Choice under concurrent VI schedules: comparison of behavior maintained by cocaine or food

 Previous research has shown that concurrent schedule responding maintained by cocaine under short variable-interval (VI) schedules is well described by the generalized matching law. That is, drug-maintained behavior was apportioned in accordance with relative frequency of reinforcement. The purpose of the present experiment was to examine the ability of the generalized matching law to account for choice under longer VI schedules of cocaine availability, and to compare cocaine-maintained to food-maintained behavior in this regard. One group of rhesus monkeys (n=4) was prepared with indwelling IV catheters and allowed to respond under concurrent VI (conc VI) schedules of cocaine delivery (0.025, 0.05 or 0.1 mg/kg per injection) with an average inter-reinforcer interval (IRI) of 10 or 30 min. In a second group of monkeys (n=4), a comparable experiment was conducted but with responding maintained by different amounts of food (one, two, or four 1-g banana-flavored pellets). For both groups, the same reinforcer followed responding on either lever, the only difference between the options being the VI schedule, i.e., frequency of reinforcement. The behavior of the cocaine-maintained group was well predicted by the generalized matching law. While both groups evidenced undermatching of both response and time allocation, lever pressing of monkeys whose behavior was maintained by food showed more undermatching than that of the cocaine-maintained group. In addition, a consistent and unexplained bias in responding toward the right lever developed in the food-maintained, but not the cocaine-maintained monkeys. Considering the present results with those of previous experiments, it appears that food-, but not cocaine-maintained behavior, deviates increasingly from strict matching as the IRI is extended. This difference across reinforcers could be due to differences between cocaine and food in the mechanisms by which they maintain behavior, or a direct effect of cocaine on choice performance. Received: 9 February 1998 / Final version: 4 June 1998     

Choice maintained by cocaine or food in monkeys: effects of varying probability of reinforcement

 Several theoretical models of choice, including matching, maximizing and probability matching, have evolved from the experimental analysis of behavior. However, these models are based largely on results of studies involving non-drug reinforcers. The extent to which the choice to self-administer a drug of abuse conforms to these models is largely unknown. The present study was designed to examine the effects of varying probability of reinforcement of two options on choice by rhesus monkeys maintained under a discrete-trials choice procedure. One group of monkeys (n=5) was prepared with chronic indwelling venous catheters and responding was maintained by IV injections of cocaine (0.05 or 0.2 mg/kg per injection). In a second group, behavioral conditions were identical, except that responding was maintained by the delivery of food pellets. Two choice options were available to each group. Each option was maintained by the identical dose of cocaine or amount of food, but with varying probabilities of delivery. The percentage of trials on which monkeys chose option 1 increased with its probability of reinforcement for cocaine (0.05 or 0.2 mg/kg per injection) and this effect did not change with dose of cocaine. When probabilities of reinforcement for option 1/option 2 were 0.75/0.25, choice was exclusive for the higher probability option. Results were identical when behavior was maintained by food. The present experiment supports the conclusion that exclusive choice of the alternative with the higher probability of reinforcement can be extended to cocaine as a reinforcer. The present results also extend the known conditions under which drug-maintained responding is similar to food-maintained responding to situations involving options with different probabilities of reinforcement, i.e., probability choice. Probability matching was not observed, arguing that this model does not predict drug or food choice. Received: 24 October 1997 / Final version: 29 January 1998     

The effects of a D1 and a D2 dopamine antagonist on behavior maintained by cocaine or food

The purpose of the present experiment was to determine whether a D1 or a D2 dopamine antagonist could alter responding maintained by cocaine at doses that did not affect responding maintained by food. Rhesus monkeys were trained to press a lever in daily experimental sessions under a 3 component multiple schedule of reinforcement. In the first and third components, food was available under a fixed-ratio 30/time-out 2 min (FR30/TO 2) schedule. In the second component, cocaine was available under identical schedule conditions. Each component lasted 15 minutes and there was a 15-minute TO between components. When behavior was stable, rates of responding for injections of saline or several doses of cocaine were determined by making each of these solutions available in the second component for at least 4 sessions. After dose-response determinations for cocaine had been determined, a dose of cocaine that maintained maximal rates of responding was available in daily sessions. When behavior was again stable in all 3 components, monkeys were injected daily before the session with each of several doses of the D1 antagonist SCH 23390 or the D2 antagonist pimozide for the same number of sessions that had been required for responding to decline to low levels when the monkeys were allowed to self-administer saline. Both antagonists caused a dose-related decrease in responding for both cocaine and food. Each antagonist decreased responding for food at the same doses that decreased responding for cocaine. Thus both a D1 and a D2 dopamine antagonist decreased behavior maintained by cocaine but only at doses that also decreased behavior maintained by another reinforcer, food.     

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

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

The effects of acutely administered cocaine on responding maintained by a progressive-ratio schedule of food presentation

Lever pressing in rats (N=5) was reinforced under a progressive-ratio (PR) schedule of food presentation, in which the number of responses required increased exponentially. The session was terminated when 1 h passed without completion of the scheduled ratio. Doses of cocaine (5.6-42.0 mg/kg; one subject received a dose of 56.0 mg/kg) as well as saline were administered i.p. prior to the session. Under non-drug conditions, breakpoints were typically less than 100, and substantial responding usually occurred only during about the first 10 min of the session. The rate of responding usually increased over the first 2-8 reinforcers and then decreased for the last few reinforcers obtained. For four of five rats, breakpoint, overall rate of response, and session duration were first increased above control and vehicle levels by increasing doses of cocaine. Larger doses produced smaller increases, no effect, or decreases. Cocaine, in the range of doses near the apex of the breakpoint dose-effect functions, suppressed rates of responding at the small ratios present at the beginning of the session. It is suggested that cocaine increases low rates of response if: (1). rates are low due to extinction; and (2). the stimuli present are those present when the response is reinforced.     

A comparison of the effects of amphetamine on fixed interval performance maintained by electrical stimulation of the brain versus food reinforcement

Rats with implanted unilateral hypothalamic bipolar electrodes were trained to bar press for both electrical stimulation of the brain (ESB) and food on a fixed interval (FI) 1-min schedule of reinforcement. A comparison in the same animals was made of the disruptive effects of d-amphetamine on FI performance maintained by these two reinforcers. Overall, FI remained more intact under the influence of amphetamine with ESB rather than with food reinforcement. The feasibility of using more complex schedules of reinforcement to study the effects of drugs on self-stimulation was demonstrated.     

Preference for ethanol and diazepam in light and moderate social drinkers: a within-subjects study

In contrast to the considerable systematic study of the pharmacologic treatment of schizophrenia and mood disorders, the pharmacologic treatment of schizoaffective disorder has been relatively ignored. The authors reviewed the available literature regarding the pharmacologic treatment of schizoaffective disorder. The total number of controlled studies of the acute and prophylactic treatment of schizoaffective disorder was small and few used modern criteria to define the disorder. In studies of schizoaffective disorder, bipolar type (manic), lithium and antipsychotics produced comparable albeit incomplete responses, except in highly agitated patients when antipsychotics exerted superior efficacy. The combination of lithium and antipsychotics appeared to be superior to antipsychotics alone for schizoaffective, bipolar type patients. In the only controlled study of schizoaffective disorder, depressed type, the presumed superiority of combined antidepressant and antipsychotic treatment to antipsychotic alone was not found. Although combined antipsychotic and thymoleptic treatment represents common prophylactic management of schizoaffective disorder in clinical practice, the efficacy of this strategy has not been studied in controlled trials. Advances in the nosology of schizoaffective disorder, emerging epidemiologic data demonstrating large numbers of patients with this disorder in clinical populations, and preliminary evidence that clozapine may have combined antipsychotic and thymoleptic properties as well as efficacy in both the psychotic and affective components of schizoaffective disorder, suggest that renewed interest in the diagnosis and treatment of this disorder may lead to improved delivery of care for this understudied but seriously ill group of patients.Supported in part by a grant from the Alliance for the Mentally Ill, Hamilton County, Ohio.     

Reconciling differences in drug effects on behavior punished or maintained by response-produced shock

Comparable patterns of behavior maintained by different events are affected similarly by certain drugs and differently by others. The present paper argues that patterns of behavior maintained by response-produced shock (“shock-maintained behavior”), although similar in appearance to lever pressing maintained by more conventional positive reinforcers, are generated through differential punishment of long interresponse times; hence, drug effects on this behavior should more closely resemble drug effects on pressing suppressed by punishment. Because the operants suppressed in these procedures are diametrically opposed (long interresponse times vs. pressing), the baseline patterns of behavior will differ (suppressing long interresponse times produces high rates of pressing, punishing pressing produces low rates). Furthermore, any drug-induced changes in the frequency of the punished operant will result in what appear to be dissimilar drug effects if the rate of only one operant class serves as the dependent variable. That is, drugs that increase the rate of pressing that has been suppressed by punishment should increase long interresponse times similarly suppressed. This results in an overall increase in pressing rate under typical punishment procedures, but a decrease in overall pressing rates (an increase in the rate of punished long interresponse times) under shock-maintenance procedures. Hence, similar drug effects on these inversely related operants should generate opposite changes in pressing rate under the two sets of procedures. A review of the literature revealed this to hold true in 12 of 15 cases. Drug effects on comparable patterns of pressing maintained by shock or food presentation split more evenly. The literature indicates that, of 21 such, comparisons between pressing maintained under fixed-interval schedules of food or shock, ten yielded comparable drug effects under both, and 11 yielded dissimilar effects. These results suggest that what appear to be dissimilar drug effects on pressing maintained or suppressed by shock may in fact be similar effects on the inversely related operants differentiated under these procedure.     

Differential effects of chlordiazepoxide on comparable rates of responding maintained by food and shock avoidance

Comparable rates and patterns of lever-pressing by rats were obtained under a multiple variable interval schedule of food reinforcement and continuous shock avoidance. Chlordiazepoxide (1.0–17.0 mg/kg) produced increases in food maintained responding at doses that decreased avoidance responding. Removing food, shock, or both in separate individual probe sessions did not produce differential effects. Under certain circumstances, the effects of chlordiazepoxide appear to be best predicted by knowledge of maintaining conditions.     

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

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

Effects of the competitive nicotinic antagonist erysodine on behavior occasioned or maintained by nicotine: comparison with mecamylamine

Rationale: The cellular effects of nicotine underlying its addictive liability are thought to be mediated by neuronal nicotinic receptors (nACHRs) in the central nervous system. It is believed that densely expressed β2-containing nACHRs in the central nervous system are responsible for these actions, but few data are available that can directly assess subtype mediation of nicotine’s acute subjective and reinforcing effects. Objective: The present study compared the effects of the competitive nACHR antagonist erysodine and the noncompetitive antagonist mecamylamine in rats trained to discriminate or self-administer nicotine. Methods: Adult male rats were trained to disciminate 0.4-mg/kg injections of nicotine from vehicle in a two-lever procedure of food-maintained behavior, or to self-administer 0.03-mg/kg injections of nicotine under fixed-ratio 5 or progressive-ratio schedules of reinforcement. Additional rats were trained under a food-maintained procedure of lever pressing. Results: Erysodine (0.3–10 mg/kg) and mecamylamine (0.1–1.0 mg/kg) blocked nicotine discrimination, although only erysodine produced the rightward shift that would be predicted of a competitive antagonist. Erysodine (0.32–32 mg/kg) and mecamylamine (0.32–3.2 mg/kg) also selectively reduced nicotine self-administration on a fixed-ratio schedule and lowered break points on a progressive-ratio schedule. Conclusions: Based on the known affinity of erysodine for α4β2 nACHRs and its selectivity relative to α7 and α1β1γδ receptors, the present data support a critical role of β2-containing nACHR constructs in the discriminative and reinforcing actions of nicotine. Received: 20 March 1999 / Final version: 22 September 1999     

Differential effects of d-amphetamine on fixed ratio 30 performance maintained by food versus brain stimulation reinforcement

Four rats with implanted unilateral hypothalamic bipolar electrodes were trained to bar press for both intracranial self-stimulation (ICSS) and food on a fixed ratio 30 schedule of reinforcement. The animals were tested at 90% and 100% body weight. d-Amphetamine (0.1, 0.5, 1.0, 1.5, 2.0 mg/kg) always decreased responding for blood reinforcement but increased responding up through the 1.0 mg/kg dose level for ICSS. An analysis of error responses emitted for ICSS reinforcement showed that perseverative responding did not occur up through the 1.0 mg/kg level.     

Effects of pyrethroid insecticides on operant responding maintained by food

The pyrethroids are potent insecticides with low concomitant mammalian lethality when compared with other major insecticides. While high doses can lead to hyperactivity, tremors, convulsion and death, low doses have not been as well studied. Since operant behavior can be a sensitive measure of CNS function, male Holtzman rats were trained on a VR25 schedule maintained by 45 mg food pellets. Rats were injected IP with one of four different technical grade pyrethroids: permethrin, allethrin, deltamethrin and fenvalerate. All agents were effective in reducing operant responding and did so in a dose-dependent manner at levels 10 to 100 times below their LD50 values. Time course studies indicated a relatively short duration of action for the Type I agents of less than 60 min for permethrin and 15 min for allethrin. Type II agents were generally effective for greater than 60 min. Results of these studies indicate that operant responding maintained by food is a sensitive measure of the behaviorally disruptive effects of subconvulsive doses of pyrethroids.     

D-Amphetamine reinstates behavior previously maintained by food: importance of context

The drug self-administration reinstatement procedure provides an important animal model of relapse. While the procedure is widely used, there has been little investigation of the basic processes involved. This experiment determined the specificity of reinstatement by examining reinstatement of food seeking by D-amphetamine. During training, 24 rats pressed levers for food. Eight rats received 3.0 mg/kg D-amphetamine before and saline after sessions. Eight rats received saline before and after sessions. The final eight rats received saline before and 3.0 mg/kg D-amphetamine after sessions. All rats then experienced saline injections and extinction. During a reinstatement test, all rats received 3.0 mg/kg D-amphetamine. D-Amphetamine significantly increased lever pressing for rats with prior exposure to amphetamine as a predictive cue for food (pre-session) and for rats with no prior exposure to amphetamine. The effect was larger for rats with pre-session exposure to amphetamine than for rats with no previous exposure. Rats with exposure to amphetamine but not as a predictive cue for food (after sessions) did not show significant reinstatement of lever pressing. Therefore, the reinstating effects of amphetamine are not restricted to behavior previously maintained by amphetamine self-administration. In animal models of relapse, reinstatement of drug seeking could be due, in part, to discriminative and direct effects of self-administered drug.     

Opioid-dependent behaviors in infant rats: effects of prenatal exposure to ethanol

Pregnant rats were given diets containing either 5% ethanol, an isocaloric (pair-fed) diet, or casein pellets. Offspring were tested at postnatal day 10 for isolation-induced ultrasonic vocalizations and subsequent stress-induced analgesia. Rats prenatally exposed to ethanol vocalized significantly less in the five minutes during isolation. The opiate, morphine, caused a greater suppression of vocalizations in alcohol-exposed pups compared to controls, while the increased calling normally seen with the opiate antagonist, naltrexone, was attenuated. In a test in which the pup withdraws a paw from a hot plate (48 degrees C), prenatal alcohol offspring demonstrated baseline latencies (no isolation) similar to controls but had greatly attenuated responses in their isolation-induced analgesia. Since both vocalization and analgesia responses have been determined to be modulated by the endogenous opioid system, the aberrant responses of the prenatal-ethanol-exposed offspring can be interpreted as failures to respond by opioid release/secretion to appropriate stimuli.     

A comparison of the effects of psychotomimetics and anxiolytics on punished and unpunished responding maintained by fixed interval schedules of food reinforcement in the rat

Characterization of anxiolytic drugs often employs conflict paradigms in which the drug effects on punished and unpunished responding can be compared. In this study, a fixed interval schedule generating a range of baseline response rates allowed comparison of the effects of anxiolytic drugs with those of psychotomimetic drugs on equivalent and differing rates of punished and unpunished responding. The first response made by the rat after a 40-s fixed interval elapsed resulted in food pellet delivery. In punished intervals, signalled by the illumination of stimulus lamps above each lever, a 0.6-mA shock was delivered after every 20th response, resulting in a lower rate of responding than that in the unpunished intervals. Three psychotomimetic agents, D-amphetamine, MK801 and DOI were compared with the anxiolytics chlordiazepoxide, NS2710 and pregabalin. The three psychotomimetics preferentially increased rates of unpunished responding compared with those of punished responding. Chlordiazepoxide, NS2710 and, to a lesser extent, pregabalin increased rates of both unpunished and punished responding. In comparison studies, yohimbine also increased rates of both unpunished and punished responding whereas the antidepressant citalopram had no effect. In conclusion, stable baseline performance over many months allowed the direct comparison of several different drugs in the same subjects with no need to adjust shock levels or equate baseline response rates. The drugs had systematic and replicable effects in this procedure, which, in the case of amphetamine and chlordiazepoxide, were similar to those in other species, and psychotomimetic drugs could clearly be distinguished from anxiolytic drugs. The procedure, however, has limited value for characterizing novel anxiolytic agents as the examples used here increased punished and unpunished responding to the same extent, and were indistinguishable in that regard from the clinically anxiogenic agent, yohimbine.     

Mental rehearsal of a task before or after ethanol: tolerance facilitating effects

Two groups of six male social drinkers learned a psychomotor skill task and then drank the same dose of ethanol (0.62 g/kg) on each of five sessions. Sessions 1 and 5 provided pre-treatment and post-treatment measures of task performance under ethanol. During treatment sessions 2, 3 and 4, one group (MRBD) mentally rehearsed the task before drinking and the other group (MRAD) mentally rehearsed the task after drinking. On the post-treatment session, the MRAD group was significantly less impaired (i.e. more tolerant) than the MRBD group. Thus, mental rehearsal of a task under ethanol facilitates the development of tolerance to the behavioral effects of the drug.     

Depression-related anhedonic behaviors caused by immobilization stress: a comparison with nicotine-induced depression-like behavioral alterations and effects of nicotine and/or "antidepressant" drugs

Anhedonia, an affective symptom related to the inability to experience pleasure, is one of the representative symptoms observed in depression. In the present study, considering that repeated nicotine (NC) also causes "depressive" symptoms, the depression-related anhedonic behavioral alterations caused by a typical depression-inducing stressor, immobilization stress (IM), combined with or without NC administration, were examined in mice and compared with the depression-like behavioral alterations caused by NC. In the repeated IM (10 min, 4 days) group, as well as the repeated NC (0.3 mg/kg, s.c., 4 days) group, depression-related behavioral despair was observed in both forced swimming and tail suspension tests. Depression-related anhedonic behavioral alterations, as judged in the sucrose test, were observed only in the IM group. In the group treated with IM plus NC (IM-NC group), NC antagonized the IM-induced anhedonic attenuation of sucrose consumption in the sucrose test. Furthermore, in the IM-NC group, NC attenuated the effects of antidepressants which inhibit the reuptake of monoamines in the forced swimming test. Against the IM-induced anhedonia in the sucrose test, the cannabinoid agonists anandamide and CP 55940, in addition to the antidepressants previously reported, restored the preference for sucrose to control levels, with or without NC co-treatment. The absence of anhedonic behavioral alterations, the antidepressant-like anti-anhedonic effects against IM, and the effects against some antidepressant drugs all seemed to be characteristic of the effects of NC. Neural mechanisms other than those involved in the depression-like effects of NC seemed to contribute to the IM-induced anhedonic component of depression.     

Chronic cocaine or ethanol exposure during adolescence alters novelty-related behaviors in adulthood

Adolescence is a time of high-risk behavior and increased exploration. This developmental period is marked by a greater probability to initiate drug use and is associated with an increased risk to develop addiction and adulthood dependency and drug use at this time is associated with an increased risk. Human adolescents are predisposed toward an increased likelihood of risk-taking behaviors [Zuckerman M. Sensation seeking and the endogenous deficit theory of drug abuse. NIDA Res Monogr 1986;74:59-70.], including drug use or initiation. In the present study, adolescent animals were exposed to twenty days of either saline (0.9% sodium chloride), cocaine (20 mg/kg) or ethanol (1 g/kg) i.p. followed by a fifteen-day washout period. All animals were tested as adults on several behavioral measures including locomotor activity induced by a novel environment, time spent in the center of an open field, novelty preference and novel object exploration. Animals exposed to cocaine during adolescence and tested as adults exhibited a greater locomotor response in a novel environment, spent less time in the center of the novel open field and spent less time with a novel object, results that are indicative of a stress or anxiogenic response to novelty or a novel situation. Adolescent animals chronically administered ethanol and tested as adults, unlike cocaine-exposed were not different from controls in a novel environment, indicated by locomotor activity or time spent with a novel object. However, ethanol-exposed animals approached the novel object more, suggesting that exposure to ethanol during development may result in less-inhibited behaviors during adulthood. The differences in adult behavioral responses after drug exposure during adolescence are likely due to differences in the mechanisms of action of the drugs and subsequent reward and/or stress responsivity. Future studies are needed to determine the neural substrates of these long lasting drug-induced changes.     

Cocaine as a discriminative stimulus for responding maintained by food in squirrel monkeys.

Squirrel monkeys were trained in a choice procedure to discriminate a dose of 100 micrograms/kg cocaine from saline. Following an injection of cocaine, responding on the right lever was reinforced with food, whereas following an injection of saline, responding on the left lever was reinforced with food. A high degree of stimulus control (100% correct) was established within 20 experimental sessions. The dose-response function of cocaine on lever choice was then determined. When intermediate doses (10, 25 and 50 micrograms/kg) were administered prior to test sessions, a dose-dependent generalization decrement was seen. One monkey was found to discriminate as low as 25 microgram/kg cocaine from saline.