedure that allowed them access to two response levers and a food pellet dispenser. Under a fixed-ratio (FR) 1 schedule, responding on one lever resulted in immediate delivery of one 45 mg pellet, while responding on the other lever resulted in delivery of three 45 mg pellets after a variable delay that increased after responses on the delay lever and decreased after responses on the immediate lever. For each rat, a mean adjusted delay (MAD) was calculated for each daily session, and stability was defined as MADs varying less than 5 s across 5 days. Based on their average MADs, rats were separated into low impulsive (LoI) and high impulsive (HiI) groups, implanted with an indwelling IV catheter, and trained to lever press for cocaine (0.2 mg/kg) under an FR1 schedule.Results There were no differences in locomotor activity between the LoI and HiI groups; however, a greater percentage of the HiI group acquired cocaine self-administration, and they did so at a significantly faster rate than the LoI rats.Conclusions Performance on the delay discounting model of impulsivity predicted vulnerability to subsequent acquisition of cocaine self-administration.     

The generalized matching law as a predictor of choice between cocaine and food in rhesus monkeys

Rationale: The generalized matching law predicts that the relative rate of behavior maintained by different reinforcers will match the relative rate of reinforcement. It has previously been shown that responding maintained by either food deliveries or cocaine injections under concurrent variable-interval (conc VI) schedules is well described by the generalized matching law. However, the generality of this conclusion to the choice between a drug and a non-drug reinforcer has not been well established. Objective: The objective of the present study was to determine the extent to which the generalized matching law could account for choice between cocaine and food. Methods: Four male rhesus monkeys (Macaca mulatta) lever pressed under various pairs of conc VI schedules with food and/or cocaine injection as the maintaining events. Two doses of cocaine (0.025 and 0.05 mg/kg per injection) were selected to provide information about reinforcer magnitude. Results: As has been found in a context of choice between identical reinforcers, the generalized matching law accounted for most behavior. As in earlier studies with identical reinforcers, there was less responding apportioned to the alternative with the greater reinforcement frequency than predicted by the generalized matching law, i.e., undermatching was observed frequently. There was a tendency for more responding to be emitted toward the food alternative when the lower dose of cocaine was available and toward the drug alternative when the higher dose of cocaine was available. Conclusion: These results suggest that, as proposed by the generalized matching law, relative reinforcement rate is an important determinant of choice between a drug and a non-drug reinforcer. Electronic Publication     

A comparison of progressive ratio schedules versus behavioral economic measures: effect of an alternative reinforcer on the reinforcing efficacy of phencyclidine

 Alternative non-drug reinforcers have been demonstrated to decrease drug-reinforced behavior by both decreasing relative reinforcing efficacy and substituting for the drug reinforcer. The effect of saccharin on responding maintained by orally delivered phencyclidine (PCP) was examined in this study using concurrent progressive-ratio (PR) schedules of reinforcement and a behavioral economic analysis of demand. Seven adult male rhesus monkeys self-administered PCP (0.06, 0.12, 0.25, 0.50 and 1.0 mg/ml) and either concurrent water or saccharin (0.03% wt/vol) from two drinking spouts under concurrent independent PR schedules. During daily sessions the response requirements (lip contacts on automatic drinking spouts) increased across 15 levels, from 8 to 4096. Each successful ratio completion resulted in the availability of 40 liquid deliveries under an FR 1 schedule and a subsequent increment in the PR. Concentrations of PCP were presented in a non-systematic order and presentation of the concurrent liquid, saccharin or water, was counterbalanced across subjects. All behaviors maintained by PCP were significantly greater than those maintained by water. Replacement of water with saccharin served to significantly decrease PCP-maintained responding and break points (BP) across the range of PCP concentrations; however, saccharin did not significantly decrease deliveries of PCP. Saccharin maintained significantly greater responding, BPs and deliveries compared to either PCP or water, across all PCP concentrations. The use of BP as a measure of reinforcing efficacy suggests that saccharin decreased the relative reinforcing efficacy of PCP. Furthermore, behavioral economic analyses suggested that saccharin decreased maximal PCP-maintained responding (P_max) in a similar fashion, suggesting that BP and P_max may be analogous measures of reinforcing efficacy. Received: 3 December 1996 / Final version: 20 February 1997     

Effects of acute and chronic nicotine on impulsive choice in rats

Impulsive choice, or preference for small immediate reinforcers over large delayed reinforcers, has been associated with cigarette smoking. The direct effects of nicotine on impulsive choice in laboratory animals are unknown. We examined the effects of acute and chronic nicotine injections, and the termination of injections, on impulsive choice in rats. Five rats made choices between a one- and a three-pellet reinforcer in a discrete trials procedure. The delay to the smaller reinforcer was always 1 s. A computer adjusted the delay to the larger reinforcer until the pattern of choices reflected indifference between the two alternatives. We assessed the effects of acute and chronic nicotine (vehicle, 0.03, 0.1, 0.3 and 1.0 mg/kg nicotine). The latency to make the first response of the session increased under the acute 1.0 mg/kg dose. There were no consistent differences in the effects of acute and chronic nicotine on response latency and lever pressing during the delays between choices. Acute injections of nicotine dose-dependently increased impulsive responding. After chronic injections, impulsive responding was increased equivalently regardless of dose, and it was increased even in the absence of nicotine. After drug injections were terminated, behavior remained impulsive for about 30 drug-free sessions, and then responding gradually returned to baseline levels. The results suggest that increases in impulsive choice were not due to anorectic effects, response biases or changes in conditioned reinforcement. Nicotine may have decreased the value of delayed reinforcers. Chronic nicotine exposure produced long-lasting but reversible increases in impulsive choice.     

Effects of acute and chronic administration of diazepam on delay discounting in Lewis and Fischer 344 rats

Impulsive choice is often examined using a delay-discounting procedure, where there is a choice between two reinforcers of different magnitudes presented at varying delays. Individual discounting rates can be influenced by many factors including strain differences and drug effects. Lewis (LEW) and Fischer 344 (F344) rats have behavioral and neurochemical differences relevant to delay discounting and were used to examine effects of acute and chronic administration of diazepam on impulsive choice. Consistent with the previous literature, larger-reinforcer choice decreased as a function of increasing delays for all rats, and steeper discounting functions were obtained for LEW relative to F344 rats. Acute and chronic administration of diazepam resulted in differential effects between rat strains and sometimes between subjects within the same rat strain. Overall, larger-reinforcer choice remained unchanged across multiple phases of the experiment for LEW rats. For F344 rats, larger-reinforcer choice increased following the acute administration of smaller doses of diazepam and decreased following the acute administration of the largest dose tested. Decreases in larger-reinforcer choice occurred for F344 rats during chronic and postchronic administration and persisted throughout a nondrug return-to-baseline phase. These results suggest potential directions for future investigation of environmental, genetic, and neurochemical variables involved in delay discounting.