Effect of anxiolytics and antidepressants on extinction and negative contrast

Pharmac. Ther. Vol. 46, pp. 309-320, 1990 Printed in Great Britain. All rights reserved

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EFFECT OF ANXIOLYTICS A N D ANTIDEPRESSANTS ON EXTINCTION A N D NEGATIVE CONTRAST CHARLES F. FLAHERTY Department of Psychology, Rutgers Unit~ersity, New Brunswick, NJ 08903, U.S.A. Abstract--Anxiolytics, particularly the benzodiazepines and barbiturates tend to retard, but not prevent, extinction, promote recovery from negative contrast, and elevate S - responding in discrimination training. Anxiolytics, administered during acquisition, tend to eliminate the partial reinforcement extinction effect, but this result is substantially influenced by parametric considerations. Behaviors that are energized in extinction may have a different pharmacological profile than behaviors that decline. Conclusions regarding the effects of antidepressants must be more tentative but, in general, acutely administered antidepressants are relatively ineffective in all of these paradigms. However, antidepressants may enhance the efficiency of responding on DRL schedules whereas anxiolytics tend to disrupt such behavior. CONTENTS 1. Introduction 2. Extinction 2.1. Anxiolytics 2.1.1, Continuous reinforcement 2.1.2. Intermittent reinforcement 2.1.3. Energized behaviors 2.1.4. Consummatory behavior 2.1.5. Discrimination learning 2.2 Antidepressants 2.2.1. Continuous reinforcement 2.2.2. DRL responding 2.2.3. Discrimination learning 3. Contrast Effects 3.1. Anxiolytics 3.1.1. Contrast in instrumental behavior 3.1.2. Contrast in consummatory behavior 3.1.3. Discrimination learning--behavioral contrast 3.2. Antidepressants 3.2.1. Contrast in consummatory behavior 3.2.2. Discrimination learning--behavioral contrast 4. Summary and Conclusions Acknowledgements References

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to the level of the shifted control group. Extinction, as befits the name, is relatively permanent. There are a number of behavioral similarities between extinction and successive negative contrast. For example, extinction generally proceeds more rapidly, and contrast is larger, the greater the acquisition reward magnitude. Also, intermittent reinforcement in acquisition retards extinction (Mackintosh, 1974) and reduces degree of negative contrast (Flaherty, 1982). There are also similarities in drug action. In general, tranquilizers slow the rate of extinction and reduce or eliminate negative contrast. There are, however, differences in detail as a function of drug, drug administration routine, and behavioral paradigm. The effects of antidepressants have been

1. I N T R O D U C T I O N The effects of anxiolytics and antidepressants on the behaviors that result from removal of positive reinforcement (extinction) or from the reduction in the amount of positive reinforcement (negative contrast) will be considered in this review. Typically, a reduction in reinforcement to some nonzero value leads to an abrupt decline in responding to a level below that of animals that have experienced only the lower value of reinforcement. The difference in performance between animals for which reward has been decreased and the unshifted control group, termed a successive negative contrast effect, is usually transitory. That is, the shifted animals eventually recover 309

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much less studied, but current evidence indicates that these agents have relatively little effect on extinction or negative contrast. Although there are many interpretations of extinction and contrast, a common theme is that an emotional response is a correlate of, and possibly causally related to, behaviors consequent to reward elimination or reduction (e.g. Amsel, 1958, 1967; Gray, 1969, 1977, 1982, 1987; Mackintosh, 1974). To some extent, the study of the effects of drugs on extinction and negative contrast is the study of drug effects in animal models of frustration, disappointment and possibly anxiety.

2. EXTINCTION 2.1. ANXIOLYTICS 2.1.1. Continuous R e i n f o r c e m e n t

The administration of benzodiazepines (BDZ) or barbiturates retards extinction following a period in which each response has been reinforced. This result has been obtained in a variety of circumstances. For example, Chlordiazepoxide (CDP; 7.5 and 15 mg/kg) increased responding in extinction after discrete-trial lever press training (Heise et al., 1970) and diazepam (2 mg/kg) increased lever pressing in extinction after free-operant lever-press training (Thiebot et al., 1983). Similarly, extinction of a panel-pushing response by pigs is retarded by diazepam (1 m g / k g - Dantzer, 1977a); and extinction of runway behavior is retarded by CDP (5 mg/kg; Buckland et al., 1986; Feldon and Gray, 1981a; McNaughton, 1984). Extinction of bar pressing for brain-stimulation reward (medial forebrain bundle) is also retarded by CDP (15 mg/kg; Gandelman and Trowell, 1968). The effect of diazepam (2 mg/kg) on extinction is blocked by the benzodiazepine antagonist flumazenil (Ro 15-1788) (Thiebot et al., 1983) but flumazenil alone apparently has little effect on extinction, except for a possible tendency for high doses (10 mg/kg or 32 mg/kg) to increase resistance to extinction (Hawkins et al., 1988; Thiebot et al., 1983). Some evidence for the involvement of gammaamino butyric acid (GABA) in the antiextinction effects of the benzodiazepines was provided by the finding that both picrotoxin and bicuculline tended to block the effects of CDP on extinction. Picrotoxin administered alone tended to facilitate extinction-possibly indicating an anxiogenic effect (Buckland et al., 1986). However, the same report failed to find effects of the G A B A A agonist muscimol and the GABA~ agonist baclofen on extinction. These drugs were administered systematically, however, and muscimol, at least, is known to penetrate the brain poorly in such circumstances (Baraldi et al., 1979). In a variation on the usual procedure, Shemer and colleagues (Shemer et al., 1984) administered CDP (5 mg/kg) for 12 days before the start of runway acquisition training, at which time drug administration was discontinued. In extinction, animals which had the prior experience with CDP administration were more resistant to extinction than controls. Thus, the effects of CDP administration were long-lasting

and the 'removal' of the drug led to effects opposite to what would have been expected from administration of the drug. The effect of barbiturates on extinction generally parallels that of the BDZs. Thus, sodium amobarbital (17.5 or 20mg/kg) increases resistance to extinction in the runway (Barry et al., 1962; Dudderidge and Gray, 1974; Feldon et al., 1979; Ison and Rosen, 1967; McNaughton, 1984). However, barbiturates may not be as effective in operant situations--Heise et al. (1970) reported that phenobarbital (20 and 30 mg/kg) and pentobarbital (5 and 10 mg/kg) did not increase resistance to extinction of a discretetrials lever-press response, and Griffiths and Thompson (1973) found that pentobarbital (20 mg/kg) led to fewer total responses in extinction following training on an FR-20 bar-press schedule. However, these effects are probably not characteristic of lever-pressing per se since Weissman (1959) reported that pentobarbital (8, 16 and 24mg/kg) increased responding during nonreinforced ( S - ) periods of a multiple schedule. Ethanol also increases resistance to extinction (e.g. Barry et al., 1962; Devenport, 1984). Devenport suggested one possible mechanism underlying this increased persistance, one that would seem to be maladaptive under natural circumstances. Rats shifted to extinction or to a lower level of reward, may normally enhance their exploration of the environment, perhaps searching for the 'missing' reward (e.g. Elliott, 1928; Flaherty et al., 1978, 1979). Evidence from Devenport's ethanol study suggested that the drug (1.5, 2.0 g/kg of a 10% solution; but not a 0.75 g/kg dose) reduces exploratory behavior in extinction and enhances perseveration to previously rewarded locations. Although ethanol, barbiturates and the benzodiazepines have generally similar effects on the extinction of positively reinforced responses, ethanol may differ from the other two drug classes in its effects on the extinction of aversively motivated behaviors (see Mason (1983) for a review of this literature; and see Dantzer (1977b) for a review of the effects of benzodiazepines in these, and related, paradigms). 2.1.2. I n t e r m i t t e n t R e i n f o r c e m e n t Animals trained with intermittent reward in acquisition are more resistant to extinction than animals given continuous reinforcement in acquisition. This partial reinforcement extinction effect (PREE) is one of the most pervasive, and most investigated, findings in the behavioral literature (cf. Mackintosh, 1974; Gray, 1982, 1987). Although there are many interpretations of the PREE, one that has maintained currency over the years is Amsel's frustration theory. In brief, the theory holds that the withdrawal of reward is frustrating, frustration is aversive, and this aversiveness promotes a decline in responding. Animals with a history of intermittent reinforcement experience frustration during acquisition of an instrumental response, but the tendency to avoid the goal region in anticipation of frustration is counterconditioned. That is, animals learn to persist in res'ponding because reward is sometimes present when frustration was anticipated and, thus, anticipation of frustration

Anxiolytics and antidepressants itself becomes a cue that controls the instrumental approach behavior. This learned tendency to continue responding in the presence of frustration then prolongs responding in extinction (Amsel, 1958, 1967). Some of the evidence taken to support the hypothesis that extinction is frustrating or aversive includes the observations that the stress hormone corticosterone is elevated in extinction and that this elevation is related to the loss of reward and not to changes in responding per se (Davis et al,, 1976; Coe et al., 1983). In addition, animals will learn to escape from a cue paired with nonreward when reward had been expected, but not from a cue simply paired with nonreward in the absence of a reward expectation (Daly, 1974; Mackintosh, 1974). Evidence relevant to the presence of frustration in the acquisition of a partially reinforced response is derived from the effect on the PREE of tranquilizers administered during acquisition. This evidence suggests that CDP administered only during the acquisition period will facilitate extinction (Demarest and MacKinnon, 1978) and reduce or eliminate the PREE (e.g. Feldon and Gray, 1981a,b; Willner and Crowe, 1977). The administration of CDP in both the acquisition and extinction phases will also reduce or eliminate the PREE (Feldon and Gray, 1981a,b; McNaughton, 1984). When CDP is given only during the extinction period following intermittent reward in acquisition, the drug has an overall effect of increasing resistance to extinction (Demarest and MacKinnon, 1978), but it does not eliminate the PREE (i.e. the drug has no differential effect on continuously reinforced and partially reinforced groups--Feldon and Gray, 1981a,b). The benzodiazepine antagonist flumazenil (l, 5, l0 mg/kg) had no effect on the PREE when given in acquisition, extinction, or both (Hawkins et al., 1988). As was the case with CDP, the administration of sodium amobarbital during acquisition only reduced or eliminated the PREE (Feldon et al., 1979; Gray, 1969; Gray and Dudderidge, 1971; McNaughton, 1984). Capaldi and Sparling (1971) varied the sequences of rewarded and nonrewarded trials experienced by the rats during acquisition and reported that the PREE was eliminated by sodium amobarbital (20 mg/kg) only when it was administered under conditions in which a rewarded trial followed a nonrewarded trial, within the same day~ in acquisition. In this study, there were six trials per day with a short (1.5 min) intertrial interval. It should be noted that the Feldon et al. study found clear effects of sodium amobarbital with a 24 hr intertrial interval. Not all results conform to a pattern consistent with the conditioned frustration interpretation. Ison and Pennes (1969) provided evidence that the effects of sodium amobarbital may be state-dependent in that the PREE was reduced in animals that were given the drug in acquisition and saline in extinction a n d in animals that were given saline in acquisition and the drug in extinction. Somewhat different results were reported by Gray (1969) who found that sodium amobarbital administered during the acquisition period only completely eliminated the PREE, whereas the change from saline in acquisition to drug

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in extinction reduced, but did not eliminate the PREE. Gray's study differed from that of Ison and Pennes in that more acquisition trials were given by Gray. Another divergence from the frustration account was reported by Ziff and Capaldi (1971) who found no effect on the PREE of sodium amobarbital given in acquisition. This experiment differed from the typical study in that there were only six acquisition trials (three in the continuously rewarded group) and in that the intertrial interval was very short (1.5 rain). An overview of the various effects of anxiolytics on the PREE suggests that the drugs are particularly likely to be effective when there is extensive acquisition training, when the intertrial interval is long (24 hr), and that CDP, particularly in doses higher than 5 mg/kg, might have clearer and more consistent effects than the barbiturates. The importance of the intertrial interval is further suggested by a comparison of the results obtained by McNaughton (1984), who reported a large PREE in animals given sodium amobarbital both in acquisition and extinction, and the results of Feldon et al. (1979) who reported the complete absence of the PREE in animals that recevied the drug both in acquisition and extinction. The McNaughton study employed an intertrial interval of between 2 and 10min, whereas the Feldon et al. experiment used a 24hr intertrial. McNaughton also reported that CDP given both in acquisition and extinction would eliminate the PREE in a discrete-trial lever-press task (FR-5) when there was a 24 hr intertrial interval. As a final complexity, it should be noted that different drug-related results are often obtained with different measures of performance. In particular, the degree to which sodium amobarbital diminishes the PREE seems to be greater in the goal region of a runway than in the start region (Feldon et al., 1979, Exp. 2). This outcome probably reflects the greater control of behavior by the anticipation of aversive events as the time/place of occurrence of those events approaches (Miller, 1959; Gray, 1987). Probably related to this factor is the finding that animals given intermittent reinforcement in acquisition often run slower than continuously reinforced animals in the goal region, but not in earlier sections of the runway--where they may even run faster (Goodrich, 1959; Haggard, 1959). Also, successive negative contrast effects are more likely to be obtained in the goal region of the runway than in the start region (Flaherty, 1982). The effects of intertrial interval and number of acquisition trials probably reflect different degrees and kinds of learning that take place during acquisition. For example, long intertrial intervals and extended acquisition training may favor the development of control over responding by cues associated with anticipated emotional events rather than by cues associated with the the rewarding event that occurred on the previous trial. In this regard it is interesting to note that lesions of the septum will eliminate the PREE if a short acquisition period is given, but not if there is extensive acquisition training (Henke, 1974). Extensive discussions of the behavioral aspects of the PREE are presented by Mackintosh (1974, Chapter~ 8), Capaldi (1966, 1974), and Gray (1982, 1987).

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2.1.3. Energized Beha~'iors

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Immediately after the onset of extinction, there is sometimes a temporary increase in rate or force of responding. Fowler (1974) reported that CDP (5 mg/kg) actually increased the response force in extinction but had no effect in acquisition. Another example of the invigorating effects of nonreward is the Amsel Frustration Effect (FE). If rats are given random 50% reinforcement in the initial goal box and 100% reinforcement in the terminal goal box of a double runway, they run faster in the second alley after nonrewarded trials in the initial goal box than after rewarded trials in the initial goal box. This difference in running speed is referred to as the FE and is usually interpreted as reflecting an energized effect of frustrative nonreward (Amsel and Roussel, 1952; Gray, 1982). The FE is not influenced by sodium amobarbital (Freedman and Rosen, 1969; Gray, 1969; Ison et al., 1967).

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2.1.4. Consummatory Behat, ior

Mixed results have been found with the extinction of consummatory behavior. Soubrie et al. (1978) reported increased licking on an empty tube that had previously contained water, if diazepam (2 and 4 mg/kg), CDP (8, but not 16 mg/kg) and lorazepam (0.25 and 0.50mg/kg) were administered. Similar results were obtained with CDP (8 mg/kg) by Bialik et al., 1982). Soubrie (1979) reported that these extinction-reducing effects of CDP were not blocked by picrotoxin (1 mg/kg). Discrepant results were obtained by Miczek and Lau (1975) who reported that empty tube licking was not affected by CDP (5, 10, 20 mg/kg) when repeated daily cycles of 15 rain of an empty tube and 15 min of access to water were given. This latter result may be due to the extended training given in this procedure and/or to the length of access to the empty tube. We recently found that licks on an empty tube that had previously contained a 32% sucrose solution for ten days were increased by CDP (8mg/kg), but reliably so only in the first 5 rain of a 20 min access period (C. F. Flaherty and K. Hrabinski, unpublished data--see Fig. 1). 2.1.5. Discrimination learning The differential responding that develops when one stimulus ( S + ) is paired with reward and another stimulus ( S - ) is paired with nonreward has been traditionally analyzed in terms of the concurrent acquisition of a response tendency to S + and extinction of a generalized response tendency to S - (e.g. Flaherty, 1985; Mackintosh, 1974; Spence, 1936), with perhaps the additional effects of emotional responses elicited by nonreward under conditions similar to those in which reward is received (Amsel, 1962). The effect of BDZs is consistent with this interpretation and with the effects of anxiolytics on extinction. That is, discrimination learning is disrupted by the benzodiazepines which generally elevate responding to the nonreward stimulus (e.g. Cole, 1988; Wedeking, 1969; reviewed by Cole, 1986). The effect of CDP on S - responding is reversed by flumazenil

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FIG. 1. Effect of chlordiazepoxide on extinction of consummatory behavior following a 10 day acquisition period (5 min per day) with 32% sucrose. Over a 20 rain exposure to an empty tube, chlordiazepoxide, given in extinction, reliably retarded extinction only in the first 5 rain block. (Cote, 1983). Buckland et al. (1986) reported dose dependent effects of CDP on S - responding in an operant discrimination. A 10mg/kg dose of CDP elevated S - responding, whereas a 5 mg/kg dose was ineffective (this same dose did enhance resistance to extinction in a runway task) and 15 and 20mg/kg doses had suppressive effects on responding. The effect of the 10 mg/kg dose was not altered by the concurrent administration of bicuculline (1.5 or 1.75 mg/kg). Paradoxically, a 2 mg/kg dose of bicuculline enhanced the rate-increasing effects of CDP to both S + and S - , Picrotoxin also enhanced the rate-increasing effects of CDP, but in this case only to responding under S + conditions. These effects of picrotoxin and bicuculline, which differ qualitatively from those obtained in the case of extinction in the straight runway, remain unexplained. Muscimol (0.00125 and 0.25 mg/kg) had no effect on discrimination performance but baclofen (1 mg/kg) suppressed S - responding whether the drug was administred alone or in combination with muscimol. Thus, baclofen, in this case, had anxiogenic-like effects rather than anxiolytic effects. Sodium amobarbital interferes with discrimination learning in a runway by elevating S - responding without influencing S + responding (Ison and Rosen, 1967). Pentobarbital has been shown to disrupt discrimination learning in a number of operant tasks (Weissman, 1959), including the acquisition of a conditional discrimination (Blough, 1957). Caul (1967) reported no interference with the acquisition of a runway choice learning task by sodium amobarbital (20 mg/kg) but the drug substantially interfered with reversal learning. The susceptibility of discriminative behavior to disruption by anxiolytics may vary as a function of stage of training. Dantzer (1977a) reported that when pigs were trained on an FR-10 schedule that alternated with a time out (TO) period, during which no reinforcement was available, diazepam (1 mg/kg) enhanced TO responding early in training, but not later

Anxiolytics and antidepressants in training. Similarly, Dantzer and Baldwin (1974) reported only a small effect of CDP (5 and 10 mg/kg) on extinction responding during a multiple FR-8 extinction schedule, but the drug was administered after stable responding had been attained. In his review, Cole noted that the disruptive effects of the BDZs on discrimination training were more apparent when the drug was administered from the beginning of acquisiton than when the drug was administered after a discrimination had developed. Anxiolytics may be less likely to impair discriminative performance when both S + and S - are available at the same time (see Cole, 1986; Gray, 1982, for reviews; the Caul (1967) study mentioned above is an exception to this pattern). The failure of anxiolytics to interfere with performance in these 'simultaneous' discrimination tasks may be because there is less of a demand that the subject inhibit responding. 2.2. ANTIDEPRESSANTS

2.2.1. Continuous Reinforcement Studies investigating the effects of antidepressants on extinction of appetitive behavior are sparse indeed. Amitriptyline (10mg/kg) and mianserin (15mg/kg) administered chronically (12 days) increased resistance to extinction in a runway task (Egan et al. 1979). In this experiment, there were eight acquisition days and four extinction days--the effects of amitriptyline were reliable on the last two extinction days, those of mianserin on the first three extinction days. Amitriptyline reduced food intake, but the effects of the drug on extinction were probably not due to altered food motivation since there were no effects of the drug on runway behavior in acquisition, and mianserin had the opposite effect on food intake, but the same effect on resistance to extinction. Contrary to the above results, a different antidepressant, desmethylimipramine (DMI, 7.5 mg/kg) was reported to have had no effect in the extinction of runway or lever-pressing tasks when the drug was administered in both acquisition and extinction. However, resistance to extinction was increased when the drug was withdrawn three days before the start of extinction (Willner et al., 1981). In a subsequent experiment it was found that the DMI effect was obtained if animals were treated with the drug between acquisition and extinction (14 days) but not if they were treated during the 14 day acquisition phase (Wilner and Towell, 1982). The explanation for these results is not obvious. However, these effects of DMI were not replicated in a study by Lucki and Frazer (1985), who reported no effects of DMI (10mg/kg) when administered chronically during both acquisition and extinction of a bar-press response, or when the drug (7.5 mg/kg) was withdrawn three days before the start of extinction, as in the Willner et al. (1981) study. 2.2.2. D R L Responding The paucity of data, and the absence of systematic results, concerning the effects of antidepressants on extinction is relieved somewhat by a coherent series J.P.T 46/2--K

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of studies in which the effect of antidepressants on differential reinforcement for low rate (DRL) responding has been investigated. On a DRL schedule animals must learn to withhold responding until a specific interval of time has elapsed since their last response. After this interval has passed, the next response is reinforced. Responses with a shorter interresponse time (IRT) than the criterion value reset the interval timer. Conventional interpretation of performance on this schedule assumes that the animals must learn to discriminate the passage of time since their last response and to inhibit responses with shorter IRTs. A series of studies by Seiden and his colleagues (Seiden and O'Donnell, 1985) has indicated a degree of sensitivity of DRL schedules to antidepressants. For example, imipramine, desipramine and chlorimipramine, administered acutely, decreased response rate and increased reinforcement rate when the rats were responding on a DRL-18 sec schedule (McGuire and Seiden, 1980). Similar effects were obtained on a DRL-72 sec schedule with a long list of tricyclic antidepressants, including desipramine (2.5-20 mg/kg), imipramine (2.5-20mg/kg) and amitryptyline (2.5-20 mg/kg). Inspection of the distribution of IRTs suggested that the drugs lengthened the average interresponse time without changing the fundamental profile of the distribution--indicating that temporal discrimination was not degraded by the drug (O'Donnell and Seiden, 1983; Seiden and O'Donnell, 1985). Antidepressants from the monoamine oxidase (MAO) inhibitor group (e.g. iproniazid 5-40 mg/kg) and atypical antidepressants such as mianserin, zimelidine and trazadone also improve efficiency in the DRL-72 sec schedule. Recently, the MAO-A inhibitors clorgyline and CGPII'305A were found to enhance DRL-72 sec performance, but the MAO-B inhibitor ( - ) d e p r e n y l did not have a performanceenhancing effect (Marek and Seiden, 1988). It has also been recently reported that centrallyacting beta adrenergic agonists clenbuterol and prenalterol have an antidepressant profile in DRL72 sec performance--reducing response rate and increasing reinforcement rate. These effects were blocked by the beta adrenergic antagonist propranolol (O'Donnell, 1987). Using a DRL-60 sec schedule, Sanger (1988) was unable to demonstrate effects of imipramine and mianserin on DRL efficiency. However, the alpha: adrenoceptor antagonists, idazoxan and yohimbine, increased responding and thereby reduced reinforcements--not an 'antidepressant profile' in this paradigm. Other agents have also been found to be without effect or to interfere with DRL responding. The atypical antidepressants nomifensine and bupropion interfered with DRL performance by increasing response rate and reducing the number of reinforcements obtained. Also, neuroleptics (e.g. chlorpromazine 1-4mg/kg, haloperidol 0.025-2mg/kg) and anxiolytics (e.g. CDP 2.5-20 mg/kg, pentobarbital 2.5-20 mg/kg) do not improve performance on the DRL-72 sec schedule (Seiden and O'Donnell, 1985). On a shorter DRL-15 sec schedule the anxiolytics CDP (3 and 10mg/kg) and phenobarbitone (30 mg/kg) interfered with performance by increasing

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response rate, whereas chlorpromazine tended to decrease response rate (Sanger and Blackman, 1975). Given that antidepressants lower the level of spontaneous motor activity in rats (Tucker and File, 1986) it would be tempting to attribute the improved efficiency produced by these drugs on DRL performance to this motor effect. However, a number of drugs which also lower response rate (e.g. chlorpromazine, pimozide, haloperidol, ethanol and clozapine) did not increase the number of reinforcements obtained (O'Connell and Seiden, 1982, 1983; Seiden and O'Donnell, 1985). Thus, there is not a simple relationship between a drug's motoric effects and its effects on DRL behavior. It is possible that antidepresants reduce level of responding without also disrupting the animals' timing ability and it is this combination that is necessary for the enhanced efficiency of DRL responding. 2.2.3. Discrimination learning Imipramine (1, 3, 10 and 17mg/kg) was found to increase S - responding in pigeons trained in a typical discrimination paradiagm in which many S responses were made during the course of learning, but the drug had no effect on S - responding in birds that learned the discrimination without making errors (Terrace, 1963). Further effects of antidepressants in discrimination learning paradigms are considered below under the topic of behavioral contrast.

3. CONTRAST EFFECTS The term 'contrast effect' refers to an exaggeration of the effect of reward on behavior when an animal experiences two or more rewards (Dunham, 1968). Contrast effects are pervasive in animal behavior, occurring in operant tasks, mazes, runways, electrical stimulation of the brain, and consummatory behavior. All that seems to be necessary is the opportunity for animals to experience two or more reward levels, within certain parametric constraints, and an experiment appropriately designed to measure the contrast effects (Bitterman, 1975, 1988; Flaherty, 1982; Mackintosh, 1974; Mellgren, 1972; Williams, 1983). As described above, successive negative contrast involves a downshift in reward (quantity, quality or frequency--shifts in reward delay have provided equivocal results--Flaherty, 1982; Mackintosh, 1974). Rats shifted from a large to a small reward in a runway generally show an abrupt decrement in running speed to a level slower than that of animals that have experienced only the lower level of reward (e.g. Crespi, 1942; Mellgren, 1972). It is the slower running by the shifted animals, as compared to the unshifted animals, that is referred to as a successive negative contrast effect (SucNCE). The degree of SucNCE varies directly with the degree of difference between preshift and postshift reward (Flaherty, 1982) and inversely with the time between the last experience with the preshift reward and the first experience with the postshift reward (e.g. Gonzalez et al., 1973).

Successive negative contrast also occurs in consummatory behavior. For example, rats given access to 32% sucrose for 5 min a day consume more than rats given access to 4% sucrose. If the 32% group is shifted to 4% sucrose there is a precipitous decline in lick frequency to a level substantially below that of animals maintained on the 4% sucrose solution. This negative contrast effect typically diminishes in degree over a three or four day postshift period (Lombardi and Flaherty, 1978; Vogel et al., 1968). As is the case with contrast obtained in runway behavior, degree of contrast in consummatory behavior varies directly with the degree of difference between preshift and postshift sucrose (Flaherty et al., 1983) and inversely with the length of the retention interval between the preshift and postshift periods (Ciszewski and Flaherty, 1977; Flaherty and Lombardi, 1977). Contrast is obtained in free-feeding as well as deprived animals. The principal difference between the two conditions seems to be faster recovery from contrast in deprived animals (Riley and Dunlap, 1979). Negative contrast in consummatory behavior also occurs if a sucrose solution is adulterated with quinine (Flaherty and Rowan, 1989b), and with shifts in the concentration of saccharin solutions. But, whether or not contrast is obtained in the latter procedure may critically depend on the degree of difference between the two solutions and also possibly on the absolute values of the solutions selected (Flaherty and Rowan, 1986; Vogel et al., 1968). Particularly robust contrast effects may be obtained by shifting rats from sucrose solutions (20% or 32%) to a saccharin solution (0.15%) (C. F. Flaherty, M. Weaver, G. A. Rowan and P. S. Grigson, unpublished data).

3.1. ANXIOLYTICS 3.1.1. Contrast in Instrumental Behavior

Negative contrast in the runway is reduced by CDP (5 and 10mg/kg administered chronically--Rosen and Tessell, 1970) and by sodium amobarbital (20mg/kg, Rosen et al., 1967; Ridgers and Gray, 1973). 3.1.2. Contrast in Consummatory Behavior Chlordiazepoxide reduces negative contrast in consummatory behavior in a dose-dependent manner. but there are paradoxes in the effectiveness of this drug. First of all, the drug is largely ineffective when administered acutely on the first postshift day, but doses of 6 or 8 mg/kg will eliminate contrast when administered acutely on the second postshift day (Flaherty et al., 1980, 1990b). This difference in the effectiveness of CDP across the first two postshift days is not due to a differential retention interval between the last preshift day and the first or second postshift days because the drug was found to be ineffective when the first postshift day was given either 24 or 48 hr after the last preshift day (Flaherty et al., 1986). However, the animals must have some experience with the postshift solution before the CDP becomes effective. When the animals were allowed access to

Anxiolytics and antidepressants the postshift 4% sucrose for 20min on the first postshift day, instead of the usual 5min, CDP (8 mg/kg) became effective during the second 5 min, a period that would normally correspond to the second postshift day (Flaherty et al., 1986). This differential effectiveness of the drug early and late in the postshift period may be related to a developing stress response. Based on the measurement of corticosterone levels, it seems that negative contrast is not stressful on the first postshift day, but it is stressful on the second postshift day (Flaherty et al., 1985). One possibility is that the elevated corticosterone on the second postshift day reflects an anticipatory frustration response, or uncertainty, or anxiety, based on the experience on the previous day. Such an interpretation would leave the differential effects of CDP on negative contrast in this paradigm consistent with Gray's model, wherein it is assumed that anxiolytics reduce anticipatory or conditioned forms of anxiety, but not primary responses to aversive events (e.g. Gray, 1982). Another possibility is that the pattern of CDP's effectiveness and corticosterone elevation reflects the operation of different psychological processes underlying negative contrast early and late in the postshift period. For example, the initial response to reward reduction may involve the activation of a search process to locate the 'missing' reward (Elliott, 1928; Flaherty et al., 1978, 1979). Subsequently, as the missing reward is not located, the animal may enter a conflict period triggered by the drive to consume the postshift reward (the animals are food deprived) balanced against the preference for the remembered preshift reward. It may be this conflict stage that is stressful and during this stage that CDP is effective in reducing contrast. Preliminary data have shown that rats downshifted in sucrose concentration in an eight-arm radial maze show marked increases in entries to the seven arms that did not contain sucrose during the acquisition period. Two benzodiazepines other than CDP have been tested in the standard consummatory contrast paradigm. Midazolam was found to reduce contrast in a dose-dependent manner (Becker, 1986) and, in an unpublished study, flurazepam had small contrastreducing properties, but only at a relatively high dose (20 mg/kg). A question might be raised regarding the role that the appetite-stimulating effects of the benzodiazepines play (e.g. Cooper and Estall, 1985) in the recovery from consummatory negative contrast. The evidence suggests that recovery from contrast is not simply related to appetite stimulation because: (a) CDP is relatively ineffective in reducing contrast on the first postshift day, even though it often has an appetite-stimulating effect on the day (e.g. Flaherty et al., 1986, 1989b); (b) CDP has appetite-stimulating effects in two other contrast procedures, anticipatory contrast and simultaneous contrast, but the drug does not reduce contrast in either of these procedures (Flaherty et al., 1977; Flaherty and Rowan, 1988). Chlordiazepoxide (8 mg/kg) was found to reduce contrast in the Syracuse Low Avoidance rats, but not in the Syracuse High Avoidance rats (Flaherty and Rowan, 1989a). It was ineffective (4 and 8 mg/kg) in

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both the Maudsley Reactive and Maudsley Nonreactive strains (Rowan, 1988). Ethanol has a pattern of effectiveness much like that of CDP. That is, it reduces negative contrast in a dose-dependent manner when administered on the second postshift day, but is ineffective on the first postshift day (Becker and Flaherty, 1982). Ethanol and CDP have additive contrast-reducing effects when administered conjointly (Becker and Flaherty, 1983). Free 24-hr access to a 5% ethanol solution, on the other hand, has no effect on contrast when animals are shifted from 32% sucrose to 4% sucrose or from 32% sucrose to 0.15% saccharin. However, the blood alcohol levels were not elevated at the time of testing (molarity = approximately 1 mg/100ml blood), even though the animals were consuming approximately 35 ml of ethanol each 24 hr. Interestingly, the experience of the contrast effect did not serve to elevate ethanol intake (M. Weaver, Czachowski and C. F. Flaherty, unpublished data). Sodium amobarbital (17.5mg/kg) also reduces SucNC when given acutely during the postshift stage (Flaherty et al., 1982; Flaherty and Driscoll, 1980). Unlike CDP, amobarbital was equally effective when administered for the first time on either the first or second postshift day, but the degree of contrast reduction was considerably less than that produced by CDP. Amobarbital was not effective when given during both the preshift and postshift periods. Morphine (4 and 8 mg/kg; but not 0.5, 1, 2 and 16 mg/kg) reduced contrast and, like sodium amobarbital, morphine was equally effective on the first and second postshift days. Also like sodium amobarbital, the degree to which morphine reduced contrast was small. Naloxone blocked the contrast-reducing effects of morphine but did not itself influence contrast (Rowan and Flaherty, 1987). The novel anxiolytic and 5-HTIA agonist buspirone (0.125, 0.250, 0.5, 1, 2 and 15 mg/kg) had no effect on negative contrast. The ineffectiveness of buspirone was demonstrated in acute studies, with the drug administered on either the first postshift day, the second postshift day, or both, and in chronic studies (24 days) (Flaherty et al., 1990a). Clonidine, an alpha2 noradrenergic agonist, has been reported to have anxiolytic effects in the potentiated startle paradigm (Davis et al., 1988) and in the Geller-Seifter conflict test (Kruse et al., 1980). However, it does not replicate the typical pattern of anxiolytics in the partial reinforcement extinction effect (Halevy et al., 1986) and it has no effect at all (3.12, 6.25, 12.5, 25.0 and 50.0#g/kg) on negative contrast in consummatory behavior (Flaherty et al., 1987). Clonidine is also ineffective as an anxiolytic in the elevated plus-maze (Johnston et al., 1988). 3.1.3. Discrimination Learning--Behavioral

Contrast

The effects of several anxiolytics on S - responding during discrimination learning were considered above. A corollary of the development in discriminative responding in certain operant schedules is behavioral contrast. In the prototypical experiment, the animals are initially trained with two cues which are equally reinforced (e.g. variable interval (VI) = l rain). After apparent asymptotic responding is

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reached, an extinction schedule is introduced in the presence of one of the cues, the reward associated with the alternative schedule is left unchanged. Often, as responding declines in the presence of the cue associated with extinction, it increases in the presence of the unchanged component. This increase, relative to the preshift baseline, is referred to as positive behavioral contrast. Much less frequently studied is negative behavioral contrast wherein reinforcement density in one component is increased (made more favorable) and, as a consequence~ responding in the unchanged component declines (for reviews see Halliday and Boakes, 1972: Dickinson, 1972; Mackintosh, 1974: McSweeney and Norman, 1979; Williams, 1983). Baltzer et al., (1979) used a variant of the typical behavioral contrast procedure and found a substantial effect of anxiolytics. Thus CDP (6mg/kg), diazepam (6 mg/kg), and amylobarbitone (15 mg/kg) substantially reduced both positive and negative behavioral contrast--suggesting that these drugs may have a "mood leveling' effect and not just an anxiolytic effect.

Ineffective

Effective

6 5 4 3 2

'

0

,iiinnnl

FIG. 2. Drug effectiveness ratios (DER) obtained in a series of dose/response studies utilizing the consummatory negative contrast procedure. The values plotted represent the results obtained with the most effective dose of each drug. The DER illustrates degree of contrast reduction by obtaining the ratio of the difference between shifted and unshifted vehicle groups and the difference between shifted and unshifted drug groups. The larger the DER value, the greater the contrast reduction. The CDP plus ethanol values were obtained with 4.0 mg/kg CDP (an ineffective dose) and 0.50 g/kg of a 15% EtOH injection (an ineffectivedose).

3.2. ANTIDEPRESSANTS

3.2.1. Contrast in Consummatory Behat#or Imipramine (8 and 16 mg/kg) has no effect on successive negative contrast when administered acutely on the second postshift day or when administered subchronically (7 days--H. C. Becker and C. F. Flaherty, unpublished data). The same doses also have no effect on simultaneous contrast (Flaherty et al., 1977). Results obtained with serotonergic antagonists have been mixed. Of three nonspecific antagonists investigated, one, methysergide (3, 6, 12 mg/kg) had no effect, whereas two, cinanserin (10 and 15, but not 5 and 20 mg/kg) and cyproheptadine (3, but not 6 and 12 mg/kg) reduced negative contrast (Becker, 1986). The drug was administered acutely on the second postshift day in these studies. A summary of the relative effects on negative contrast in consummatory behavior of a variety of drugs is presented in Fig. 2 in terms of a Drug Effectiveness Ratio (DER). The DER reflects the extent to which contrast was reduced by the most effective dose of each drug, relative to vehicle contrast and relative to the preshift baseline lick frequencies of each group. 3.2.2. Discrimination Learning--Behavioral Contrast The administration of DMI (5 mg/kg) completely prevented the occurrence of positive behavioral contrast when pigeons were shifted from a multiple V I - 1 ' , V I - 1 ' to a multiple V I - 1 ' , extinction schedule (Bloomfield, 1972). However, this effect was not specific to antidepressant action because chlorpromazine (10mg/kg) had exactly the same effect. Blough (1957) also reported that chlorpromazine (10 and 30 mg/kg) reduced responding in a discrimination task). From an inspection of the published data, it appears that the two drug groups responded at a consistently lower rate than the saline controls. The

failure of response elevation (behavioral contrast) to occur may have been related to this motor-depressant function of the drugs rather than to any contrastspecific action (cf. Ortiz et al., 1971). Baltzer et al. (1979), in their variant of the behavioral contrast paradigm mentioned above, also investigated antidepressants. They found that pargyline (1 mg/kg) had no effect on either positive or negative behavioral contrast, imipramine (3 mg/kg) had no effect on positive contrast and a 'weakly significant' effect in reducing negative behavioral contrast, and maprotiline (3 mg/kg) had a small but reliable effect in enhancing positive behavioral contrast. Given that all of these effects were small and inconsistent, and that the profile produced by impramine did not differ substantially from that produced by chlorpromazine (0.5 mg/kg), the most reasonable conclusion would seem to be that antidepressants, at least those tested, do not have a particularly robust or meaningful effect on behaviorual contrast.

4. SUMMARY AND CONCLUSIONS By-and-large, anxiolytics retard the course of extinction and alleviate successive negative contrast. The effects of antidepressants are less certain, but the little evidence that is available suggests minimal effects in both paradigms. Although anxiolytics retard extinction, extinction does take place under the influence of the drugs and, in fact, the retardation is often not a major effect. Even the moderate effect demonstrated in these studies may overstate the case because a consistently nonreinforced group injected with the drug is usually not included in these experiments. The inclusion of such a control group would allow for an estimate of the rate-enhancing effect of the drugs independently of any specific effects that the agents may have on extinction.

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Anxiolytics and antidepressants The moderate effect of emotion-related drugs no doubt reflects the likelihood that extinction is largely an associative process--the disconfirmation of the expectancy that a specific response will lead to reward (e.g. Mackintosh, 1974), or will lead to reward in the specific extinction context (Bouton, 1990). The emotional response that accompanies extinction may serve to hasten the process, but it is not the prime mover. In a naturalistic setting, the animals would be expected to go elsewhere in search of sustenance and, in this sense, an anxiolytic effect would be maladaptire if it enhanced persistence in an unprofitable endeavor. This might be demonstrated by the use of multiple reward locations, such as in a radial-arm maze, as suggested by Devenport's results obtained with ethanol (Devenport, 1984). The procedural similarity between extinction and negative contrast is paralleled in the effectiveness of the anxiolytics in moderating both, and the failure of antidepressants to substantially influence either. A difference between extinction and negative contrast is that there is still a reward available in the contrast paradigm and, in the usual restricted experimental setting, an orderly endogenous recovery process, in deprived animals, seems to drive them to the acceptance of the postshift reward (Flaherty, 1982, 1989; Klinger, 1975, 1977). Anxiolytics accelerate this process, with varying degrees of effectiveness and at varying points in the recovery cycle (Flaherty, 1989). Although there is no direct evidence, inferences based on the interactions between benzodiazepines, barbiturates, and ethanol on the one hand, and GABAergic mechanisms on the other hand (e.g. Biggio and Costa, 1986) would suggest a role for a GABAergic system in this endogenous recovery process. Given the relative ineffectiveness of CDP in alleviating negative contrast in the period immediately following the downshift, it may be that agents which are effective through the modulation of a GABAergic system are inert until the endogenous recovery process is initiated (Flaherty, 1989). Several of the procedural and empirical characteristics of the successive negative contrast paradigm (i.e. the reduction in reward, the availability of one or more less desirable alternatives, an orderly recovery process) suggest that it may be useful as an animal model of disappointment. The data showing that antidepressants do not systematically affect either contrast or extinction complement other data showing that such agents also do not influence either exploratory behavior or the reward value of food and water (see review by File and Tucker, 1986). If it may be concluded that the current review also suggests a lack of a disinhibitory effect of antidepressants in extinction, contrast, DRL responding, and discrimination training (although the evidence is less clear in the latter case), then three elements important for extinction and contrast (reward value, tendency to explore when reward value is decreased, and inhibition of behaviors leading to the reduced reward) are all apparently unaffected by antidepressants. However, given that extended chronic treatment (e.g. 25 days) with impramine (2.5mg/kg), DMI (10 mg/kg), or amitriptyline (10 mg/kg) yields some, perhaps small, degree of anxiolytic activity in other

animal models of anxiety such as punished drinking and novelty suppressed feeding (e.g. Fontana and Commissaris, 1988; Bodnoff et al., 1988), perhaps more chronic studies in the extinction paradigm are needed before the book is closed on this issue. Other conclusions suggested by this review are as follows: (1) The extinction of consummatory behavior seems to share a common pharmacological profile with the extinction of instrumental behavior. (2) The evidence suggests that anxiolytics administered during acquisition of an intermittent reinforcement schedule reduce or eliminate the partial reinforcement extinction effect, but these effects are not simple--being dependent on parametric considerations such as the number of acquisition trials, the intertrial interval, and the location in a runway in which the dependent measures are taken. (3) Behaviors that are 'energized' in extinction have a different pharmacological profile from the behaviors that decline in extinction. (4) Responding to the unrewarded stimulus in a discrimination learning paradigm is affected by anxiolytics in a fashion similar to standard extinction, but there are not enough data to make a dear statement regarding the effects of antidepressants in this paradigm. (5) Anxiolytics reduce behavioral contrast, possibly both positive and negative behavioral contrast, and antidepressants have minimal and possibly nonspecific effects in this paradigm. However, the conclusions regarding antidepressants are based on scanty data. (6) Responding on a DRL schedule, particularly a DRL-72 sec schedule, has a very different profile from that of extinction or contrast, with antidepressants facilitating behavior and anxiolytics being ineffective or disruptive of behavior. The facilitatory effects of antidepressants may be related to a slowing of motor behavior without concomitant disruptions of timing behavior and without the occurrence of response disinhibitory effects. There is some evidence that centrallyacting beta adrenergic agonists have an antidepressant profile in this task. Acknowledgements--Preparation of this chapter was aided by a grant from the National Institute of Mental Health (MH-40489) and a Charles and Johanna Busch Memorial Grant. The comments of Patricia Grigson and Sandra File on an earlier draft are appreciated.

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