Psychopharmacologia (Berl.) 44, 153-156 (1975) - 9 by Springer-Verlag 1975

The Effects of Tranquillizing Drugs on Timing Behaviour in Rats D. J. SANGER and D. E. BLACKMAN Department of Psychology, University of Birmingham, Birmingham, England Received April 18, 1975 Abstract. Timing behaviour was generated in rats by a schedule which required responses to be spaced at least 15 sec apart in order for them to produce food reinforcement (DRL 15 sec). The behaviour maintained by this schedule was then studied after administration of chlordiazepoxide, phenobarbitone and chlorpromazine. Several doses of both chlordiazepoxide and phenobarbitone were found to disrupt timing behaviour by increasing overall response rates although the highest dose of each of these two drugs produced sedative effects. Chlorpromazine produced mainly a decrease in overall response

rates. Analysis of performance in terms of interresponse times (IRTs) showed that both chlordiazepoxide and phenobarbitone markedly increased the percentage of IRTs less than 1.5 sec in duration (response bursts). Chlorpromazine had no consistent effect on response bursts. Reduction of the animals' body weights from 85 ~o to 75 ~ of their preexperimental levels had no effect on operant performance, suggesting that the effects of the drugs were probably not due to actions on motivational processes.

Key words: Chlordiazepoxide - Phenobarbitone - Chlorpromazine - DRL Responding - Rats.

Introduction Operant responding which is maintained by a schedule which differentially reinforces low rates of responding ( D R L schedule) has been described as timing behaviour (Sidman, 1955). This pattern of behaviour is known to be sensitive to the actions of a variety of psychoactive agents. Drugs from several classes including stimulants (Morrison, :1968; Pradhan and Dutta, 1970; Sidman, 1955), psychotomimetics (Appel, 1971) and antidepressants (Kornetsky, 1965) have been shown to disrupt timing behaviour by producing a greater number of premature responses. Such results suggest that behaviour maintained by D R L schedules may not be particularly sensitive to differences between classes of psychoactive drugs. However, it has recently been shown that the effects of a minor tranquillizer and those of a stimulant may be distinguished in terms of their effects on bursts of responding, i.e. responses occurring within 1.5 sec of a previous response (Sanger et al., 1974). Chlordiazepoxide was found to increase the percentage of these response bursts following unreinforced responses while d-amphetamine had no consistent effect on this measure. The present experiment was designed to extend these observations by comparing the effects of chlordiazepoxide on responding maintained by a D R L schedule with those of phenobarbitone. Previous reports have shown that barbiturates may disrupt timing behaviour by producing a pattern of responding characterized by long pauses alternating with periods

of fairly high response rates (Kelleher et al., 1961; Sidman, 1956; Stretch and Dalrymple, 1968). It is not clear, however, whether this action is mediated by a specific increase in the percentage of response bursts. The effects ofchlorpromazine were also studied, in order to compare the actions of a major tranquillizer with those of the minor tranquillizer and the barbiturate. It has been suggested that the rate-increasing effects o f chlordiazepoxide on food reinforced operant responding may be related to an appetite stimulating action of this drug (Bainbridge, 1968). Dews (1956) has pointed out that if the effects of a drug on operant behaviour are related to actions on such motivational processes it should be possible to mimic the drug effects by appropriate manipulations of deprivation conditions. There appear to be relatively few published experiments in which the effects of motivational Changes on timing behaviour have been studied (Kramer and Rilling, 1970). In the present experiment, therefore, deprivation conditions were modified in order to determine whether this would mimic the actions of chlordiazepoxide on either overall response rate or response bursts. Method Subjects. Six male albino rats served as subjects. They were approximately t 50 days old at the start of the experiment and were maintained at 85 ~ of their pre-experimental weights. They were housed in individual cages in which water was available at all times.

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Apparatus. The apparatus consisted of 6 standard operant test chambers (L.V.E.) enclosed in sound and light proof cubicles. Each chamber was fitted with two levers but only presses on the right hand lever had any programmed consequences. During sessions illumination was provided by house lights. The experiment was controlled by an on-line computer which also recorded responses and interresponse times (IRTs). Procedure. The rats were adapted to the test chambers, magazine trained and then trained to press the right hand lever to obtain 45 nag food pellets. After 5 days on a schedule which reinforced every response, a DRL 15 sec schedule was put into operation. This required that responses be spaced at least 15 sec apart in order for reinforcers to be obtained. Responses which were emitted before the 15 sec had elapsed caused the 15 sec interval to restart. Sessions were an hour in duration and were given daily. The animals were exposed to 30 daily sessions on the DRL schedule before drug administration was begun. The drugs used were chlordiazepoxide hydrochloride in doses of 1, 3, 10 ~md 30 mg/kg body weight, phenobarbitone sodimn in doses of 3, 10, 30 and 100 mg/kg and chlorpromazine hydrochloride in doses of 0.3, 1.0, 3.0 and 5.6 mg/kg. Drugs were prepared in normal saline to give an injection volume of 2 ml/kg body weight and saline was injected on all non-drug days. Injections were administered approximately 10 rain before sessions and at least three non-drug days were allowed between two successive drug injections. Doses of the three drugs were given in a mixed order, the order being different for each animal. After administration of the drugs had been completed the body weights of the rats were reduced to observe whether this procedure would affect performance on the DRL schedule. The body weights were gradually reduced from 85 ~o to 75 of pre-experimental weights and were maintained at this level for four sessions. Measures of operant performance during these four sessions were then compared with the same measures taken during the last 4 days at which the animals were at 85 ~o of their pre-experimental weights.

Results The six rats developed steady response rates in the first 30 sessions. Mean dose response curves showing the effects of the three drugs on overall response rates are presented in Fig. 1. The response rate after any drug injection was converted to a percentage of the response rate on the preceding day. This figure shows that chlordiazepoxide produced pronounced increases in response rates at doses up to 10 mg/kg while the highest dose (30 mg/kg) reduced rates. The effects of phenobarbitone were similar, response rates being increased except at the highest dose (100 mg/kg) which produced marked reductions in response rates in all six animals. Chlorpromazine did not consistently increase response rates at any of the doses studied and in fact doses of 1.0 and 5.6 mg/kg reduced overall rates. Five animals also showed reductions in overall response rate after the 3.0 mg/kg dose of chlorpromazine but in the sixth animal this dose produced a marked increase in rate. This atypical reaction on the

part of one animal accounts for the irregular shape of the dose response curve for this drug. I R T s were recorded and placed in categories of 1.5 sec duration. Since the main interest, however, was in response bursts only I R T s from the first category ( 0 - 1 . 5 sec), which represent such bursts, are presented. Fig.2 shows mean dose response curves for the effects of the three drugs on these response bursts expressed as a percentage of the total number of responses. The values used to calculate the 0 mg/kg point were obtained from sessions immediately preceding drug sessions. The figure shows that all four doses of chlordiazepoxide markedly increased the percentage of response bursts. Phenobarbitone also increased the percentage of response bursts while chlorpromazine had no consistent effect on this measure. Reduction of the animals' body weights from 85 ~o to 75 ~o pre-experimental weights had no consistent effect on performance on the D R L schedule. Table 1 shows the mean response rate and percentage of response bursts at 85 ~ and 75 ~ . It is clear that there is very little difference between the values calculated at the two body weights.

Discussion The results of this experiment confirm and extend those of previous reports in which chlordiazepoxide has been shown to increase rates of responding maintained by D R L schedules (Richelle et al., 1962; Sanger et al., 1974). Phenobarbitone was found to exert a similar stimulant action on responding. Similarities between the actions of benzodiazepines and those of barbiturates on operant behaviour have been reported before (Thompson, 1972; Wedeking, 1974). In contrast, the actions of chlorpromazine were predominantly depressant. Only in one animal and at one dosage was a rate-increasing effect observed. It m a y be that this anomaly is related to the observation that this rat consistently responded by biting the lever rather than pressing it with its paws. There are several other reports showing that chlorpromazine can depress rates of operant responding (Boren, 1961 ; Clark, 1969; Ray and Bivens, 1966). Chlordiazepoxide was again found to disrupt the patterning of D R L responding by increasing the percentage of response bursts, an effect which occurred at all doses regardless of the effect on overall response rate (Sanger et al., 1974). Phenobarbitone exerted a similar action while chlorpromazine had no consistent effect on this measure. Barbiturates have previously been reported to produce a pattern of responding on D R L schedules characterised by long pauses alternating with periods of fairly high response rates

D. J. Sanger and D. E. Blackman: Drugs and Timing Behaviour Chlorpromazine

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Fig. 1. Mean dose response curves showing the effects of chlordiazepoxide, phenobarbitone and chlorpromazine on overall response rates maintained by the DRL 15 sec schedule. Response rates after drug administration are expressed as percentages of the values on the preceding (non-drug) days. Vertical lines show _+ S.E.

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Fig. 2. Mean dose response curves showing the effects of chlordiazepoxide, phenobarbitone and chlorpromazine on the percentage of response bursts (IRTs < 1.5 sec) on the DRL 15 sec schedule. The 0 mg/kg point is the mean of the values taken on days preceding drug injections. No point is presented for the 100 mg/kg dose ofphenobarbitone since very few responses were emitted by any of the 6 rats after administration of this dose. Vertical lines show _+ S.E.

mg/kg

Table 1. Effects of body weight change on timing behaviour Response rate (responses/ session)

Percentage of response bursts

85 ~ of pre-experimental weights

276 + 52

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Each value is the mean _+ SD. of 24 readings, 4 for each of 6 animals. (Kelleher et al., 1961; Sidman, 1956; Stretch and Dalrympte, 1968). In the present experiment phenobarbitone increased the percentage of response bursts although long pauses were not observed except at the highest dose when all animals were markedly

sedated. It should be pointed out that the ability of a drug to increase the percentage of response bursts is not shared by all drugs which increase overall response rate since it has been shown previously that d-amphetamine does not consistently increase the percentage of bursts (Sanger et al., 1974). At this stage, however, it is not possible to say whether this effect is restricted to drugs referred to as anxiolytics. Eating behaviour is known to be stimulated by chlordiazepoxide (Bainbridge, 1968; Randall et al., 1960) and it has been suggested that this action may underly the increased rates of operant responding produced by the drug (Bainbridge, 1968). In order to investigate this possibility the weights of the rats used in this experiment were reduced from 85 ~ to 75 ~ of their pre-experimental values, a procedure which has previously been used in operant research on

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motivation (Ferster and Skinner, 1957). I f the effects of chlordiazepoxide were due to an increase in appetite it might be expected that this increase in deprivation would at least partially mimic the actions of the drug (Dews, 1956). However, this reduction in body weight had very little effect on either overall response rates or the percentage of response bursts, thus providing no evidence for the view that the effects of chlordiazepoxide on these measures are related to actions of the drug on motivational processes. The rats which served as subjects in this experiment were in fact drawn from the Maudsley reactive and non-reactive strains which are selectively bred for levels of emotionality as measured in an open field (Broadhurst, 1960). Rats of these strains have previously been shown to differ in their responses to several psychoactive drugs (Garg, 1969; G u p t a and Holland, 1972; Satinder, 1971) and it has also recently been reported that rats selected, though not bred, for open field performance show some differences in their responses to chlordiazepoxide (Soubrie et al., 1974). It was, therefore, considered of interest to use animals of the Maudsley strains in the present experiment. However, no consistent differences either in baseline performance or in responses to any of the drugs used were observed between animals of the two strains and thus the data have been presented for the animals of both strains combined. This lack of any consistent strain differences may, of course, reflect the fact that only three animals of each strain were used in this study.

Acknowledgements. Financial support was provided by the Medical Research Council (Grant G972/262/B). Chlordiazepoxide was kindly supplied by Roche Products Limited.

R@FCTICeS Appel, J. B. : Effects of LSD on time based schedules of reinforcement. Psychopharmacologia (Berl.) 21, 174- t86 (1971) Bainbridge, J. G. : The effect of psychotropic drugs on food reinforced behaviour and on food consumption. Psychopharmacologia (Berl.) 12, 204-213 (1968) Boren, J. J. : Some effects of adiphenine, benactyzine and chlorpromazine upon several operant behaviors. Psychopharmacologia (Berl.) 2, 416-424 (1961) Broadhurst, P. L. : Experiments in psychogenetics: Application ofbiometrical genetics to the inheritance ofbehaviour. In: Experiments in personality, vol. 1, H. J. Eysenck, ed., pp. t-- 102. London: Routledge and Kegan Paul 1960 Clark, F. C. : Effects of chlorpromazine on behaviour maintained by a multiple schedule of reinforcement. J. Pharmacol, exp. Ther. 166, 179-188 (1969)

Dews, P. B. : Modification by drugs of performance on simple schedules of positive reinforcement. Ann. N.Y. Acad. Sci. 65, 268-281 (1956) Ferster, C. B., Skinner, B. F. : Schedules of reinforcement. New York: Appleton-Century-Crofts 1957 Garg, M. : Variation in effects of nicotine in four strains of rats. Psychopharmacologia (Berl.) 14, 432-438 (1969) Gupta, B. D., Holland, H. C. : An examination of the effects of stimulant and depressant drugs on escape/avoidance conditioning in strains of rats selectively bred for emotionality/non-emotionality: a multivariate analysis of the effects of drugs on conditioned avoidance responses and intertrial activity. Neuropharmacology 11, 23-30 (1972) Kelleher, R. T., Fry, W., Deegan, J., Cook, L.: Effects of meprobamate on operant behavior in rats. J. Pharmacol. exp. Ther. 133, 271-280 (1961) Kornetsky, C. : A comparison of the effects of desipramine and imipramine on two schedules of reinforcement. Neuropharmacology 4, 13 - 16 (i 965) Kramer, T. J., Rilling, M. : Differential reinforcement of low rates: a selective critique. Psychol. Bull. 74, 225-254 (1970) Morrison, C. F. : A comparison of the effects of nicotine and amphetamine on DRL performance in the rat. Psychopharmacologia (Berl.) 12, 176-180 (1968) Pradhan, S. N., Dutta, S. N. : Comparative effects of nicotine and amphetamine on timing behaviour in rats. Neuropharmacology 9, 9 - 1 6 (1970) Randall, L. O., Schalleck, W., Heise, G. A., Keith, E. P., Bagdon, R.E. : The psycho-sedative properties of methaminodiazepoxide. J. Pharmacol. exp. Ther. 129, 163 - t 71 (1960) Ray, O. S., Bivens, L. W. : Chlorpromazine and amphetamine effects on three operant and four discrete trial reinforcement schedules. Psychopharmacologia (Berl.) 10, 32-43 0966) Richelle, M., Xhenseval, B., Fontaine, O., Thone, L. : Action of chlordiazepoxide on two types of temporal conditioning in rats. Int. J. Neuropharmacol. 1,381-391 (1962) Sanger, D. J., Key, M., Blackman, D. E. : Differential effects of chlordiazepoxide and d-amphetamine on responding maintained by a DRL schedule of reinforcement. Psychopharanacologia (Berl.) 38, 159-171 (1974) Satinder, K. P. : Genotype-dependent effects of d-amphetamine sulphate and caffeine on escape-avoidance behavior of rats. J. comp. physiol. Psychol. 76, 359-364 (1971) Sidman, M. : Technique for assessing the effects of drugs on timing behavior. Science 122, 925 (1955) Sidman, M.: Drug-behavior interaction. Ann. N.Y. Acad. Sci. 65, 282-302 (1956) Soubrie, P., Wlodaver, C., Schoonhoed, L., Simon, P., Boissier, J. P.: Preselection of animals in studies of antianxiety drugs. Neuropharmacology 13, 719- 728 (1974) Stretch, R., Dalrymple, D. : Effects of methylphenidate, pentobarbital and reserpine on behavior controlled by a schedule of interresponse time reinforcement. Psychopharmacologia (Berl.) 13, 49-64 (1968) Thompson, D. M.: Enhancement of progressive ratio performance by chlordiazepoxide and phenobarbital. J. exp. Anal. Behav. 17, 287-292 (1972) Wedeking, P. W. : Schedule-dependent differences among antianxiety drugs. Pharmac. Biochem. Behav. 2, 465-472 (1974)

D. J. Sanger, Department of Psychology, University of Birmingham, P.O. Box 363, Birmingham B15 2TT, England

The effects of tranquillizing drugs on timing behaviour in rats.

Timing behaviour was generated in rats by a schedule which required responses to be spaced at least 15 sec apart in order for them to produce food rei...
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