Drug effects on behavior maintained by food, electric-shock presentation and stimulus-shock termination

2015

Although early experiments did not find differences in drug effects depending on the type of event, more recent studies have reported several instances in which the maintaining event appeared to influence the effects of several drugs on behavior. For example, morphine, methadone, and the narcotic antagonists naloxone and nalorphine decreased responding maintained under 5-minute fixed-interval food-presentation schedules at doses that increased responding comparably maintained by the presentation of an electric shock (). Under similar schedule conditions, both amphetamine () and cocaine () increased responding maintained by these two events. However, appropriate doses of pentobarbital, ethanol, and chlordiazepoxide increased responding maintained by food, while only decreasing responding under shock-presentation schedules ().

These findings suggested that there were several conditions under which certain drugs appeared to affect similar performances maintained under comparable schedules in an event-dependent manner. Further, as shown in Figure Effects of chlordiazepoxide on different control rates of responding under S-minute fixed-interval schedules of food or shock presentation. The event pen was defected downward during the shock-presentation component. The top record of each pair represents control performance and the lower record the effects of Chlordiazepoxide. Panel A: top record: comparable rates of responding maintained by food and shock; lower record: effects of 5.6 mg/kg chlordiazepoxide. Panel B: top record: substantially higher control rates of shock-maintained responding; lower record: effects of 17.0 mg/kg chlor-diazepoxide. Shock intensity was 4 mA in panels A and B. Panel C: control response rates maintained by food were higher than those maintained by 1 mA shock; lower record shows changes in performance with 17.0 mg/kg chlordiazepoxide. Although control rates of responding maintained by shock differed widely, chlordiazepoxide consistently decreased shock-maintained responding, while responding maintained by food was only increased at least the differential effects of chlordiazepoxide appeared to be relatively independent of the control rate of responding maintained by the presentation of food and shock ().

In subsequent research the effects of several different drugs were studied on comparable rates and patterns of responding of squirrel monkeys maintained under 5-minute fixed-interval schedules by food presentation or by the termination of a stimulus associated with shock (). Responding under both consequent events was decreased with promazine and increased by d-amphetamine. However, chlordiazepoxide produced effects that depended on the type of event: food-maintained responding was increased at doses that decreased responding under the stimulus-shock termination schedule.

Chlordiazepoxide also differentially affected responding maintained under concurrent variable-interval and concurrent fixed-interval food- and shock-presentation schedules. In these experiments responses on one lever produced shock while responses on a second lever produced food. Despite the fact that these performances were occurring simultaneously, chlordiazepoxide selectively increased responding maintained by food while decreasing that maintained by shock (). Figure Control performances and effects of Chlordiazepoxide under concurrent variable-interval schedules of food (1.5 minute) or shock (6 minute) presentation (MS-58). Abscissae: time; ordinates: cumulative responses. Recordings of food-maintained (left panels) and shock-maintained (right panels) responding were made simultaneously. On the records showing food-maintained responding diagonal marks on the upper tracing denote food delivery and the marks on the lower line represent shock delivery. On the records showing shock-maintained responding diagonal marks on the upper tracing denote shock delivery and marks on the lower line represent food delivery. Pens reset to base after 1100 responses. Note that chlordiazepoxidee increased responding maintained by food but only decreased responding maintained by shock illustrates this effect under the concurrent variable-interva1 schedule. Finally, in a recent study with rats, where comparable rates and patterns of responding were maintained under variable-interval food-presentation and shock-cancellation schedules, chlordiazepoxide increased responding maintained by food but decreased responding under the shock-cancellation schedule ().

Evidence indicating that the nature of the event could be a factor determining the effects of certain drugs under interval schedules prompted additional work in which responding was maintained by different events under fixed-ratio schedules. In one experiment similar rates and patterns of responding of squirrel monkeys were maintained under a multiple fixed-ratio loo-response schedule of food presentation or stimulus-shock termination. In contrast to the differential effects found under fixed-interval schedules with these different consequent events, chlordiazepoxide, pentobarbital, and ethanol decreased responding under both fixed-ratio schedules regardless of whether food or stimulus-shock termination maintained responding ().

The finding that the different behavioral effects of drugs are related to the maintaining event under one schedule but not another reaffirmed the importance of schedule factors. In addition, the result that differential drug effects occur under one schedule but not another, implies that unitary motivational accounts of the effects of drugs based simply on the type of consequent event are implausible.

Although only decreases in responding were obtained under the fixed-ratio schedules with pentobarbital, chlordiazepoxide, and ethanol, other experiments have reported increases in responding maintained under fixed-ratio stimulus-shock termination schedules with d-amphetamine (). Increases in responding maintained by food did not occur with d-amphetamine, however, in those studies that examined these effects under comparable schedules. Since these results differed from those reported earlier by Kelleher and Morse (). several other experiments were conducted in which the effects of d-amphetamine were examined under a broad range of fixed-interval and fixed-ratio parameter values, as well as under multiple fixed-ratio fixed-interval schedules (). Over a range of fixed-ratio values, from 30 to 300 (30 to 170 for food-maintained monkeys) and a range of response rates from approximately 1.5 to 3.0 responses per second, most doses of d-amphetamine consistently increased responding maintained by stimulus-shock termination, but only decreased responding under the food schedule (Effects of d-amphetamine on responding under different parameter values of fixed-ratio (top) or fixed-interval (bottom) schedules of food presentation or stimulus-shock termination. Each point represents the mean usually of at least two determinations. The points on the left represent the mean of control observations + 1 S.E. Note that at all of the fixed-ratio parameter values studied, d-amphetamine decreased responding maintained by food but markedly-increased responding under the stimulus-shock termination schedule. Under the fixed-interval schedules, a broad range of doses of d-amphetamine increased responding under all parameter values of the fixed-interval stimulus-shock termination schedule. Increases in response rate were slightly less or did not occur under the food-presentation schedule at the 30-second value, whereas at the 3- and lo-minute values rates were markedly increased. Note the different ordinates for the two graphs in the lower figure).

Under fixed-interval schedules, however, that were varied from 30 seconds to 10 minutes, and over a range of response rates, d-amphetamine usually increased responding maintained by both-food and stimulus-shock termination (). The differential effects of d-amphetamine on responding under fixed-ratio schedules with different events, but not under the fixed interval, were also found when these schedules were studied together as components of a multiple schedule (Effects of d-amphetamine on responding under a multiple 40-response fixed-ratio 3-minute fixed-interval schedule of food presentation or stimulus-shock termination. Figures shown are percent changes in control rates of responding. Circles denote responding under the fixed-interval schedules, triangles responding under the fixed-ratio schedules. Points with vertical lines on the extreme left of each curve represent control observations + 1 S.E.; where there are no vertical lines, this measure of variability fell within the area encompassed by the point. Average control rates under the fixed-interval food-presentation schedule were 0.412 and 0.606 responses per second for MS-6 and MS-13, respectively; under the fixed-ratio schedule these rates were 3.799 (MS-6) and 3.851 (MS-13) responses per second. When responding was maintained by stimulus-shock termination schedules, rates under the fixed-interval were 0.651 (MS-9) and 1.605 (MS-25); under the fixed-ratio schedule these rates were 2.903 (MS-9) and 2.336 (MS-25) responses per second).

These studies suggest quite convincingly that d-amphetamine differentially affects responding maintained by food and stimulus-shock termination under fixed-ratio schedules. Under fixed-interval schedules, however, the effects of d-amphetamine are largely independent of the event that maintains responding. Significantly. the different effects of amphetamine on responding maintained by food and stimulus-shock termination occur over a wide range of parameter values and response rates. The results, therefore, cannot be regarded as being of limited generality; the type of event can play a more significant role than was apparent in early studies.

Sweeping generalizations about the relative independence of drug effects and consequent behavioral events are not possible. A number of different drugs have shown effects that depend on the event; the specific outcome, however, depends on the drug, the schedule, and the event. Under some conditions drug effects may also depend on the parameter value of the schedule. For example, figure Effects of pentobarbital on responding under a multiple 40-response fixed-ratio 3-minute fixed-interval schedule of food presentation or stimulus-shock termination. Details are the same as in figure 5. Note that pentobarbital increased responding under both fixed-interval and fixed-ratio schedules of food presentation, but only decreased responding under these schedules when the maintaining event was stimulus-shock termination shows that pentobarbital increased responding under 40-response fixed-ratio schedules of food presentation but not under comparable schedules of stimulus-shock termination (); in the study described above (), pentobarbital decreased responding maintained by both events under higher-valued fixed-ratio schedules. Other studies have indicated that drug effects under one component of a multiple schedule can be dramatically modified by changing the parameter value in another component, even when performance in the unchanged component is not affected (). The conclusion that the event can play an important function in determining the behavioral effects of many drugs is inescapable; the conclusion that such effects are exclusively dependent on the type of event, independent of other factors, however, is clearly wrong. The same drug will produce similar effects on responding maintained by different events under one schedule, but dissimilar effects under another schedule. Although the findings described in this section suggest that certain modifications are necessary in existing views of the role of the event, they also reaffirm the fundamental importance of schedule-controlled responding in determining the behavioral effects of drugs.

Response Duration and the Effects of d-Amphetamine

The effects with d-amphetamine were unexpected and somewhat difficult to reconcile with-earlier work. As reproducible results accumulated and response rate appeared to play a less important role in determining some of these effects (), it seemed reasonable to examine a dimension of the response other than rate. Recordings were made, therefore, of response duration under the 30-response fixed-ratio schedules of food presentation or stimulus-shock termination with squirrel monkeys. Subsequently, the effects of d-amphetamine on both response rate and response duration measures were examined. Figure Effects of d-amphetamine on response rate and response duration under fixed-ratio 30-response schedules of stimulus-shock termination (MS-31) or food presentation (MS-51 and MS-39). Note that response duration was longer under the termination schedule than under the food schedules but that at low to intermediate doses this measure decreased for all animals regardless of the maintaining event. Response rates were higher under the food schedules and were not increased with d-amphetamine; responding under the stimulus-shock termination schedule, however, was increased substartiatly with d-amphetamine shows data from these experiments. Average response duration was considerably longer under the stimulus-shock termination (MS-31) schedule than under that maintained by food (MS-51 and MS-39); response rates maintained by food were slightly higher than those maintained by termination of the stimulus associated with shock.

Even though there were initial differences in response duration, the effects of d-amphetamine on this measure under the two schedules were similar: duration decreased at low to intermediate doses (.0l-0.1 mg/kg) and increased at the higher doses (0.3-1.0 mg/kg). As in the work described above, however, response rates were affected differentially; sizeable increases in rates occurred under the termination schedule at doses that did not affect or decreased food-maintained responding. Thus, whether differential or comparable effects of d-amphetamine are obtained under fixed-ratio schedules utilizing different consequent events depends on whether the experimental focus is on response rate or response duration. Different conclusions would be drawn depending on which response characteristic was examined. Although response rate has been the traditional measure used in behavioral studies and in behavioral pharmacology, other dimensions may also provide beneficial information. As has been the case with response rate, however, further research would necessarily have to examine conditions where response duration maintained by the different events was comparable or was manipulated over a wide range.

Although these several findings are somewhat difficult to summarize, it clearly appears that the type of maintaining event can influence the specific effects a drug will have on behavior. At the present time it is not possible to provide a general framework within which these several different findings can be easily placed and evaluated. Such problems are often true initially when newer findings do not confirm earlier results. Different events can unquestionably produce different behavioral effects. At the present time it is difficult to determine which, if any, of these multiple effects contribute to the differential behavioral effects of drugs. Further experiments addressed to this issue, which may eventually help in formulating general principles, are summarized below.

Second-Order Schedules

In the experiments described thus far, all of the procedures involved schedules where the completion of each schedule requirement produced the consequent-maintaining event. Within the past ten years several experiments have been conducted in which responding has been maintained by stimuli paired with consequent events such as food or drug administration (). Formally termed second-order schedules Kelleher, such procedures arrange for responding to produce a brief, usually visual, stimulus according to a particular schedule; responding under that schedule is then treated as a unitary response that is then also reinforced according to a specific schedule.

The control performances in figure 8 illustrate characteristic rates and patterns of responding of squirrel monkeys under second-order schedules of food or shock presentation [fixed-ratio 10 (fixed-interval 3-minute:S)]. Under these schedules the first response after 3 minutes produced a 3-second change in the color of the visual stimulus illuminating the experimental chamber; after completion of ten fixed intervals, the brief stimulus was followed by the delivery of ten food pellets (MS-43) or ten 8 mA shocks (MS-29). The presentation of food or shock occurred only once, at the end of the complete session. This aspect of arranging the consequent events to occur at the end of the entire session may be particularly advantageous in experiments where one is interested in examining the effects of presession drug administration on drug-maintained responding. It has not always been possible to prevent interactions between the drug given prior to the session and the maintaining drug because of the occurrence of repeated injections throughout the session which were required to maintain performance. Second-order schedules, where responding is maintained by brief stimuli only eventually paired with drug injection at the end of the session, eliminate most direct interactions with the presession drug and provide a convenient means for assessing several experimental issues ().

Similar interactions between presession drugs and consequent events could also exist when events other than drugs maintain responding and are presented intermittently throughout the session. For example, during an experimental session in which a drug is given as a pretreatment, the recurrence of shock or food could produce changes in behavior and in drug effects which may differ from those obtained when the maintaining event is presented only once at the end of the session.

Several studies conducted over the past few years have examined these possibilities using second-order schedules of food or shock presentation, stimulus-shock termination, or intramuscular cocaine administration as maintaining events. Figure Control performances and effects of chlordiazepoxide on responding maintained under second-order schedules of brief stimuli paired with either food or electric shock when those events occurred only at the completion of each daily session. Abscissae: time; ordinates: cumulative responses. The diagonal marks on each record denote the occurrence of the 3-second visual stimulus. The recording pen was reset with the presentation of either food (MS-43, left) or shock (MS-29, right) at the end of the session. Note that chlordiazepoxide increased responding maintained by food but only decreased responding maintained by shock, for example, in addition to depicting performances under second-order schedules of food or shock presentation, also shows that chlordiazepoxide increased responding maintained under second-order food-presentation schedules but only decreased comparable responding maintained under similar schedules by the presentation of shock (). These differential effects are similar to those found under single-component fixed-interval schedules described earlier and suggest that those effects are not influenced substantially by the recurring delivery of food or shock. Together with the effects of chlordiazepoxide on responding maintained under the concurrent variable-interval schedules () and under stimulus-shock termination schedules, these several experiments provide rather compelling evidence for the event-dependent effects of chlordiazepoxide on responding maintained under interval schedules of reinforcement.

In the studies using basic schedules summarized previously the effects of c-amphetamine under fixed-interval schedules were largely independent of the type of maintaining event. C-Amphetamine also produced similar effects under second-order schedules of food or shock presentation, stimulus-shock termination or intramuscular cocaine administration (). Both promazine () and chlorpromazine () decreased responding under second-order schedules where responding was maintained by food or by intramuscular cocaine administration. Other experiments comparing the effects of drugs on performances maintained by food and drug administration under similar second-order schedules have not typically found differential effects with pentobarbital, cocaine or chlordiazepoxide ().

These several experiments indicate that, at least thus far, the effects of drugs on behaviors under basic schedules are similar to those obtained when those same events occur under second-order schedules. It is interesting that drugs such as pentobarbital and chlordiazepoxide which produce different effects on responding maintained by food and shock, appear to affect responding maintained by food and cocaine administration in a similar manner. Further experiments that examine a wider variety of different maintaining and pretreatment drugs, as well as different experimental procedures (e.g., termination of a stimulus associated with naloxone administration in morphine-dependent monkeys), will undoubtedly help clarify these issues.

 

Selections from the book: “Behavioral Pharmacology of Human Drug Dependence”. Travis Thompson, Ph.D., and Chris E. Johanson, Ph.D., eds. Presents a growing body of data, systematically derived, on the behavioral mechanisms involved in use and abuse of drugs. National Institute on Drug Abuse Research Monograph 37, July 1981.