Effect of streptozotocin-induced diabetes on performance on a progressive ratio schedule

Rationale

It has been suggested that streptozotocin (STZ)-induced diabetes causes a motivational deficit in rodents. However, some of the evidence adduced in support of this suggestion may be interpreted in terms of a motor impairment rather than a motivational deficit.

Objective

This experiment examined the effect of STZ-induced diabetes on performance on a progressive ratio schedule. The data were analysed using a new model derived from Killeen’s (Behav Brain Sci 17:105–172, 1994) Mathematical Principles of Reinforcement model which enables the effects of interventions on motivation or incentive value to be separated from effects on motor function.

Method

Animals were trained under a progressive ratio schedule using food-pellet reinforcement. Then they received a single intraperitoneal injection of 50 mg/kg of STZ or the vehicle. Training continued for 30 sessions after treatment. Running and overall response rates in successive ratios were analysed using the new model, and estimates of the model’s parameters were compared between groups.

Results

The parameter expressing incentive value was reduced in the group treated with STZ, whereas the parameters expressing motor capacity and post-reinforcement pausing were not affected by the treatment. Blood glucose concentration was significantly elevated in the STZ-treated group compared to the vehicle-treated group.

Conclusions

The results are consistent with the suggestion that STZ-induced diabetes is associated with a reduction of the incentive value of food.     

The effects of scopolamine on performance on a geometric progressive ratio schedule

Rats were trained to respond on a geometric progressive ratio schedule until performance was stable. They were then injected with the anticholinergic drug scopolamine at doses of 0.05, 0.1, 0.25, 1.0 and 2.0 mg/kg. Control animals were administered atropine methyl nitrate (1–20 mg/kg). Increasing doses of scopolamine typically produced first an increase, then a decrease in behavior compared with baseline levels, measured by total number of responses, total number of reinforcements, and final completed ratio, per session. Atropine methyl nitrate had no effect on the behaviour of the control animals.This indicates that the effects of scopolamine are due to its central action. The inverted-U dose-response curve found for scopolamine resembles that found for chlordiazepoxide, phenobarbital, and d-amphetamine on progressive schedules.Research supported by grants C70/20, 70/44, and 72/24 to N.M.B. Preparation of the paper was aided by a grant to W.J.S. from the Canterbury Branch, N.Z. Psychological Society. An early version of this paper was presented to the Annual Conference, N.Z. Ps. S., Auckland, 1973. Research reported was performed in partial fulfilment of the requirements of the M. Sc. degree by W. J. S.     

Effect of orexin-B-saporin-induced lesions of the lateral hypothalamus on performance on a progressive ratio schedule

It has been suggested that a sub-population of orexinergic neurones whose somata lie in the lateral hypothalamic area (LHA) play an important role in regulating the reinforcing value of both food and drugs. This experiment examined the effect of disruption of orexinergic mechanisms in the LHA on performance on the progressive ratio schedule of reinforcement, in which the response requirement increases progressively for successive reinforcers. The data were analysed using a mathematical model which yields a quantitative index of reinforcer value and dissociates effects of interventions on motor and motivational processes. Rats were trained under a progressive ratio schedule using food-pellet reinforcement. They received bilateral injections of conjugated orexin-B-saporin (OxSap) into the LHA or sham lesions. Training continued for a further 40 sessions after surgery. Equations were fitted to the response rate data from each rat, and the parameters of the model were derived for successive blocks of 10 sessions. The OxSap lesion reduced the number of orexin-containing neurones in the LHA by approximately 50% compared with the sham-lesioned group. The parameter expressing the incentive value of the reinforcer was not significantly altered by the lesion. However, the parameter related to the maximum response rate was significantly affected, suggesting that motor capacity was diminished in the OxSap-lesioned group. The results indicate that OxSap lesions of the LHA disrupted food-reinforced responding on the progressive ratio schedule. It is suggested that this disruption was brought about by a change in non-motivational (motor) processes.     

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.     

Nicotine self-administration in rats on a progressive ratio schedule of reinforcement

Rationale: Robust intravenous (i.v.) nicotine self-administration (SA) in rats has been reported by several laboratories, including our own, using fixed ratio (FR) schedules of reinforcement. Studies on other drugs of abuse, however, suggest that progressive ratio (PR) schedules may provide additional information not gained using FR schedules. Objective: Here, we attempt to establish and characterize nicotine SA on a PR. Methods: One study allowed animals to acquire SA on a FR at four doses of nicotine (0.02, 0.03, 0.06, 0.09 mg/kg) before being switched to a PR. A second study examined extinction by saline substitution or pretreatment with the nicotinic antagonist, mecamylamine, including a preliminary analysis into the role of secondary reinforcers in the extinction process. Results: SA of nicotine on a PR was stable across repeated sessions. The number of infusions earned on a PR correlated with infusion rate on a FR; however, a large portion of the variance in SA on a PR could not be accounted for by infusion rate on a FR. Infusions on a PR increased across the same range of doses that produced a decrease in the infusion rate on a FR. Extinction of responding occurred after saline substitution or pretreatment with mecamylamine, and animals re-acquired when nicotine was again available without pretreatment. The presence of drug-paired stimuli appeared to lengthen the extinction process. Conclusions: Nicotine supports stable SA on a PR. Since PR and FR schedules may measure different aspects of nicotine reinforcement, PR schedules may be valuable in further characterizing group and individual differences in nicotine reinforcement. Received: 28 December 1998 / Final version: 14 June 1999     

Intra-VTA baclofen attenuates cocaine self-administration on a progressive ratio schedule of reinforcement

The effect of microinjections of baclofen into the ventral tegmental area (VTA), nucleus accumbens, or striatum on cocaine self-administration reinforced on a progressive ratio schedule was investigated. Intra-VTA baclofen produced the most potent modulation of cocaine intake, causing a significant reduction in cocaine-reinforced break points at a dose (56 ng/side) that was substantially lower than doses necessary to produce comparable reductions in the nucleus accumbens or striatum. During the time that cocaine-reinforced responding was suppressed, rats demonstrated the capacity to complete several hundred responses on a concurrently available food-reinforced lever, indicating that the effect of baclofen on cocaine intake was not due to a generalized disruption in operant responding. The results indicate that GABA(B) receptors in the VTA may have the potential to modulate reward processes associated with cocaine use.     

Clozapine enhances breakpoint in common marmosets responding on a progressive ratio schedule

RATIONALE: Motivational effects of psychotropic drugs may contribute to their therapeutic profile and progressive ratio (PR) schedules provide a method of measuring these effects in animals. OBJECTIVE: Determine effects of selected antipsychotic, psychotomimetic, anxiolytic and antidepressant drugs on PR performance in common marmosets. METHOD: Marmosets were trained to lever press for banana milkshake reinforcement using a PR schedule, in which the number of lever presses to achieve successive reinforcements increased by one until responding ceased (breakpoint). RESULTS: Clozapine administered intramuscularly (0.01-2 mg/kg IM; 30 min pretreatment time (ptt) or by oral gavage (0.1-4 mg/kg PO; 60 min ptt) significantly increased the breakpoint. Independent tests of fluid consumption failed to show enhanced fluid intake after clozapine pretreatment, suggesting this effect was not due to drug induced polydipsia. Neither haloperidol (0.005-0.1 mg/kg PO; 60 min ptt) nor risperidone (0.0025-0.05 mg/kg PO; 60 min ptt) altered breakpoint. Olanzapine (0.01-1 mg/kg PO; 60 min ptt) significantly enhanced the breakpoint at 0.05 mg/kg PO, but the effect was not robust. Amphetamine (0.2-2 mg/kg SC; 30 min ptt) significantly reduced the breakpoint at 2 mg/kg and fluoxetine (0.1-1 mg/kg PO; 60 min ptt) was without effect. Diazepam significantly increased the breakpoint at 0.5 mg/kg PO. Drug-induced polydipsia might play a role in this response as independent tests showed increased fluid consumption following diazepam. CONCLUSIONS: These results demonstrate that, unlike other antipsychotics, clozapine over a wide dose range increased the motivational state of marmosets to respond for banana milkshake. This motivational aspect of clozapine's actions may contribute to its unique clinical profile and the PR procedure may provide a method for detecting novel antipsychotics with a clozapine-like profile.     

A new progressive ratio schedule for support of morphine self-administration in opiate dependent rats

Rationale and objectives In preliminary studies, we observed that opiate dependent rats self-administered only a small number of morphine injections under a PR (progressive ratio) schedule developed to study psychostimulant self-administration. Therefore, a new schedule was developed to support morphine self-administration by incrementing response requirements in a relatively gradual manner. The present study compared morphine self-administration under a commonly used PR schedule to self-administration maintained by our modified PR schedule. Methods After pretreatment with non-contingent morphine, rats acquired self-administration under fixed-ratio (FR) schedules of intravenous morphine delivery. Morphine-maintained behavior was evaluated under a standard PR schedule (termed "PR3–4", because the third response requirement was four lever presses), and our modified PR schedule (termed "PR9–4", because the ninth response requirement was four lever presses). The PR9–4 schedule was also evaluated for self-administration of morphine doses of 0.001–3.2 mg/kg per injection. Results The number of ratios completed for morphine self-administration on the PR9–4 schedule, but not the PR3–4 schedule, exceeded values obtained during extinction. Dose-related increases in completed ratios occurred for morphine self-administration on the PR9–4 schedule, with stable patterns emerging after three sessions. A relatively flat dose-response relationship was observed, which did not increase monotonically with morphine dose. Morphine self-administration on the PR9–4 schedule decreased mean inter-injection interval and prolonged the duration of responding during 6-h sessions. Conclusions In the present study, a schedule that incremented response requirement gradually (PR9–4) supported reliable self-administration across a range of morphine doses.     

Delayed access to alcohol accelerates self-administration of alcohol on a progressive ratio schedule

In a previous report, we found that a 5-min. delay in alcohol access increases ethanol intake in rats trained to self-administer 5% ethanol. To assess the effects of this delay on the motivation to self-administer ethanol, Wistar rats were trained on a progressive ratio schedule of reinforcement and presented with the 5-min. delay. There was no change in break point (6 presses/delivery), active (125 presses/30 min.) or inactive (10 presses/30 min.) lever presses after the 5-min. delay compared to baseline. However, response cessation occurred 10 min. earlier in this delay session compared to baseline indicating that consumption was accelerated by delayed access to alcohol.     

Heroin self-administration in rats under a progressive ratio schedule of reinforcement

Heroin self-administration behavior under a progressive ratio (PR) schedule of reinforcement was evaluated in rats. The schedule was designed to restrict drug intake, minimize opiate dependency, and quantify the number of responses emitted (final response ratio) in order to receive a limited number of heroin infusions. Final ratios were found to be stable and did not increase with chronic (31 days) PR reinforcement. The ability of the PR schedule to detect changes in heroin reinforcement was demonstrated by evaluating the effect of naltrexone pretreatment and unit dose alteration on final ratios. Naltrexone (0.4 mg/kg) reduced final ratios and an inverted U dose-response relationship was established for the unit heroin doses 12.5–100 µg/injection. Maximal final ratios occurred with 50 µg/injection heroin reinforcement. This PR schedule may provide a useful method for evaluating the effects of pharmacological manipulations or lesions on opiate reinforcement.     

A dopamine partial agonist and antagonist block amphetamine self-administration in a progressive ratio schedule

A recently characterized class of compounds, dopamine partial agonists, have been suggested as potential therapeutic candidates for pharmacological intervention in psychostimulant addiction. These drugs bind to dopamine receptors with high affinity and low intrinsic activity and are thought to behave as functional antagonists in conditions of high dopaminergic tone, and as agonists in conditions of low receptor occupancy by dopamine. The aim of the present study was to characterize the effects of terguride, a partial dopamine agonist at the D2 receptor subtype, on intravenous self-administration of amphetamine in a progressive ratio schedule and to compare it with the effects produced by the dopamine D2 antagonist eticlopride and the dopamine D2 full agonist quinpirole. Terguride at the doses of 0.2 and 0.4 mg/kg i.p. significantly decreased the maximum number of responses delivered for a single injection of amphetamine ("breaking point"), an effect similar to that produced by the antagonist eticlopride (0.01-0.1 mg/kg s.c.). In contrast, administration of quinpirole (0.1-1 mg/kg s.c.) did not significantly modify the breaking point for amphetamine responding. Also, terguride dose-dependently increased responding for amphetamine self-administration on a continuous reinforcement schedule. These data further confirm the effects of terguride on psychostimulant self-administration and indicate that under these conditions partial dopamine agonists act as functional dopamine receptor antagonists.     

The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats

Although it has been demonstrated that many of the behavioral responses to psychomotor stimulants are gender dependent and hormonally sensitive, few studies have examined the possibility that the estrous cycle interacts with drug reinforcement in laboratory animals. The present experiment assessed the effect of the estrous cycle on two aspects of cocaine self-administration behavior: the breaking point on a progressive ratio (PR) schedule and the rate of cocaine intake on a fixed ratio one (FR1) schedule. On the PR schedule, the first lever response produced a drug infusion. Subsequent response requirements escalated with each injection until the behavior extinguished. Breaking points were defined as the final ratio completed. On a FR1 schedule, the estrous cycle had no effect on the rate of drug intake. On a PR schedule, female rats reached higher breaking points during estrus than during other stages of the estrous cycle. Furthermore, female rats displayed higher breaking points than male rats. It appears that the estrous cycle influences an animal's motivation to self-administer cocaine.     

Effects of cocaine on responding for ethanol or sucrose under a progressive ratio schedule

Progressive ratio (PR) schedules have been increasingly used to study motivation for self-administered drugs of abuse, such as psychostimulants and ethanol. In these and other studies, the breaking point (BP) is thought to be a measure of the motivation of the animal to work for a particular reward. Ethanol, a highly abused drug, maintains only low BPs. The present experiment was designed to examine if the low BP achieved by animals working for ethanol could be increased by the administration of a psychostimulant. A group working for a sucrose reinforcer was included for comparison. Rats previously trained to lever press under a PR schedule for 0.1 ml aliquots of 10% ethanol or 5% sucrose reinforcers were dosed once a week with cocaine (0, 5 and 15 mg/kg intraperitoneally) 30 min prior to their daily operant session using a Latin square design. Vehicle and 5 mg/kg cocaine had no effect on BP for any reinforcer, but 15 mg/kg cocaine produced a significantly higher BP (P<0.05) for animals working for either ethanol or sucrose. The same doses of cocaine decreased consumption of, and preference for, a 5% sucrose solution. These results indicate that, although cocaine administration does not increase sucrose preference, it may increase BP values in PR schedules. It is therefore unlikely that the increases in BP reflect cocaine-induced increased motivation, and they may be due to cocaine's stimulant or other properties. These data reinforce opinions that PR schedules may be unsuitable for assessing the effects of experimental manipulations on motivation for drugs with stimulant actions.     

Beta-funaltrexamine affects cocaine self-administration in rats responding on a progressive ratio schedule of reinforcement

Many studies have shown interactions between mu-opiates and the mesolimbic dopamine (DA) system. Mu-opiate receptor antagonists have been reported to either increase or decrease the rate of cocaine self-administration, and the interpretation of these data has been difficult. In an attempt to further characterize and localize the effect of opiate receptor blockade on the reinforcing effects of cocaine, the mu-opiate irreversible antagonist beta-funaltrexamine (betaFNA) was administered locally to different regions of the mesocorticolimbic system. Microinjection of betaFNA into the ventral tegmental area (VTA) or the nucleus accumbens (NAcc) had no effect on cocaine self-administration under a fixed ratio (FR) schedule of reinforcement. However, blockade of opiate receptors in both brain regions did attenuate responding for cocaine maintained by a progressive ratio (PR) schedule. Administration of betaFNA in the dorsal striatum had no effect under either schedule condition. The present findings suggest that endogenous opiate systems within the mesolimbic DA system modulate the reinforcing effects of cocaine; however, this modulation seems to be schedule dependent.     

Effect of quinolinic acid-induced lesions of the nucleus accumbens core on performance on a progressive ratio schedule of reinforcement: implications for inter-temporal choice

Rationale The nucleus accumbens core (AcbC) is believed to contribute to the control of operant behaviour by reinforcers. Recent evidence suggests that it is not crucial for determining the incentive value of immediately available reinforcers, but is important for maintaining the values of delayed reinforcers. Objective This study aims to examine the effect of AcbC lesions on performance on a progressive-ratio schedule using a quantitative model that dissociates effects of interventions on motor and motivational processes (Killeen 1994 Mathematical principles of reinforcement. Behav Brain Sci 17:105–172). Materials and methods Rats with bilateral quinolinic acid-induced lesions of the AcbC (n = 15) or sham lesions (n = 14) were trained to lever-press for food-pellet reinforcers under a progressive-ratio schedule. In Phase 1 (90 sessions) the reinforcer was one pellet; in Phase 2 (30 sessions), it was two pellets; in Phase 3, (30 sessions) it was one pellet. Results The performance of both groups conformed to the model of progressive-ratio performance (group mean data: r ²  > 0.92). The motor parameter, δ, was significantly higher in the AcbC-lesioned than the sham-lesioned group, reflecting lower overall response rates in the lesioned group. The motivational parameter, a, was sensitive to changes in reinforcer size, but did not differ significantly between the two groups. The AcbC-lesioned group showed longer post-reinforcement pauses and lower running response rates than the sham-lesioned group. Conclusions The results suggest that destruction of the AcbC impairs response capacity but does not alter the efficacy of food reinforcers. The results are consistent with recent findings that AcbC lesions do not alter sensitivity to reinforcer size in inter-temporal choice schedules.     

Cocaine self-administration reinforced on a progressive ratio schedule decreases with continuous d-amphetamine treatment in rats

Rationale

To date, there is no medication specifically approved for cocaine addiction. Agonist medications are used clinically in the treatment of other addictions, which suggests that this method of drug therapy could potentially be successful in treating cocaine addiction as well.

Objective

The objective of this study was to determine the effect of extended d-amphetamine treatment on responding on a progressive ratio (PR) schedule reinforced by cocaine.

Materials and methods

Rats were trained to self-administer cocaine (0.19, 0.38, 0.75, or 1.5 mg/kg/injection) or food on a PR schedule. After stable baseline breakpoints (the number of reinforcers earned in one session) were established over 3 days, animals were implanted with osmotic mini-pumps that continuously delivered d-amphetamine (5 mg/kg/day) for a duration of either 7 or 14 days. Breakpoints were then determined during and/or after this treatment period.

Results

Rats demonstrated dose-dependent decreases in cocaine-reinforced responding over the d-amphetamine treatment period. Breakpoints for doses of 0.75 mg/kg/injection and below decreased significantly when compared to baseline and remained decreased for up to 14 days after mini-pump removal, whereas those for the highest dose of cocaine remained unchanged. Additionally, d-amphetamine treatment during a 14-day abstinence period from cocaine self-administration had no effect on breakpoints when tested the day after mini-pump removal.

Conclusions

These data suggest that the reduction in cocaine-reinforced responding after continuous d-amphetamine treatment cannot be accounted for by tolerance alone. Instead, the roles of learning and the interaction between cocaine and d-amphetamine must be considered and examined in future studies.     

Effects of repeated withdrawal from chronic ethanol on oral self-administration of ethanol on a progressive ratio schedule

Male hooded Lister rats were trained using a sucrose-fading technique, to perform an operant lever press response to obtain ethanol. Initial training, using an FR4 schedule in which each reinforcement required four lever presses, included varying the concentration of ethanol in the liquid reinforcer. Changes in reinforcer concentration between 7 and 15% (vol/vol) had little effect on either numbers of lever pressing responses, or reinforcers obtained during the 3h session. Increasing the reinforcer concentration to 20% caused a decline in responding. The effects of varying reinforcer concentration (0-20% ethanol) were also studied in the same animals performing a progressive ratio schedule, in which the number of responses required to obtain a reinforcer was successively increased during the session. In these experiments the point at which rats ceased to respond (breaking point) was taken as a measure of their motivation to obtain ethanol. The function describing the relationship between ethanol concentration and number of responses, and number of reinforcers obtained in a session was an inverted U, with the maximum values occurring at an ethanol concentration of 10%. The value of the breaking point (highest ratio achieved) depended on the criterion used to define cessation of responding, but was between 15 and 22. Rats performing for ethanol showed higher breaking points than when responding for water, but there was no statistically reliable effect of ethanol concentration on the breaking point parameter. The effects of feeding the rats a liquid diet containing ethanol, and its subsequent withdrawal, on progressive ratio responding for 5% ethanol, were studied over four cycles of exposure and withdrawal. Intakes of ethanol of 11 g/kg/day had no effect on the animals' breaking point on the progressive ratio schedule, but withdrawal from the ethanol diet resulted in breaking points significantly higher than those in a control group pair-fed a nutritionally equivalent, ethanol-free diet. Although there was no further effect of repeated exposure and withdrawal on responding during the acute withdrawal phase, baseline levels of responding were elevated in the animals which had received multiple cycles of ethanol diet and withdrawal. These results are discussed in the context of the consequences of sensitization to repeated withdrawal from ethanol in dependent animals and humans.     

Break-points on a progressive ratio schedule reinforced by intravenous cocaine increase following depletion of forebrain serotonin

The effect of intracerebral injections of 5,7-dihydroxy-tryptamine (5,7-DHT) on cocaine self-administration behavior was assessed. Rats were tested on a progressive ratio (PR) schedule for cocaine reinforcement. The first response on the lever each day produced an IV infusion of cocaine (0.6 mg/injection) after which the requirements of the schedule escalated with each reinforcement until the behavior extinguished. The final ratio completed was defined as the breaking point. Bilateral injections of 5,7-DHT into either the medial forebrain bundle (MFB) or amygdala (AMY) significantly increased the breaking points on the PR schedule compared to vehicle-injected control animals. We interpret these data to indicate that depletion of forebrain serotonin increases the incentive value of cocaine.     

Pre-exposure of rats to amphetamine sensitizes self-administration of this drug under a progressive ratio schedule

 Two groups of male rats were tested to determine whether pre-exposure to d-amphetamine would enhance the motivation to self-administer the drug under a progressive ratio schedule of reinforcement. In the first phase of the experiment, one group of rats received d-amphetamine (2 mg/kg IP), while a second group received saline on alternate days for a total of ten injections. Following a 21-day drug withdrawal period, behavioral sensitization was confirmed by a significant increase in amphetamine-induced stereotypy in the d-amphetamine-pretreated group, relative to the saline-pretreated group. In the second phase of the study, all rats were implanted with chronic jugular catheters and trained to self-administer d-amphetamine (0.2 mg/kg per infusion) under a fixed-ratio schedule of reinforcement. The progressive ratio paradigm was then imposed for 7 consecutive days; d-amphetamine-pretreated rats attained significantly higher break points than saline-pretreated animals. These data suggest that pre-exposure to d-amphetamine may enhance the motivation to self-administer this drug. Received: 16 July 1997 / Final version: 22 October 1997