Raymond C. Pitts

Quantitative analyses of methamphetamine’s effects on self-control choices: implications for elucidating behavioral mechanisms of drug action

The purpose of the present research was to utilize quantitative methods to identify behavioral mechanisms involved in the effects of stimulant drugs on choice in a self-control procedure. A logarithmic equation based upon a combination of the matching law and hyperbolic discounting was used to separate drug-induced changes in sensitivity to reinforcement delay from drug-induced changes in sensitivity to reinforcement amount. Pigeons responded under a concurrent-chains schedule. In the initial link, two keys were illuminated simultaneously and access to the terminal link was controlled by a single random-interval (RI) schedule; pecks on one or the other key lead to its terminal link with a 0.5 probability. In the terminal links, one alternative provided 1-s access to food (the smaller reinforcer) and the other alternative provided 4-s access to food (the larger reinforcer). The signaled delay to the smaller reinforcer always was 2s, whereas the signaled delay to the larger reinforcer increased from 2 to 40s within each session, across 10-min blocks. In general, intermediate doses of methamphetamine increased preference for the larger more delayed reinforcer. Quantitative analyses indicated that, in most cases, methamphetamine decreased sensitivity to reinforcement delay. In a few instances, concomitant decreases in sensitivity to reinforcement amount also occurred. These results suggest that a reduced sensitivity to reinforcement delay may be important behavioral mechanism of the effects of stimulants on self-control choices, and that this effect sometimes can be accompanied by a decreased sensitivity to reinforcement amount.

Effects of MDMA, methamphetamine and methylphenidate on repeated acquisition and performance in rats

Repeated-acquisition procedures that include performance controls for effects not specific to acquisition permit the assessment of drug effects on learning on a within-subject, within-session basis. Despite the advantages of this methodology, few studies have examined effects of psychomotor stimulants on repeated acquisition in rodents. The purpose of the present study was to investigate the effects of methylenedioxymethamphetamine (MDMA, 0.3-10mg/kg), methamphetamine (MA, 0.1-3mg/kg) and methylphenidate (MPD,1-17 mg/kg) using repeated-acquisition procedures with performance controls in rats using a touch-screen apparatus. Rats were presented a 2x3 array of stimuli using a computer touch-screen and nose-pokes to target locations within the array were reinforced. In the acquisition component, the correct location changed across sessions, whereas during the performance component, the correct location was constant across sessions. All three drugs reduced accuracy of responding to target locations in a dose-dependent fashion. None of the compounds enhanced learning at any dose. MPD and MA produced significant disruptions of acquisition accuracy only at doses that also disrupted performance, but the 3mg/kg dose of MDMA impaired acquisition of target responding without affecting performance. The selective impairment of acquisition found in the present study adds to the evidence of learning and memory disruption produced by acute MDMA administration and raise questions about the mechanisms for these actions.

Repeated spatial acquisition: effects of NMDA antagonists and morphine.

Effects of morphine and 2 N-methyl-D-aspartate (NMDA) receptor antagonists, phencyclidine and LY235959, were studied using a within-subject, repeated-acquisition/performance procedure adapted to the Morris Swim Task. In the performance component, subjects swam to a hidden platform that was always in the same location in the pool. In the acquisition component, the platform was moved to a different place for each session. Baseline training produced rapid and direct swims to the platform in the performance component and steep within-session learning curves in the acquisition component. All 3 compounds increased swim distances, escape latencies, and slowed swim speed in a dose-dependent manner, but only morphine consistently produced selective impairments on acquisition. NMDA antagonists generally affected acquisition only at doses that also disrupted performance, although phencyclidine produced selective effects in some animals. These outcomes were different than those from studies of response chains in primates, suggesting that task and species variables may be important determinants of drug effects on acquisition.

Rapid acquisition of preference in concurrent schedules: Effects of d-amphetamine on sensitivity to reinforcement amount

In the present study, effects of d-amphetamine on sensitivity to reinforcement amount under concurrent schedules were examined using a rapid-acquisition procedure. Four pigeons key pecked under single concurrent variable-interval 30-s schedules of grain presentation. Two different reinforcer-amount ratios (7:1 and 1:7) changed across sessions according to a 31-step pseudo-random binary sequence (PRBS). After at least four times through the PRBS, response ratios generally tracked the session-to-session changes in amount ratios; estimates of sensitivity ranged from 0.26 to 0.31 across the four pigeons. Effects of a range of doses of d-amphetamine (0.3-5.6mg/kg) then were determined. For 3 of 4 pigeons, at least one dose, which did not dramatically alter overall response output or bias, decreased sensitivity to reinforcement amount. These results suggest that reducing sensitivity of responding to reinforcement amount may be one behavioral mechanism of stimulants, which may have implications for interpreting drug effects on self-control.

DEVELOPMENT AND MAINTENANCE OF CHOICE IN A DYNAMIC ENVIRONMENT

Four pigeons were exposed to a concurrent procedure similar to that used by Davison, Baum, and colleagues (e.g., Davison & Baum, 2000, 2006) in which seven components were arranged in a mixed schedule, and each programmed a different left∶right reinforcer ratio (1∶27, 1∶9, 1∶3, 1∶1, 3∶1, 9∶1, 27∶1). Components within each session were presented randomly, lasted for 10 reinforcers each, and were separated by 10-s blackouts. These conditions were in effect for 100 sessions. When data were aggregated over Sessions 16-50, the present results were similar to those reported by Davison, Baum, and colleagues: (a) preference adjusted rapidly (i.e., sensitivity to reinforcement increased) within components; (b) preference for a given alternative increased with successive reinforcers delivered via that alternative (continuations), but was substantially attenuated following a reinforcer on the other alternative (a discontinuation); and (c) food deliveries produced preference pulses (immediate, local, increases in preference for the just-reinforced alternative). The same analyses were conducted across 10-session blocks for Sessions 1-100. In general, the basic structure of choice revealed by analyses of data from Sessions 16-50 was preserved at a smaller level of aggregation (10 sessions), and it developed rapidly (within the first 10 sessions). Some characteristics of choice, however, changed systematically across sessions. For example, effects of successive reinforcers within a component tended to increase across sessions, as did the magnitude and length of the preference pulses. Thus, models of choice under these conditions may need to take into account variations in behavior allocation that are not captured completely when data are aggregated over large numbers of sessions.

Reconsidering the concept of behavioral mechanisms of drug action

A half-century of research in behavioral pharmacology leaves little doubt that behavior-environment contingencies can determine the behavioral effects of drugs. Unfortunately, a coherent behavior-analytic framework within which to characterize the myriad ways in which contingencies interact with drugs, and to predict effects of a given drug under a given set of conditions, still has not developed. Some behavioral pharmacologists have suggested the concept of behavioral mechanisms of drug action as a foundation for such a framework. The notion of behavioral mechanisms, however, does not seem to have been fully embraced by behavioral pharmacologists. It is suggested here that one reason for this is that the concept itself has not been sufficiently clarified (i.e., stimulus control over use of the phrase is not sufficiently precise). Furthermore, early behavioral pharmacologists may not have possessed an adequate set of analytic tools to develop a viable framework based upon behavior mechanisms. In the first part of this paper, the notion of behavioral mechanisms of drug action is explored, and the sort of data that might provide evidence of a behavioral mechanism is considered. In the second part, it is suggested that the increased availability of quantitative models in behavior analysis may help provide the tools needed for elucidating behavioral mechanisms of drug action. Some examples of how these models have been, and could be used are provided.

Olfactory repeated discrimination reversal in rats: effects of chlordiazepoxide, dizocilpine, and morphine.

Effects of a benzodiazepine (chlordiazepoxide), an N-methyl-D-aspartate receptor antagonist (dizocilpine), and an opiate agonist (morphine) were studied with a procedure designed to assess effects of drugs and other manipulations on nonspatial learning in rats. In each session, rats were exposed to 2 different 2-choice odor-discrimination problems with food reinforcement for correct responses. One problem (performance discrimination) remained the same throughout the study. That is, 1 odor was always correct (S+) and the other was never correct (S-). For the other problem (reversal discrimination), stimuli changed every session. Six different odors were used to program the reversal discrimination; on any given session, S+ was a stimulus that had served as S- the last time it had appeared, S- was a stimulus that had been S+ on its last appearance. Thus, in each session, learning a discrimination reversal could be studied along with the performance of a comparable, but previously learned, discrimination. Chlordiazepoxide interfered with reversal learning at doses that had no effect on the performance discrimination. Morphine and dizocilpine also impaired reversal learning but only at doses that also affected performance of the well-learned performance discrimination.

Chlordiazepoxide interactions with scopolamine and dizocilpine: novel cooperative and antagonistic effects on spatial learning.

The authors investigated the effects on spatial behavior of coadministrations of a benzodiazepine, chlordiazepoxide (CDP), with a noncompetitive N-methyl-d-aspartate receptor antagonist (NMDAR), dizocilpine (DZP), and a muscarinic cholinergic receptor antagonist, scopolamine (SCP). Rats solved the Morris swim task in 2 settings; 1 in which a hidden escape platform was always in the same location (performance) and a 2nd in which the platform had been moved to a different location (acquisition) for repeated daily sessions. CDP (3.0 mg/kg) administered alone did not disrupt escape latencies or swim path accuracies. SCP and DZP each impaired acquisition and performance in a dose-dependent manner. CDP coadministered with 0.3 mg/kg SCP impaired escape only in the acquisition setting and when coadministered with 1.0 mg/kg SCP selectively exacerbated the escape impairment in the acquisition setting. CDP ameliorated deleterious effects of DZP in both settings.

Effects of d-amphetamine on behavior maintained by signaled and unsignaled delays to reinforcement.

Four pigeons responded under a progressive-delay procedure. In a signaled-delay condition, a chained variable interval (VI) 30-s progressive time (PT) 4-s schedule was arranged; in an unsignaled-delay condition, a tandem VI 30-s PT 4-s schedule was arranged. Two pigeons experienced a signaled-unsignaled-signaled sequence; whereas, two pigeons experienced an unsignaled-signaled-unsignaled sequence. Effects of saline and d-amphetamine were determined under each condition. At intermediate doses (1.0 and 1.78m/kg) delay functions were shallower, area under the curve was increased, and, when possible, break points were increased compared to saline; these effects were not systematically related to signaling conditions. These effects on control by delay often were accompanied by decreased response rates at 0s. These results suggest that stimulus conditions associated with the delay may not play a crucial role in effects of d-amphetamine and other stimulants on behavior controlled by reinforcement delay.

Tolerance and cross tolerance to the accuracy- and rate-decreasing effects of μ opioids in rats responding under a fixed-consecutive-number schedule

The purpose of the present investigation was to examine the development of tolerance to the effects of morphine and other mu opioids in rats responding under a fixed-consecutive-number (FCN) schedule of food presentation. To this end, five rats were trained under an FCN schedule and subsequently tested with a variety of mu opioids both before and during chronic exposure to a 0.4 mg/ml morphine drinking solution. Morphine, fentanyl, buprenorphine, butorphanol and nalbuphine produced dose-dependent decreases in both accuracy and response rate when tested prior to the chronic regimen. In most instances, doses of these drugs that decreased accuracy also decreased response rate. During chronic treatment, tolerance developed to the effects of morphine and cross-tolerance was conferred to the effects of fentanyl, buprenorphine and butorphanol. A greater degree of tolerance was conferred to the effects of butorphanol than to the other opioids examined, and the degree of tolerance conferred to butorphanols rate-decreasing effects was greater than the degree of tolerance conferred to its accuracy-decreasing effects. Doses of naloxone that had no effect prior to morphine treatment produced large decreases in accuracy and response rate when tested during the chronic regimen. In contrast to the other opioids examined, the potency of nalbuphine was not altered by chronic morphine administration. These data emphasize the importance of both pharmacological and procedural variables in the development of tolerance and cross tolerance to the behavioral effects of opioids.