Psychopharmacology

Rowlett, J. K.

doi: 10.1007/s002130000610pmid: 11255919

Rationale: Under a progressive-ratio (PR) schedule, a subject must complete increasing fixed-ratio (FR) response requirements to obtain reinforcers. Response requirements are increased until responding stops; the final ratio completed being the "break point" and providing an index of the relative effectiveness, or value, of the reinforcer to maintain behavior. Objectives: This review examines the historical and conceptual framework underlying the PR procedure and examines the concept of relative reinforcer value. Pharmacological analysis (based on receptor theory), and behavior analysis (based on microeconomic theory) are reviewed. Methods: Using a microeconomic adaptation of the reinforcement model referred to as conservation, a mathematical model of PR performance is proposed based on the curvilinear relationship between economic supply and labor. Drug consumption and instrumental responding were assumed to reflect deviations from a balance point, defined as the levels of consumption and responding under no scheduled restraint. Data sets were re-analyzed in which several response sequences were examined in rhesus monkeys maintained on PR schedules of intravenous cocaine delivery. Results: The modified conservation equation fitted the PR data accurately, and results consistent with both linear and concave labor-supply functions were obtained. These results suggest that cocaine self-administration under PR schedules conforms to labor-supply relationships characterized as inelastic (consumption is resistant to increases in schedule requirements) and unit elastic (at high response costs, consumption declines with no corresponding increase or decrease in total responding). Conclusions: The labor-supply methodology allows for a definition of the relative value of a drug reinforcer in PR studies based on changes in consumption across response costs. Specifically, relative reinforcer value is defined in terms of changes in behavior from a balance point, rather than as a property that determines the strength of the instrumental response.

Everitt, Barry J.; Robbins, Trevor W.

doi: 10.1007/s002130000566pmid: 11255926

Rationale and objectives: To review the literature on the use of second-order schedules of drug reinforcement in the context of experimental investigations of the neural and pharmacological mechanisms underlying addictive behaviour in general and drug-seeking behaviour in particular. Methods: Second-order schedules of drug reinforcement are described in which responding is maintained not only by the self-administered drug, but also by contingent presentation of drug-paired stimuli that serve as conditioned reinforcers of instrumental behaviour. Results: The behaviour of rats and monkeys responding under second-order schedules is discussed in relation to self-administered drug dose and the importance of drug-associated cues in maintaining responding for cocaine, morphine or heroin. Drug-seeking behaviour during the period before drug is self-administered is described and compared with drug-seeking behaviour derived from other procedures. In addition, results are summarised that demonstrate the differential involvement of the amygdala and prefrontal cortex in the acquisition of cue-controlled cocaine- and heroin-seeking behaviour, as well as the effects of drugs interacting with D3 dopamine, NMDA and AMPA receptors on drug-seeking behaviour and dopaminergic correlates of drug-paired stimuli presented non-contingently and during responding for cocaine under a second-order schedule. Conclusions: We argue that the first, drug-free interval (or other period) of responding under a second-order schedule of reinforcement has particular utility in that it provides a measure of drug-seeking behaviour and reinforcing efficacy that are not affected by the pharmacological effects of recently administered drug. It also provides a means of investigating the role of drug-paired stimuli in drug-seeking behaviour, including its behavioural, neural and neurochemical basis.

Bardo, M.T.; Bevins, R.A.

doi: 10.1007/s002130000569pmid: 11255927

Rationale: Among the various experimental protocols that have been used to measure drug reward in laboratory animals, conditioned place preference (CPP) has been one of the most popular. However, a number of controversial issues have surrounded the use of this experimental protocol. Objective: The present review provides a theoretical overview of some critical issues relevant to CPP. The advantages and limitations of CPP are also covered. Results: Based on modern and traditional theoretical formulations of Pavlovian conditioning, CPP appears to reflect a preference for a context due to the contiguous association between the context and a drug stimulus. Within this theoretical framework, it seems clear that CPP measures a learning process that is fundamentally distinct from drug self-administration. The main advantages of CPP are that it: (1) tests animals in a drug-free state; (2) is sensitive to both reward and aversion; (3) allows for simultaneous determination of CPP and locomotor activity; (4) is adaptable to a variety of species; (5) typically yields dose-effect curves that are monophasic rather than biphasic; and (6) has utility in probing the neural circuits involved in drug reward. The main limitations of CPP are that it: (1) is subject to interpretation based on the notion of novelty seeking; (2) is cumbersome for providing the graded dose-effect curves needed for answering some pharmacological questions; (3) is difficult to interpret when animals prefer one context prior to drug conditioning; and (4) lacks face validity as an experimental protocol of drug reward in humans. Conclusion: Despite some limitations, CPP provides unique information about the rewarding effect of contextual cues associated with a drug stimulus.

Bickel, Warren K.; Marsch, Lisa A.; Carroll, Marilyn E.

doi: 10.1007/s002130000589pmid: 11255928

Background: Relative reinforcing efficacy has been assumed to be a homogeneous phenomenon referring to the behavior-strengthening or behavior-maintaining effects of a drug reinforcer. However, a variety of studies suggest that relative reinforcing efficacy may be heterogeneous. Objectives: The purpose of this theoretical proposal is to examine the difficulties associated with this conception of reinforcing efficacy and to explore whether relative reinforcing efficacy is a homogenous concept or whether it is composed of several functionally related heterogeneous phenomena. In examining this issue, we explore whether behavioral economic theory may address some of the challenges to the current conception of relative reinforcing efficacy and use this theory to suggest how the differing measures of reinforcing efficacy may relate to one another. Results: Results indicate that peak-response rate and breakpoint are related to the economic measure of maximal output and elasticity of demand, respectively. Preference is related to and predicted by the relative location of the demand curves obtained under single schedule conditions. This behavioral economic analysis may provide a theoretical understanding of reinforcement that can reconcile results of studies that both support and fail to support the notion of reinforcing efficacy as a homogenous phenomenon. Conclusions: If this theoretical proposal is validated by additional studies, then like other natural phenomena found to be heterogeneous, the study of drug reinforcers may require the adoption of several new scientific terms, such as those used in behavioral economics, each of which has analytical precision and refers to homogeneous phenomena.

Sizemore, Glen M.; Martin, Thomas J.

doi: 10.1007/s002130000611pmid: 11255929

Rationale: The interpretation of dose-effect functions for self-administered drugs remains elusive. Since, for self-administered drugs, the amount of drug in an animal depends on its behavior, a mathematical theory of drug self-administration must include terms relevant to receptor theory, as well as a description of how an organism's behavior affects the amount of drug in the animal over time. Objective: A theory was constructed in which the ability of a dose to maintain responding was described in terms of receptor theory and the function relating rate of responding to amount of drug self-administered. The main predictions of the theory were that: 1) there should be no ascending limb for drugs self-administered under ratio schedules, 2) running rate of response should not change as a function of dose and, 3) pause duration should be an exponential function of dose. Results: Low doses of cocaine were either self-administered at high rates, or not at all. Run rates, though somewhat variable, did not change as an orderly function of dose. Pause duration could be well described by an exponential function. Conclusions: The theory provides an acceptable, though no doubt preliminary, description of drug self-administration.

Bergman, J.; France, C.P.; Holtzman, S.G.; Katz, J.L.; Koek, W.; Stephens, D.N.

doi: 10.1007/s002130000567pmid: 11255930

Background: The general premise that receptor theory provides a useful framework for understanding the behavioral effects of psychoactive drugs has been a central tenet of behavioral pharmacology. Objectives: The purpose of this review is to reiterate this basic theme and, in particular, the proposition that current concepts of pharmacological efficacy can be effectively used to examine behavioral effects of drugs with abuse or dependence potential in a way that contributes to the discovery of drugs to treat drug dependence. Experimental data: The review begins by briefly introducing the concept of efficacy and follows with several illustrations of how our current understanding of efficacy can be used to address important research questions in drug discovery. In the first, the likelihood of developing novel opioid analgesics with reduced abuse potential is addressed by considering the different efficacy requirements for the discriminative-stimulus and antinociceptive effects of µ-opioids. From a pharmacologically different perspective within drug abuse research, the review continues with an exposition of efficacy-related differences in the behavioral effects of dopamine D1 agonists and how such differences might be exploited in different medications strategies for treating cocaine dependence. The principles of pharmacological efficacy also have come to guide the development of novel GABAA-related antianxiety medications, and this is illustrated in a discussion of the utility of low-efficacy agonists in the treatment of benzodiazepine dependence. The second half of the paper provides counterpoint to the several examples of how principles of efficacy can be applied in drug discovery. The counterpoint includes, first, a critical evaluation of how the concept of efficacy has been applied in the development of monoamine transport inhibitors as anti-cocaine medications and, in particular, the difficulties this may pose for data analysis. The review ends with a discussion of efficacy-based analysis in drug discrimination research and illustrates some of the obstacles that may be encountered in pharmacologically classifying drugs on this basis. Conclusions: Ample evidence indicates that many receptor systems can be activated in a graded manner and that principles of efficacy can be judiciously applied to understand and exploit the behavioral effects of drugs that result from such graded activation. However, as cautioned in the last sections, the misapplication of pharmacological concepts in behavioral studies of drugs may obscure their behavioral pharmacology and potentially confound drug discovery.

Tidey, Jennifer W.; O'Neill, Suzanne C.; Higgins, Stephen T.

doi: 10.1007/s002130000600pmid: 11255931

Rationale: Psychomotor stimulants previously have been found to increase the frequency of cigarette smoking, but it is unclear whether this is due to a non-specific increase in general activity or a specific increase in the reinforcing effects of smoking. Objectives: To investigate whether d-amphetamine increases the relative reinforcing effects of cigarette smoking. Methods: Ninety minutes after d-amphetamine (7.5, 15 mg/70 kg) or placebo administration, 13 male and female subjects participated in 3-h sessions during which they could make a maximum of 20 choices between cigarette smoking (two puffs per choice), earning money ($0.25 per choice), or neither. In separate sessions, using the same subjects, the effects of d-amphetamine on the frequency of ad libitum smoking was assessed. Results: During choice sessions, d-amphetamine dose-dependently increased smoking choices from 4.2±0.6 to 5.7±0.6. During sessions in which subjects smoked ad libitum, d-amphetamine increased number of cigarettes smoked from 2.8±0.4 to 3.8±0.6. Breath carbon monoxide (CO) levels, a measure of smoke exposure, showed corresponding dose-related increases. Conclusions: These results are consistent with previous findings that d-amphetamine increases smoking and provide evidence that this effect is due to a drug-produced increase in the relative reinforcing effects of cigarette smoking.

Hölter, Sabine M.; Henniger, Markus S.H.; Lipkowski, Andrzej W.; Spanagel, Rainer

doi: 10.1007/s002130000601pmid: 11255932

Rationale: The role of the dynorphin/κ-opioid receptor system in ethanol reinforcement is unclear. Objective: Examination of the effects of the highly selective κ-opioid receptor agonist CI-977 (enadoline) and of the long-acting selective κ-opioid receptor antagonist nor-binaltorphimine (nor-BNI) on relapse-like drinking measured by the alcohol deprivation effect (ADE) in long-term ethanol-experienced rats. Methods: Rats were either implanted with mini-osmotic pumps delivering 0 or 0.01 mg/kg per h CI-977 or received two injections (12 h apart) of nor-BNI (0 or 5 mg/kg i.p.) before re-presentation of alcohol after 2 weeks of alcohol deprivation in a four-bottle home cage drinking paradigm. In a second experiment, long-term ethanol-experienced rats trained in an operant ethanol self-administration paradigm received either acute CI-977 treatment (0, 0.003–0.1 mg/kg i.p.) or two injections (12 h apart) of nor-BNI (0 or 5 mg/kg i.p.) before a 23-h session. Results: Chronic CI-977 potentiated ethanol intake and preference during the ADE. Acute CI-977 dose-dependently reduced total lever pressing activity demonstrating an unspecific sedative effect, except for the lowest dose (0.003 mg/kg), which selectively increased lever pressing for ethanol during basal drinking. Nor-BNI did not affect relapse-like drinking at all. Conclusions: Stimulation of κ-opioid receptors can increase ethanol intake, at least in long-term ethanol-experienced rats. Since κ-opioid receptor agonists have aversive motivational consequences, increased ethanol drinking might be an attempt to counteract the aversive effects of this treatment. On the other hand, the nor-BNI experiments indicate that endogenous κ-opioid receptor stimulation does not seem to be involved in relapse-like drinking after protracted abstinence.

Ranaldi, Robert; Anderson, Karen G.; Ivy Carroll, F.; Woolverton, William L.

doi: 10.1007/s002130000602pmid: 11255920

Rationale: The neuronal actions of methamphetamine (MA) include an increase in extracellular levels of monoamines, presumably via reverse transport involving the monoamine transporters. This action is thought to play an important role in the effects of MA. Therefore, in the present experiment, it was hypothesized that a monoamine uptake blocker would block behavioral effects of MA related to its abuse. Objective: RTI 111, a newly synthesized 3-phenyltropane analog with high affinity for the dopamine, norepinephrine, and serotonin transporters, was evaluated alone and in combination with MA for its ability to block the reinforcing and discriminative stimulus effects of MA in rhesus monkeys. Methods: RTI 111 (0.0003–0.03 mg/kg, i.v.) was made available to four rhesus monkeys for self-administration under a fixed-ratio 25 (FR 25) schedule of reinforcement. RTI 111 (0.01–0.1 mg/kg, i.m.) was also administered as a pretreatment (15 min prior) to four monkeys self-administering MA (0.0–0.3 mg/kg per injection, i.v.) on a progressive-ratio schedule of reinforcement. MA (0.01–1.0 mg/kg, i.m.), RTI 111 (0.001–0.1 mg/kg, i.m.), or the combination of MA and RTI 111 were administered to four monkeys trained to discriminate (+)-amphetamine (AMPH; 1.0 or 1.7 mg/kg, intragastric) from saline. Results: When RTI 111 was made available for self-administration under an FR 25 schedule it functioned as a positive reinforcer in all four monkeys tested. When RTI 111 was given as a pretreatment to monkeys self-administering MA under a progressive-ratio schedule, the MA dose-response function shifted to the left and down. When RTI 111 or MA were given to monkeys trained to discriminate AMPH from saline, full AMPH-like responding was observed for both drugs. Given in combination, RTI 111 shifted the MA dose-response function to the left. Conclusions: These data suggest that RTI 111 is behaviorally similar to traditional psychomotor stimulants that act at the DA transporter and that it increases, rather than blocks, the behavioral potency of MA.

Alderson, Helen L.; Robbins, Trevor W.; Everitt, Barry J.

doi: 10.1007/s002130000527pmid: 11255921

Rationale: Second-order schedules of drug-self-administration provide a method of examining drug-seeking behaviour, which is maintained in part by the presentation of a discrete, drug-associated light CS. Previous results have found that lesions of the basolateral amygdala (BLA) impair the acquisition of IV cocaine self-administration under this type of schedule. Objectives: The present experiments examined the effects of excitotoxic lesions of the BLA on the acquisition of IV heroin self-administration under both continuous reinforcement and second-order schedules, in order to investigate possible commonalties in the neural basis of heroin- and cocaine-seeking behaviour. Methods: Rats received quinolinic acid or sham vehicle lesions of the BLA prior to IV self-administration training. Initially, heroin self-administration under a continuous reinforcement schedule was acquired. Each active lever-press resulted in a 0.04 mg IV heroin infusion, paired with presentation of a 20-s light conditioned stimulus. Following acquisition of responding under this schedule, the response requirement was gradually increased to a second-order schedule of FI15(FR5:S). Results: There was no effect of lesions of the BLA on the acquisition of heroin self-administration under a continuous reinforcement schedule. The acquisition of heroin-seeking behaviour under a second-order schedule of self-administration was not affected by lesions of the BLA, but lesioned rats showed a significantly higher baseline level of responding. Conclusions: These results indicate that the rewarding effects of heroin do not depend on the integrity of the BLA. The BLA is also not critically involved in mediating heroin-seeking behaviour under a second-order schedule of reinforcement, and this stands in marked contrast to the effects of BLA lesions on the acquisition of cocaine-seeking behaviour. These findings suggest that discrete heroin cues were not critical in maintaining heroin-seeking behaviour under the second-order schedule used here and that other learning systems are engaged in the control of this behaviour.