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Behavioral resistance to haloperidol and clozapine
Behavioural Processes 46 (1999) 1 – 13
Behavioral resistance to haloperidol and clozapine David N. Harper * School of Psychology, Victoria Uni6ersity of Wellington, PO Box 600, Wellington, New Zealand Received 27 August 1998; received in revised form 12 October 1998; accepted 13 October 1998
Abstract Using a procedure to assess behavioral resistance to change, the effects of two drugs (haloperidol and clozapine) were compared to each other and to the effect of response-independent food delivered between multiple-schedule components. Using rats as subjects, responding in one component was maintained on a variable-interval 30-s schedule, whereas responding in another component was maintained on a variable-interval 30-s schedule that operated concurrently with a variable-time 30-s schedule. Consistent with previous findings, responding in the component with the greater overall amount of reinforcement displayed the greater resistance to response-independent food delivery. Similarly, increasing the dose of haloperidol or clozapine increased the overall extent of disruption (relative to baseline levels), with the greatest disruption occurring to responding in the component associated with the smaller overall amount of food reinforcement. Thus, as with the disruption caused by alterations in reinforcement conditions, the extent of disruption to reinforced responding caused by haloperidol and clozapine is specifically dependent upon baseline reinforcement conditions rather than baseline response rates. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Clozapine; Haloperidol; Multiple schedules; Resistance to change
1. Introduction The strength of a reinforced response is reflected in its rate of occurrence under constant conditions and in its resistance to change when those conditions are altered. Resistance to change is normally assessed by introducing a disruptive * Tel.: +64-4-4721000; fax: + 64-4-4965402. E-mail address: [email protected] (D.N. Harper)
event prior to or during a session of training. Typical disruptive events have been prefeeding subjects prior to the session (Nevin et al., 1990), the introduction of response-independent variable-time food during a session (Nevin, 1974; Nevin et al., 1983; Harper and McLean, 1992; Harper, 1996) and the reduction of the maintaining reinforcement schedule to extinction (Nevin, 1974; Nevin et al., 1983, 1990). The introduction of such disruptive events into the training envi-
0376-6357/99/$ - see front matter © 1999 Elsevier Science B.V. All rights reserved. PII: S 0 3 7 6 - 6 3 5 7 ( 9 8 ) 0 0 0 5 6 - 4
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ronment reduces the level of operant responding. However, the degree to which responding decreases (relative to its baseline level) is determined by the reinforcement conditions present during baseline. Specifically, the common finding has been that responding associated with the higher rate, magnitude, or immediacy of reinforcement is relatively more resistant to disruption (see Nevin, 1992, for a review). Although both rate of responding and its resistance to change are dependent upon the rate, magnitude and immediacy of reinforcement, Nevin and colleagues (Nevin et al., 1983, 1990; Nevin, 1984, 1992) have argued that rate of responding and resistance to change are independent dimensions of behavior, because rate of responding is determined by response-reinforcer contingencies, but resistance to change is determined by stimulus-reinforcer contingencies. Such a conclusion is supported by the results from Nevin et al. (1990). Nevin and colleagues trained pigeons on multiple schedule components in which the variable-interval (VI) schedules were identical but in some conditions alternative reinforcers were also arranged concurrent with one of the components on a variable-time (VT) schedule. The additional VT reinforcers weakened the response-reinforcer contingency for the concurrent VI VT component relative to the VI-only component. However, VT reinforcers simultaneously increased the amount of food available during the VI VT component, thus increasing the contingency between the stimuli signaling this component and reinforcement relative to the VI-only component. Nevin et al. found that, although the absolute rate of responding was lower in the VI VT component, the resistance to prefeeding and extinction was greater. Therefore, they concluded that steady-state response rate depended on response-reinforcer contingencies, whereas the resistance of responding to disruption depended upon the contingency between component stimuli and reinforcement. Similar conclusions have subsequently been reached in other studies using humans, pigeons and rats as subjects (e.g. Cohen, 1986; Mace et al., 1990; McLean and Blampied, 1995; Mauro and Mace, 1996).
A challenge to the generality of the claim that behavior in the presence of a more highly reinforced stimulus is more resistant to disruption comes from a study by Cohen (1986) that examined the disruptive effects of drugs on free-operant responding. Across several experiments, Cohen demonstrated that, although a number of different drugs could reduce response rates relative to baseline levels, these drugs did not necessarily result in a relatively greater reduction for responding maintained by longer delays to reinforcement (experiment 1) or lower rates of reinforcement (experiments 2 and 3). Cohen interpreted these findings as showing that a number of drugs (including haloperidol and amphetamine) do not act as a force to disrupt operant responding in the same way as responseindependent food, presession feeding and extinction. In contrast to Cohen (1986), the findings from a more recent study by Egli et al. (1992) are supportive of the possibility that drugs can be viewed as disruptive forces acting on reinforced responding in the same way as extinction or response-independent food. Using pigeons, they examined changes in response rates in multiple-schedule components (ranging between VI 5-s and VI 150s) as a function of two opioid drugs. Their data generally supported the conclusion that the extent of disruption to responding was dependent on the dose of the drug (greater doses led to greater disruption) and rate of reinforcement maintaining responding (responding changed relatively less in components associated with higher reinforcer rates). However, in the Egli et al. (1992) study, as in the study by Cohen (1986), the role of stimulusreinforcer contingencies could not be separated from response-reinforcer contingencies in determining the resistance to change to drug-induced changes in responding. In both studies the behavior maintained by the strongest response-reinforcer contingency also occurred in the presence of the discriminative stimuli associated with the strongest stimulus-reinforcer contingency. Consequently, not only was the rate of reinforcement higher in the most resistant component but also the baseline rate of responding. Therefore, it is not possible to determine whether greater resis-
D.N. Harper / Beha6ioural Processes 46 (1999) 1–13
tance to change was directly dependent upon baseline reinforcement per se or on the rate of responding established in baseline. One way to determine whether it is baseline reinforcer rate or baseline response rate that is critical for determining subsequent resistance to drug-induced disruption is to use the schedule arrangement of Nevin et al. (1990), because one target component is simultaneously associated with a low response-reinforcer contingency and a relatively high stimulus-reinforcer contingency. In the other component, responding occurs at a higher rate (because it is associated with a relatively high response-reinforcer contingency) but is simultaneously associated with a relatively lower stimulus-reinforcer contingency than that established in the first component. Given these considerations and the findings of Egli et al. (1992), it is worthwhile re-examining the effects of some of the drugs explored by Cohen (1986). In particular it is worthwhile exploring the effects of drugs that reduce the activity of the neurotransmitter dopamine in the brain. Dopamine is of interest with respect to the role it plays in the reinforcement process, because stimuli that increase dopamine activity (e.g. electrical stimulation of the medial forebrain bundle and drugs that enhance dopamine activity) can act as effective reinforcers in maintaining operant responding (e.g. Olds and Fobes, 1981; Wise and Bozarth, 1987), whereas drugs that block dopamine activity reduce the effectiveness of reinforcers (such as food or brain stimulation) to maintain responding (e.g. Rolls et al., 1974; Fouriezos and Wise, 1976). Therefore, given that antipsychotic drugs such as haloperidol and clozapine reduce brain dopamine activity (albeit at different neurotransmitter sites), they are likely to disrupt reinforced responding. The specific question posed in the present study was whether either haloperidol or clozapine might disrupt reinforced responding in multiple schedules in a manner analogous to the disruptive effect of delivering response-independent food in another component. That is, do haloperidol or clozapine disrupt responding relatively more if that responding occurs in the presence of a stimulus associated with a relatively low overall reinforcer rate? Or, is the
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magnitude of disruption caused by each drug independent of the stimulus-reinforcer contingency associated with responding in a given component. This question was addressed by comparing the disruptive effects of response-independent food delivered between components against the disruptive effects of haloperidol and clozapine on responding in two target multiple schedule components. The two target components differed from one another in that a relatively low response-reinforcer contingency was established in one component by occasionally delivering response-independent food during that component in addition to the reinforcers arranged on a VI schedule for responding. In the second target component, food was only delivered by responding on a VI schedule identical to that used in the first component. Therefore, one component was associated with a relatively greater stimulus-reinforcer contingency than the other, but simultaneously possessed a relatively poorer response-reinforcer contingency. If haloperidol or clozapine act to disrupt reinforced responding in a manner analogous to the effects of response-independent food delivered between components, then responding should be much more disrupted in the component associated with the weaker stimulusreinforcer contingency. Also, if these drugs act to disrupt responding via a similar mechanism as response-independent food delivery between components, then the effect of both should be additive. That is, when rats are given a drug and presented with response-independent food, their responding should be much more disrupted relative to baseline than in the presence of either condition alone.
2. Materials and methods
2.1. Subjects Six male Norway Hooded rats, approximately 6 months old at the start of training, were maintained at 85% of their free-feeding body weights. Prior to the experimental conditions being conducted, rats were autoshaped to lever press for
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food reinforcement and had received 6 months of training at different schedule values in the multiple schedule procedure described below. Supplementary feed was given after each session of training to maintain prescribed body weights. Rats were housed in pairs, with water and untreated wood shavings available continuously in their home cages. The housing room was maintained at a constant 22°C with lights on between 07:00 and 19:00 h each day.
2.2. Apparatus Rats were trained individually in a single experimental chamber, measuring approximately (31× 32 × 24 cm). A red stimulus light (12 W) was situated above each of two response levers. One lever was located on the left side of the front wall and the other was located on the right side (with both levers being equidistant from the midline). Reinforcers (0.1 ml of a mixture of 15% sweetened milk and 85% water) were delivered via a dipper mechanism located in the center of the front wall. All experimental events were scheduled and recorded by an IBM-compatible computer running MED-PC software in a room remote from the experimental chamber.
2.3. Procedure Throughout the experiment, sessions were conducted daily, 7 days per week, and comprised 26 multiple-schedule components presented equally often and in a pseudo-random order. Target components (during which responding was reinforced) were 60 s in duration and signaled by illuminating the light above either the left or right lever. Components were separated from one another by a 30-s inter-component interval (i.e. no stimulus lights were lit and responding on levers was not reinforced). During reinforcer delivery (2.5 s of access to the dipper), component and reinforcement schedule timing were suspended. For the first 69 sessions of training the reinforcement schedules during both left- and rightlever components were kept equal at VI 30-s. These sessions of training were used to reduce any inherent side bias to either the left or right lever
prior to establishing a differential response rate in the next phase of training. The mean number of responses on session 69 of training was 486 on the left lever and 444 on the right lever. At an alpha level of PB 0.05, a paired t-test revealed no significant difference between the number of responses across both levers [t(5)= 1.5]. Also established at this point of training was whether a disruptive drug (haloperidol in this case) would decrease responding equally on both levers if responding was maintained by equal reinforcer rates on both levers. This test was performed in order to support any subsequent conclusions that differences in resistance to the disruptive effects of drugs was a product of the unequal reinforcer conditions rather than a spurious result of any systematic inherent spatial bias to favor one lever over the other. On session 70 of training all rats were given 0.1 mg/kg of haloperidol (in the manner described in Section 2.4). As expected, delivery of haloperidol reduced the mean number of responses made in a session in both components (down to 301 in the left-lever component and 289 in the right-lever component). This decrease in responding was equivalent for both levers in that there was still no significant difference between the number of response made on the left versus right lever following haloperidol delivery [tB 1.0]. Therefore, the proportion of responses made relative to baseline following delivery of haloperidol was virtually identical for both components (0.62 and 0.65 for left- and right-lever components, respectively) when identical reinforcement schedules were arranged on both levers. The behavioral procedure during the subsequent experimental sessions was identical to the prior training sessions except that during left-lever components a VI 30-s and a VT 30-s schedule were both concurrently in effect. Whereas, during right-lever components a single VI 30-s schedule was in effect as before. Rats received 111 sessions of training in this procedure and at these schedule values prior to the introduction of response-independent food delivered during the inter-component interval and/or the administration of drugs in subsequent conditions. Table 1 outlines the experimental conditions conducted and the order in which they were con-
D.N. Harper / Beha6ioural Processes 46 (1999) 1–13
ducted. Each condition was in place for a single probe session. In Condition 1 rats were presented with response-independent food delivered during the inter-component interval arranged on a VT 15-s schedule. In Conditions 2 – 6, rats were given either haloperidol or clozapine prior to being placed in the response chamber for the session. In the remaining conditions, rats were presented with response-independent food delivered during the inter-component interval (at VT 15-s) in combination with either haloperidol or clozapine administered prior to the subject being placed in the chamber. In all conditions, the arranged schedule values for the two components remained the same (VI 30-s plus VT 30-s for the left-lever component and VI 30-s for the right-lever component). Thirteen sessions of training in the baseline condition (no food presented during the inter-component interval and no exposure to drugs) occurred between each condition.
2.4. Drug procedure On each day of use, the haloperidol or clozapine was first dissolved in 0.1 N HCl and then diluted with 0.9% saline to the required dose. Prior to oral administration, the drug solution was mixed with 1.0 ml of the sweetened milk mixture used as a reinforcer. This milk – drug soTable 1 Conditions conducted listed in the order they were presented to subjects Condition
Drug/dose (mg/kg)
Rate of response-independent food delivery during inter-component interval
1 2 3 4 5 6 7 8 9 10 11
– Haloperidol 0.1 Haloperidol 0.5 Clozapine 5.0 Clozapine 2.0 Clozapine 10.0 Haloperidol 0.1 Haloperidol 0.5 Clozapine 5.0 Clozapine 2.0 Clozapine 10.0
VT 15-s EXTa EXT EXT EXT EXT VT 15-s VT 15-s VT 15-s VT 15-s VT 15-s
a
EXT= extinction.
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Table 2 Mean number of responses made across all subjects in the left-lever and right-lever components for all baseline sessions combined and each probe session of disruption
Baseline Inter-component interval food Haloperidol 0.1 Haloperidol 0.5 Clozapine 2.0 Clozapine 5.0 Clozapine 10.0 Haloperidol 0.1+food Haloperidol 0.5+food Clozapine 2.0+food Clozapine 5.0+food Clozapine 10.0+food a
Left-lever
Right-lever
174 (12)a 117 (14)
304 (23) 93 (14)
154 96 171 123 168 89 32 160 95 132
196 109 240 213 264 81 21 191 96 139
(20) (9) (30) (29) (44) (10) (7) (22) (17) (26)
(26) (13) (27) (62) (71) (11) (6) (33) (23) (34)
Numbers in parentheses are S.E.M.
lution was given to each subject 30–40 min before the start of their respective session. In every case the solution was completely consumed within 1 min of it being made available to the subject.
3. Results In order to examine the resistance of responding to disruption, responding in a single probe session of inter-component interval food and/or drug delivery was expressed relative to the number of responses made in the immediately preceding baseline session. Table 2 shows the mean group data for the number of responses made in a single probe session of disruption as well as the overall average number of responses made in the preceding baseline sessions. These averages are presented separately for the left- and right-lever components. The data in Table 2 show that the schedules arranged for the left- and right-lever components were successful in establishing a higher rate of responding in the presence of the right-lever component than the left-lever component. The data from individual subjects was also consistent with the group results shown in Table 2. Across 66 determinations of the baseline level of responding (across all subjects and conditions)
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there were only two cases where the baseline level of responding was greater for the left-lever component (and both of these were for Rat 5 in Conditions 2 and 3). Therefore, the absolute level of responding was consistently greater for the component associated with the lowest overall amount of food reinforcement (right lever) and lower for the component associated with the highest overall amount of food reinforcement (left lever). Fig. 1 shows the decrease in responding displayed by each subject following the delivery of inter-component food in terms of the proportion of baseline responding for left-lever (unfilled bars) and right-lever (filled bars) components separately. This figure shows that probe session delivery of response-independent food produced a decrease in the overall number of responses made. Furthermore, in every single case, the greatest decrease occurred for responding in the right-lever component [t(5)= 4.98, P B 0.01]. Thus, consistent with previous findings, responding in the component associated with the smallest overall amount of food reinforcement (right-lever component) was more disrupted relative to baseline than responding in the component associated with the
greatest overall amount of reinforcement (leftlever component). Fig. 2 shows the proportion of baseline responding for left-lever and right-lever components for each subject as a function of the dose of haloperidol alone (Conditions 2 and 3) and when haloperidol was administered in combination with VT 15-s food during the inter-component interval (Conditions 7 and 8). This figure shows that, as with response-independent food delivery during the inter-component interval, haloperidol generally produced a decrease in the responses made in both components. In addition, the 0.5 mg/kg dose generally produced a greater decrease in responding than the 0.1 mg/kg dose (except Rat 62 in the right-lever component and Rat 63 in the left-lever component). For all 12 cases in which haloperidol was administered on its own, the relative reduction in responding was greater in the right-lever component compared to the left-lever component [t(5)= 4.70, PB 0.01 and t(5)= 3.43, P B 0.01 at the 0.1 and 0.5 doses, respectively]. When haloperidol was administered concurrently with response-independent food delivery, the effects of these two disruptors were additive. That is, in all cases, haloperidol plus response-independent food
Fig. 1. Proportion of baseline responding in the left-lever (unfilled bars) and right-lever (filled bars) components following the introduction of response-independent food delivered between components for each subject and the group as a whole. Proportions were calculated by dividing the number of responses made in a component for the single probe session of each condition by the number of responses made in the immediately preceding baseline session during which food was not delivered between components.
D.N. Harper / Beha6ioural Processes 46 (1999) 1–13
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Fig. 2. Proportion of baseline responding in the left-lever (unfilled bars) and right-lever (filled bars) components as a function of the dose of haloperidol (administered alone or concurrently with response-independent food delivered between components) for each subject and the group as a whole. Proportions were calculated by dividing the number of responses made in a component for the single probe session of each condition by the number of responses made in the immediately preceding baseline session during which food was not delivered between components.
produced a greater disruption to responding compared to when haloperidol was administered alone
at the corresponding dose (paired t-tests were all significant at PB 0.05 for both left and right-lever
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D.N. Harper / Beha6ioural Processes 46 (1999) 1–13
components at all dose levels). Therefore, consistent with the effects of response-independent food, greater doses of haloperidol caused correspondingly greater behavioral disruption relative to baseline. The greatest decreases in responding were consistently in the component associated with the smallest overall amount of food reinforcement (right-lever component). Fig. 3 shows the proportion of baseline responding for left-lever and right-lever components for each subject as a function of the dose of clozapine alone (Conditions 4 – 6) and when clozapine was administered in combination with VT 15-s food during the inter-component interval (Conditions 9–11). This figure shows that at the lowest doses clozapine, administered on its own, had inconsistent effects on responding. For example, two rats displayed very little change in responding (Rats 61 and 63), two rats displayed a decrease in responding in one component (Rats 62 and 66) and the other two rats displayed an increase in responding in both components (Rats 64 and 65). Also, there was no consistent difference in the degree of disruption to responding in the left-lever component versus the right-lever component at the 2.0 mg/kg dose [t(5) = 0.84, P \0.05]. At the 5.0 mg/kg dose there was a more consistent pattern of change in responding across rats. In four of the six rats (Rats 61 – 64) there was an overall decrease in responding relative to baseline in both components. For all four of these subjects, the degree of disruption was greater in the right-lever component. Overall there was a significant difference between the proportion of baseline responding in the left- versus right-lever components [t(5)= 4.23, P B 0.01]. The highest dose of clozapine (10.0 mg/kg) produced the most consistent effects of clozapine on responding across rats. At this dose there was a consistent decrease in responding across all subjects in both components (with 11 out of 12 cases showing a proportion of baseline responding value less than 1.0). Also, for every subject the degree of disruption, relative to baseline, was greatest for responding in the right-lever component [t(5) = 3.60, PB 0.01]. Therefore, when clozapine was administered on its own there was a dose-dependent decrease in overall responding. When overall re-
sponding was reduced (for four subjects at 5.0 mg/kg and all subjects at 10.0 mg/kg), the extent of disruption was always greater in the component associated with the smallest overall amount of reinforcement. When clozapine was administered concurrently with VT 15-s food delivered during the inter-component interval, there was a consistent decrease in responding in both components compared to when clozapine was administered alone at the corresponding dose (33 out of 36 cases). As with haloperidol, when clozapine was administered concurrently with inter-component food delivery, the effects of disruption were generally additive. That is, clozapine plus response-independent food produced greater disruption to overall responding compared to when clozapine was administered alone at the corresponding dose (paired t-tests were all significant at PB 0.05 for both left- and right-lever components at all dose levels). Furthermore, the extent to which right-lever component responding was more disrupted than left-lever component responding was greater when clozapine was administered concurrently with inter-component food delivery than when clozapine was administered alone.
4. Discussion The present findings demonstrated that both haloperidol and clozapine disrupted behavior in a manner similar to that observed when responseindependent food is presented between target components on a multiple schedule. That is, both drugs caused a decrease in responding (haloperidol at all doses and clozapine at the two highest doses) and did so to a relatively greater degree in the component associated with the smallest overall amount of food reinforcement. The greater effect of these drugs on behavior associated with relatively low reinforcement further extends the generality of Nevin’s claim that behavioral resistance to change is dependent on stimulus-reinforcer contingencies (Nevin, 1992). That is, responding in the presence of stimuli associated with the lowest overall amount of rein-
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forcement is less resistant to disruption irrespective of the relative strength of the responsereinforcer relationship maintaining responding.
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In the present case, responding in the component associated with the highest baseline response rate (but lowest overall amount of rein-
Fig. 3. Proportion of baseline responding in the left-lever (unfilled bars) and right-lever (filled bars) components as a function of the dose of clozapine (administered alone or concurrently with response-independent food delivered between components) for each subject and the group as a whole. Proportions were calculated by dividing the number of responses made in a component for the single probe session of each condition by the number of responses made in the immediately preceding baseline session during which food was not delivered between components.
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forcement) was the least resistant to disruption from haloperidol or clozapine. Therefore, both drugs acted as a disruptor in the same manner as other forms of disruption such as prefeeding subjects prior to the session (Nevin et al., 1990), reducing the maintaining reinforcement schedule to extinction (Nevin, 1974; Nevin et al., 1983, 1990) and the delivery of response-independent food outside of the target components (Nevin, 1974; Nevin et al., 1983; Harper and McLean, 1992; the current experiment). The present findings were consistent with those of Egli et al. (1992), who found that the extent of behavioral disruption from opioid drugs was dependent on the dose level (greater doses led to greater disruption) and rate of reinforcement maintaining responding (responding changed less in a component associated with a higher reinforcer rate). What Egli et al. (1992) did not assess was whether it was the baseline rate of reinforcement per se that determined relative resistance to drug-induced disruption or whether it was the baseline rate of responding that was critical. However, such a determination of the independent variable which controls resistance to drug effects is important, because different views exist about which aspects of baseline conditions are important in determining the extent of change. For example, Nevin and colleagues have asserted that resistance to change is dependent upon baseline stimulus-reinforcer contingencies. However, several authors have claimed that the extent of behavioral disruption caused by some drugs (e.g. pentobarbital and D-amphetamine) is dependent upon baseline response rates (Sanger and Blackman, 1976; Lucki and DeLong, 1983; Rees et al., 1985). The present study used a schedule arrangement that established the highest response rate in the component associated with the lowest overall amount of reinforcement, thus allowing for the separation of stimulus-reinforcer versus responsereinforcer contingencies (see Nevin et al., 1990). As a consequence, the present findings suggest that haloperidol and clozapine (as with the opioid drugs used by Egli et al. 1992) can be considered to disrupt behavior in a manner analogous to the disruption that occurs follow-
ing alterations in the environmental or reinforcement context. Furthermore, these results demonstrate that the extent of disruption is dependent upon baseline stimulus-reinforcer contingencies rather than the baseline response rate which is established via the response-reinforcer contingencies. With respect, specifically, to the effects of haloperidol, the present results are in contrast to the findings of Cohen (1986). Cohen failed to demonstrate that haloperidol produced a greater decrease in responding in the component associated with the longest delay to reinforcement. There are several differences between the present study and Cohen’s that may have contributed to these disparate findings. Firstly, the method of drug administration was different across the two studies. However, the route of administration is unlikely to be a critical difference because both studies demonstrated that haloperidol caused a sizable decrease in responding, although the doses tended to be lower in the Cohen study than used here. Another difference is that Cohen attempted to establish a differential resistance to change across two components by using a chained random interval RI 30-s RI 30-s schedule (in which the first component was signaled by a flashing houselight and the second component was signaled by a steady houselight). Because food reinforcers were only delivered after the second component, the first component was associated with a greater delay to reinforcement (and therefore, responding should have displayed less resistance to disruption), whereas, in the present study, a differential resistance to change was established across two randomly alternating components that were spatially separated (left versus right lever) by associating each with a different overall rate of food delivery. One possible way to account for the difference between the effects of haloperidol in the present study versus Cohen (1986) concerns the effects that drugs as disruptors may have on discrimination performance in the two different procedures. Generally, disruptors are thought of as devaluing the experimental reinforcer (relative to other ‘background’ reinforcers; see, for example, Nevin
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et al., 1990). However, drugs may, in addition, degrade stimulus control by component stimuli. If one of haloperidol’s effects was to reduce stimulus control, then responding would increase in the component in which responding was relatively lower during baseline training, whereas responding would decrease in the component in which responding was relatively higher during baseline. If, in addition, haloperidol was to cause an overall decrease in responding then its relative effects across components would be confounded by this disruption to stimulus control. Essentially, in Cohen’s study, responding in the component maintained by the lower rate of reinforcement (which also showed the lowest baseline rate of responding) could appear to be as equally resistant to haloperidol as responding in the more highly reinforced component (which showed the highest baseline rate of responding). However, in the present study, the component associated with the higher overall amount of reinforcement displayed the lowest baseline rate of responding. Under this situation, reduced stimulus control on its own could have enhanced responding in the richer component and reduced responding in the leaner component, thereby enhancing the apparent difference between components in terms of resistance to change. Although neither the present study nor the Cohen (1986) study directly assessed the effects of haloperidol on stimulus control, an examination of the responses made on the left and right levers during the inter-component interval suggests that stimulus control was not degraded at the doses used here. If the stimulus control exerted by the light stimuli had been degraded, then subjects would exhibit more indiscriminate responding and therefore would show an increase in inappropriate lever pressing during the intercomponent interval (e.g. responding on the left lever during the inter-component interval). Contrary to this possibility, an examination of the responses made during the inter-component interval indicated that there was no increase of these inappropriate responses during any session of disruption. It is possible that the lack of differential resistance to change to haloperidol in the Cohen (1986) study occurred because the stimulus con-
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trol across components was poorly established during baseline training (irrespective of any possible effect of haloperidol itself on stimulus control). There was some evidence that rats were discriminating between components in that they displayed a greater response rate in the component that immediately preceded reinforcement. However, this difference only demonstrates that rats were responding more quickly the more time that elapsed and the closer they got to receiving reinforcement. What is not known is whether the rats in Cohen’s study were discriminating between the stimuli signaling components. Because rats responded on only one lever and the stimuli signaling components were all in one location, it may have been that there was a great deal of overlap in the stimulus-reinforcer contingencies responsible for establishing the degree of resistance to change in each component. Nevin (1992) has argued that resistance to change depends on the correlation of reinforcement with both the component stimuli and response location (however, see also McLean et al., 1996). Therefore, if rats were not discriminating between components in Cohen’s study, then it would not be expected that they were exposed to a relatively stronger stimulus-reinforcer relationship in the component that was closest to reinforcement. In such a case, haloperidol would have had an equivalent effect on responding in each component. Despite the possibility that the method Cohen used to assess behavioral resistance to haloperidol may not have provided an adequate test of resistance to change, there is other evidence that suggests that not all drugs may act as a disruptor in the way that haloperidol and clozapine were found to in the present study. In experiments 2 and 3 of Cohen (1986), D-amphetamine, CCK-8 (cholecystokinin) and sodium pentobarbital caused an equivalent decrease in responding in both components of a multiple schedule, irrespective of the rate of reinforcement associated with each component. The inability of these drugs to produce a differential resistance to change across components was in contrast to the effects of changing the reinforcer rate to extinction for several sessions in the same study. Thus, although haloperidol and clozapine (in the present study)
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and opioids (in Egli et al., 1992) may disrupt responding in a manner analogous to other forms of behavioral disruption (such as reducing the reinforcer rate to extinction or response-independent food), there may be a variety of drugs which are not best characterized in this way. A task for future research is to determine what are the defining characteristics of drugs which act as disruptors in the way conceived of in Nevin’s resistance to change research (Nevin, 1974, 1992) . Such an examination may help determine the neurochemical pathways involved in establishing behavioral resistance to change. The results from the current study suggest that, in addition to both clozapine and haloperidol influencing dopamine activity in the brain (albeit at different receptor sites), they are also similar in terms of their disruptive effects on reinforced responding. Both drugs acted to decrease responding in the same way as observed when response-independent food was delivered between components. That is, these drugs caused a proportionally greater decrease in responding in the component associated with the smaller overall amount of reinforcement. Note, however, that although the drugs were qualitatively similar, haloperidol tended to result in greater overall disruption and a larger extent of disruption in the right-lever component versus the left-lever component (even when compared to a relatively very high dose of clozapine). This differential quantitative effect of the two drugs may be associated with their different specific sites of action in the brain. Haloperidol is considered to have a greater affinity for the dopamine D2 receptor site, whereas clozapine is an atypical neuroleptic that has greater affinity for serotonin (5-HT2), D1 and D4 receptors over the D2 site (Ellenbroek et al., 1991 Van Tol et al., 1991; Gingrich and Caron, 1993). Thus, although the neurotransmitter dopamine has been generally implicated in the reinforcement process, it may be that the action of dopamine at the D2 site plays a particularly important role in terms of the establishment and maintenance of response-reinforcer contingencies. Consistent with this conclusion a recent study using similar methods to those reported here found that the specific D2 agonist quinpirole
caused decreases in responding consistent with those observed following haloperidol delivery in the present study (Harper, 1999). Therefore, reducing dopamine activity at the D2 site may degrade the contingency maintaining the absolute level of responding, but leave the stimulus-reinforcer contingency relatively intact (i.e. the conditions responsible for behavioral resistance to change). One implication of this conclusion is that, consistent with Nevin and colleague’s claim (Nevin et al., 1990; Nevin, 1992), response rate and resistance to change are independent aspects of overall response strength and are established through different processes.
Acknowledgements The author wishes to thank all the people working in the VUW School of Psychology animal laboratory for their help. This research was supported with financial assistance from the VUW Internal Grants Committee.
References Cohen, S.L., 1986. A pharmacological examination of the resistance-to-change hypothesis of response strength. J. Exp. Anal. Behav. 46, 363 – 379. Egli, M., Schaal, D.W., Thompson, T., Cleary, J., 1992. Opioid-induced response-rate decrements in pigeons responding under variable-interval schedules: reinforcement mechanisms. Behav. Pharmacol. 3, 581 – 591. Ellenbroek, B.A., Artz, M.T., Cools, A.R., 1991. The involvement of dopamine D1 and D2 receptors in the effects of the classical neuroleptic haloperidol and the atypical neuroleptic clozapine. Eur. J. Pharmacol. 196, 103 – 108. Fouriezos, G., Wise, R.A., 1976. Pimozide-induced extinction of intracranial self-stimulation: response patterns rule out motor or performance deficits. Brain Res. 103, 377 – 380. Gingrich, J.A., Caron, M.G., 1993. Recent advances in the molecular biology of dopamine receptors. Annu. Rev. Neurosci. 16, 299 – 321. Harper, D.N., 1996. Response-independent food delivery and behavioral resistance to change. J. Exp. Anal. Behav. 65, 549 – 560. Harper, D.N., 1998. Drug-induced changes in responding are dependent upon baseline stimulus-reinforcer contingencies. Psychobiology (in press). Harper, D.N., McLean, A.P., 1992. Resistance to change and the law of effect. J. Exp. Anal. Behav. 57, 317 – 337.
D.N. Harper / Beha6ioural Processes 46 (1999) 1–13 Lucki, I., DeLong, R.E., 1983. Control rate of response or reinforcement and amphetamine’s effect on behavior. J. Exp. Anal. Behav. 54, 163–172. Mace, F.C., Lalli, J.S., Shea, M.C., Lalli, E.P., West, B.J., Roberts, M., Nevin, J.A., 1990. The momentum of human behavior in a natural setting. J. Exp. Anal. Behav. 54, 163 – 172. Mauro, B.C., Mace, F.C., 1996. Differences in the effect of Pavlovian contingencies upon behavioral momentum using auditory versus visual stimuli. J. Exp. Anal. Behav. 65, 389 – 399. McLean, A.P., Blampied, N.M., 1995. Resistance to reinforcement change in multiple and concurrent schedules assessed in transition and steady state. J. Exp. Anal. Behav. 63, 1–17. McLean, A.P., Campbell-Tie, P., Nevin, J.A., 1996. Resistance to change as a function of stimulus-reinforcer and locationreinforcer contingencies. J. Exp. Anal. Behav. 66, 169–191. Nevin, J.A., 1974. Response strength in multiple schedules. J. Exp. Anal. Behav. 21, 389–408. Nevin, J.A., 1984. Pavlovian determiners of behavioral momentum. Anim. Learn. Behav. 12, 363–370. Nevin, J.A., 1992. An integrative model for the study of behavioral momentum. J. Exp. Anal. Behav. 57, 301–316. Nevin, J.A., Mandell, C., Atak, J.R., 1983. The analysis of behavioral momentum. J. Exp. Anal. Behav. 39, 49–59.
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Nevin, J.A., Tota, M.E., Torquato, R.D., Shull, R.L., 1990. Alternative reinforcement increases resistance to change: Pavlovian or operant contingencies? J. Exp. Anal. Behav. 53, 359 – 379. Olds, M.E., Fobes, J.L., 1981. The central basis of motivation: Intracranial self-stimulation studies. Annu. Rev. Psychol. 32, 523 – 574. Rees, D.C., Wood, R.W., Laties, V.G., 1985. The roles of stimulus control and reinforcement frequency in modulating the behavioral effects of D-amphetamine in the rat. J. Exp. Anal. Behav. 43, 243 – 255. Rolls, E.T., Rolls, B.J., Kelly, P.H., Shaw, S.G., Wood, R.J., Dale, R., 1974. The relative attenuation of self-stimulation, eating and drinking produced by dopamine-receptor blockade. Psychopharmacologia 38, 219 – 230. Sanger, D.J., Blackman, D.E., 1976. Rate-dependent effects of drugs: a review of the literature. Pharmacol. Biochem. Behav. 4, 73 – 83. Van Tol, H.H., Bunzow, J.R., Guan, H.C., Sunahara, R.K., Seeman, P.K., Niznik, H.B., Civelli, O., 1991. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350, 610 – 614. Wise, R.A., Bozarth, M.A., 1987. A psychomotor stimulant theory of addiction. Psychol. Rev. 94, 469 – 492.
Behavioral resistance to haloperidol and clozapine David N. Harper * School of Psychology, Victoria Uni6ersity of Wellington, PO Box 600, Wellington, New Zealand Received 27 August 1998; received in revised form 12 October 1998; accepted 13 October 1998
Abstract Using a procedure to assess behavioral resistance to change, the effects of two drugs (haloperidol and clozapine) were compared to each other and to the effect of response-independent food delivered between multiple-schedule components. Using rats as subjects, responding in one component was maintained on a variable-interval 30-s schedule, whereas responding in another component was maintained on a variable-interval 30-s schedule that operated concurrently with a variable-time 30-s schedule. Consistent with previous findings, responding in the component with the greater overall amount of reinforcement displayed the greater resistance to response-independent food delivery. Similarly, increasing the dose of haloperidol or clozapine increased the overall extent of disruption (relative to baseline levels), with the greatest disruption occurring to responding in the component associated with the smaller overall amount of food reinforcement. Thus, as with the disruption caused by alterations in reinforcement conditions, the extent of disruption to reinforced responding caused by haloperidol and clozapine is specifically dependent upon baseline reinforcement conditions rather than baseline response rates. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Clozapine; Haloperidol; Multiple schedules; Resistance to change
1. Introduction The strength of a reinforced response is reflected in its rate of occurrence under constant conditions and in its resistance to change when those conditions are altered. Resistance to change is normally assessed by introducing a disruptive * Tel.: +64-4-4721000; fax: + 64-4-4965402. E-mail address: [email protected] (D.N. Harper)
event prior to or during a session of training. Typical disruptive events have been prefeeding subjects prior to the session (Nevin et al., 1990), the introduction of response-independent variable-time food during a session (Nevin, 1974; Nevin et al., 1983; Harper and McLean, 1992; Harper, 1996) and the reduction of the maintaining reinforcement schedule to extinction (Nevin, 1974; Nevin et al., 1983, 1990). The introduction of such disruptive events into the training envi-
0376-6357/99/$ - see front matter © 1999 Elsevier Science B.V. All rights reserved. PII: S 0 3 7 6 - 6 3 5 7 ( 9 8 ) 0 0 0 5 6 - 4
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ronment reduces the level of operant responding. However, the degree to which responding decreases (relative to its baseline level) is determined by the reinforcement conditions present during baseline. Specifically, the common finding has been that responding associated with the higher rate, magnitude, or immediacy of reinforcement is relatively more resistant to disruption (see Nevin, 1992, for a review). Although both rate of responding and its resistance to change are dependent upon the rate, magnitude and immediacy of reinforcement, Nevin and colleagues (Nevin et al., 1983, 1990; Nevin, 1984, 1992) have argued that rate of responding and resistance to change are independent dimensions of behavior, because rate of responding is determined by response-reinforcer contingencies, but resistance to change is determined by stimulus-reinforcer contingencies. Such a conclusion is supported by the results from Nevin et al. (1990). Nevin and colleagues trained pigeons on multiple schedule components in which the variable-interval (VI) schedules were identical but in some conditions alternative reinforcers were also arranged concurrent with one of the components on a variable-time (VT) schedule. The additional VT reinforcers weakened the response-reinforcer contingency for the concurrent VI VT component relative to the VI-only component. However, VT reinforcers simultaneously increased the amount of food available during the VI VT component, thus increasing the contingency between the stimuli signaling this component and reinforcement relative to the VI-only component. Nevin et al. found that, although the absolute rate of responding was lower in the VI VT component, the resistance to prefeeding and extinction was greater. Therefore, they concluded that steady-state response rate depended on response-reinforcer contingencies, whereas the resistance of responding to disruption depended upon the contingency between component stimuli and reinforcement. Similar conclusions have subsequently been reached in other studies using humans, pigeons and rats as subjects (e.g. Cohen, 1986; Mace et al., 1990; McLean and Blampied, 1995; Mauro and Mace, 1996).
A challenge to the generality of the claim that behavior in the presence of a more highly reinforced stimulus is more resistant to disruption comes from a study by Cohen (1986) that examined the disruptive effects of drugs on free-operant responding. Across several experiments, Cohen demonstrated that, although a number of different drugs could reduce response rates relative to baseline levels, these drugs did not necessarily result in a relatively greater reduction for responding maintained by longer delays to reinforcement (experiment 1) or lower rates of reinforcement (experiments 2 and 3). Cohen interpreted these findings as showing that a number of drugs (including haloperidol and amphetamine) do not act as a force to disrupt operant responding in the same way as responseindependent food, presession feeding and extinction. In contrast to Cohen (1986), the findings from a more recent study by Egli et al. (1992) are supportive of the possibility that drugs can be viewed as disruptive forces acting on reinforced responding in the same way as extinction or response-independent food. Using pigeons, they examined changes in response rates in multiple-schedule components (ranging between VI 5-s and VI 150s) as a function of two opioid drugs. Their data generally supported the conclusion that the extent of disruption to responding was dependent on the dose of the drug (greater doses led to greater disruption) and rate of reinforcement maintaining responding (responding changed relatively less in components associated with higher reinforcer rates). However, in the Egli et al. (1992) study, as in the study by Cohen (1986), the role of stimulusreinforcer contingencies could not be separated from response-reinforcer contingencies in determining the resistance to change to drug-induced changes in responding. In both studies the behavior maintained by the strongest response-reinforcer contingency also occurred in the presence of the discriminative stimuli associated with the strongest stimulus-reinforcer contingency. Consequently, not only was the rate of reinforcement higher in the most resistant component but also the baseline rate of responding. Therefore, it is not possible to determine whether greater resis-
D.N. Harper / Beha6ioural Processes 46 (1999) 1–13
tance to change was directly dependent upon baseline reinforcement per se or on the rate of responding established in baseline. One way to determine whether it is baseline reinforcer rate or baseline response rate that is critical for determining subsequent resistance to drug-induced disruption is to use the schedule arrangement of Nevin et al. (1990), because one target component is simultaneously associated with a low response-reinforcer contingency and a relatively high stimulus-reinforcer contingency. In the other component, responding occurs at a higher rate (because it is associated with a relatively high response-reinforcer contingency) but is simultaneously associated with a relatively lower stimulus-reinforcer contingency than that established in the first component. Given these considerations and the findings of Egli et al. (1992), it is worthwhile re-examining the effects of some of the drugs explored by Cohen (1986). In particular it is worthwhile exploring the effects of drugs that reduce the activity of the neurotransmitter dopamine in the brain. Dopamine is of interest with respect to the role it plays in the reinforcement process, because stimuli that increase dopamine activity (e.g. electrical stimulation of the medial forebrain bundle and drugs that enhance dopamine activity) can act as effective reinforcers in maintaining operant responding (e.g. Olds and Fobes, 1981; Wise and Bozarth, 1987), whereas drugs that block dopamine activity reduce the effectiveness of reinforcers (such as food or brain stimulation) to maintain responding (e.g. Rolls et al., 1974; Fouriezos and Wise, 1976). Therefore, given that antipsychotic drugs such as haloperidol and clozapine reduce brain dopamine activity (albeit at different neurotransmitter sites), they are likely to disrupt reinforced responding. The specific question posed in the present study was whether either haloperidol or clozapine might disrupt reinforced responding in multiple schedules in a manner analogous to the disruptive effect of delivering response-independent food in another component. That is, do haloperidol or clozapine disrupt responding relatively more if that responding occurs in the presence of a stimulus associated with a relatively low overall reinforcer rate? Or, is the
3
magnitude of disruption caused by each drug independent of the stimulus-reinforcer contingency associated with responding in a given component. This question was addressed by comparing the disruptive effects of response-independent food delivered between components against the disruptive effects of haloperidol and clozapine on responding in two target multiple schedule components. The two target components differed from one another in that a relatively low response-reinforcer contingency was established in one component by occasionally delivering response-independent food during that component in addition to the reinforcers arranged on a VI schedule for responding. In the second target component, food was only delivered by responding on a VI schedule identical to that used in the first component. Therefore, one component was associated with a relatively greater stimulus-reinforcer contingency than the other, but simultaneously possessed a relatively poorer response-reinforcer contingency. If haloperidol or clozapine act to disrupt reinforced responding in a manner analogous to the effects of response-independent food delivered between components, then responding should be much more disrupted in the component associated with the weaker stimulusreinforcer contingency. Also, if these drugs act to disrupt responding via a similar mechanism as response-independent food delivery between components, then the effect of both should be additive. That is, when rats are given a drug and presented with response-independent food, their responding should be much more disrupted relative to baseline than in the presence of either condition alone.
2. Materials and methods
2.1. Subjects Six male Norway Hooded rats, approximately 6 months old at the start of training, were maintained at 85% of their free-feeding body weights. Prior to the experimental conditions being conducted, rats were autoshaped to lever press for
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food reinforcement and had received 6 months of training at different schedule values in the multiple schedule procedure described below. Supplementary feed was given after each session of training to maintain prescribed body weights. Rats were housed in pairs, with water and untreated wood shavings available continuously in their home cages. The housing room was maintained at a constant 22°C with lights on between 07:00 and 19:00 h each day.
2.2. Apparatus Rats were trained individually in a single experimental chamber, measuring approximately (31× 32 × 24 cm). A red stimulus light (12 W) was situated above each of two response levers. One lever was located on the left side of the front wall and the other was located on the right side (with both levers being equidistant from the midline). Reinforcers (0.1 ml of a mixture of 15% sweetened milk and 85% water) were delivered via a dipper mechanism located in the center of the front wall. All experimental events were scheduled and recorded by an IBM-compatible computer running MED-PC software in a room remote from the experimental chamber.
2.3. Procedure Throughout the experiment, sessions were conducted daily, 7 days per week, and comprised 26 multiple-schedule components presented equally often and in a pseudo-random order. Target components (during which responding was reinforced) were 60 s in duration and signaled by illuminating the light above either the left or right lever. Components were separated from one another by a 30-s inter-component interval (i.e. no stimulus lights were lit and responding on levers was not reinforced). During reinforcer delivery (2.5 s of access to the dipper), component and reinforcement schedule timing were suspended. For the first 69 sessions of training the reinforcement schedules during both left- and rightlever components were kept equal at VI 30-s. These sessions of training were used to reduce any inherent side bias to either the left or right lever
prior to establishing a differential response rate in the next phase of training. The mean number of responses on session 69 of training was 486 on the left lever and 444 on the right lever. At an alpha level of PB 0.05, a paired t-test revealed no significant difference between the number of responses across both levers [t(5)= 1.5]. Also established at this point of training was whether a disruptive drug (haloperidol in this case) would decrease responding equally on both levers if responding was maintained by equal reinforcer rates on both levers. This test was performed in order to support any subsequent conclusions that differences in resistance to the disruptive effects of drugs was a product of the unequal reinforcer conditions rather than a spurious result of any systematic inherent spatial bias to favor one lever over the other. On session 70 of training all rats were given 0.1 mg/kg of haloperidol (in the manner described in Section 2.4). As expected, delivery of haloperidol reduced the mean number of responses made in a session in both components (down to 301 in the left-lever component and 289 in the right-lever component). This decrease in responding was equivalent for both levers in that there was still no significant difference between the number of response made on the left versus right lever following haloperidol delivery [tB 1.0]. Therefore, the proportion of responses made relative to baseline following delivery of haloperidol was virtually identical for both components (0.62 and 0.65 for left- and right-lever components, respectively) when identical reinforcement schedules were arranged on both levers. The behavioral procedure during the subsequent experimental sessions was identical to the prior training sessions except that during left-lever components a VI 30-s and a VT 30-s schedule were both concurrently in effect. Whereas, during right-lever components a single VI 30-s schedule was in effect as before. Rats received 111 sessions of training in this procedure and at these schedule values prior to the introduction of response-independent food delivered during the inter-component interval and/or the administration of drugs in subsequent conditions. Table 1 outlines the experimental conditions conducted and the order in which they were con-
D.N. Harper / Beha6ioural Processes 46 (1999) 1–13
ducted. Each condition was in place for a single probe session. In Condition 1 rats were presented with response-independent food delivered during the inter-component interval arranged on a VT 15-s schedule. In Conditions 2 – 6, rats were given either haloperidol or clozapine prior to being placed in the response chamber for the session. In the remaining conditions, rats were presented with response-independent food delivered during the inter-component interval (at VT 15-s) in combination with either haloperidol or clozapine administered prior to the subject being placed in the chamber. In all conditions, the arranged schedule values for the two components remained the same (VI 30-s plus VT 30-s for the left-lever component and VI 30-s for the right-lever component). Thirteen sessions of training in the baseline condition (no food presented during the inter-component interval and no exposure to drugs) occurred between each condition.
2.4. Drug procedure On each day of use, the haloperidol or clozapine was first dissolved in 0.1 N HCl and then diluted with 0.9% saline to the required dose. Prior to oral administration, the drug solution was mixed with 1.0 ml of the sweetened milk mixture used as a reinforcer. This milk – drug soTable 1 Conditions conducted listed in the order they were presented to subjects Condition
Drug/dose (mg/kg)
Rate of response-independent food delivery during inter-component interval
1 2 3 4 5 6 7 8 9 10 11
– Haloperidol 0.1 Haloperidol 0.5 Clozapine 5.0 Clozapine 2.0 Clozapine 10.0 Haloperidol 0.1 Haloperidol 0.5 Clozapine 5.0 Clozapine 2.0 Clozapine 10.0
VT 15-s EXTa EXT EXT EXT EXT VT 15-s VT 15-s VT 15-s VT 15-s VT 15-s
a
EXT= extinction.
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Table 2 Mean number of responses made across all subjects in the left-lever and right-lever components for all baseline sessions combined and each probe session of disruption
Baseline Inter-component interval food Haloperidol 0.1 Haloperidol 0.5 Clozapine 2.0 Clozapine 5.0 Clozapine 10.0 Haloperidol 0.1+food Haloperidol 0.5+food Clozapine 2.0+food Clozapine 5.0+food Clozapine 10.0+food a
Left-lever
Right-lever
174 (12)a 117 (14)
304 (23) 93 (14)
154 96 171 123 168 89 32 160 95 132
196 109 240 213 264 81 21 191 96 139
(20) (9) (30) (29) (44) (10) (7) (22) (17) (26)
(26) (13) (27) (62) (71) (11) (6) (33) (23) (34)
Numbers in parentheses are S.E.M.
lution was given to each subject 30–40 min before the start of their respective session. In every case the solution was completely consumed within 1 min of it being made available to the subject.
3. Results In order to examine the resistance of responding to disruption, responding in a single probe session of inter-component interval food and/or drug delivery was expressed relative to the number of responses made in the immediately preceding baseline session. Table 2 shows the mean group data for the number of responses made in a single probe session of disruption as well as the overall average number of responses made in the preceding baseline sessions. These averages are presented separately for the left- and right-lever components. The data in Table 2 show that the schedules arranged for the left- and right-lever components were successful in establishing a higher rate of responding in the presence of the right-lever component than the left-lever component. The data from individual subjects was also consistent with the group results shown in Table 2. Across 66 determinations of the baseline level of responding (across all subjects and conditions)
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there were only two cases where the baseline level of responding was greater for the left-lever component (and both of these were for Rat 5 in Conditions 2 and 3). Therefore, the absolute level of responding was consistently greater for the component associated with the lowest overall amount of food reinforcement (right lever) and lower for the component associated with the highest overall amount of food reinforcement (left lever). Fig. 1 shows the decrease in responding displayed by each subject following the delivery of inter-component food in terms of the proportion of baseline responding for left-lever (unfilled bars) and right-lever (filled bars) components separately. This figure shows that probe session delivery of response-independent food produced a decrease in the overall number of responses made. Furthermore, in every single case, the greatest decrease occurred for responding in the right-lever component [t(5)= 4.98, P B 0.01]. Thus, consistent with previous findings, responding in the component associated with the smallest overall amount of food reinforcement (right-lever component) was more disrupted relative to baseline than responding in the component associated with the
greatest overall amount of reinforcement (leftlever component). Fig. 2 shows the proportion of baseline responding for left-lever and right-lever components for each subject as a function of the dose of haloperidol alone (Conditions 2 and 3) and when haloperidol was administered in combination with VT 15-s food during the inter-component interval (Conditions 7 and 8). This figure shows that, as with response-independent food delivery during the inter-component interval, haloperidol generally produced a decrease in the responses made in both components. In addition, the 0.5 mg/kg dose generally produced a greater decrease in responding than the 0.1 mg/kg dose (except Rat 62 in the right-lever component and Rat 63 in the left-lever component). For all 12 cases in which haloperidol was administered on its own, the relative reduction in responding was greater in the right-lever component compared to the left-lever component [t(5)= 4.70, PB 0.01 and t(5)= 3.43, P B 0.01 at the 0.1 and 0.5 doses, respectively]. When haloperidol was administered concurrently with response-independent food delivery, the effects of these two disruptors were additive. That is, in all cases, haloperidol plus response-independent food
Fig. 1. Proportion of baseline responding in the left-lever (unfilled bars) and right-lever (filled bars) components following the introduction of response-independent food delivered between components for each subject and the group as a whole. Proportions were calculated by dividing the number of responses made in a component for the single probe session of each condition by the number of responses made in the immediately preceding baseline session during which food was not delivered between components.
D.N. Harper / Beha6ioural Processes 46 (1999) 1–13
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Fig. 2. Proportion of baseline responding in the left-lever (unfilled bars) and right-lever (filled bars) components as a function of the dose of haloperidol (administered alone or concurrently with response-independent food delivered between components) for each subject and the group as a whole. Proportions were calculated by dividing the number of responses made in a component for the single probe session of each condition by the number of responses made in the immediately preceding baseline session during which food was not delivered between components.
produced a greater disruption to responding compared to when haloperidol was administered alone
at the corresponding dose (paired t-tests were all significant at PB 0.05 for both left and right-lever
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components at all dose levels). Therefore, consistent with the effects of response-independent food, greater doses of haloperidol caused correspondingly greater behavioral disruption relative to baseline. The greatest decreases in responding were consistently in the component associated with the smallest overall amount of food reinforcement (right-lever component). Fig. 3 shows the proportion of baseline responding for left-lever and right-lever components for each subject as a function of the dose of clozapine alone (Conditions 4 – 6) and when clozapine was administered in combination with VT 15-s food during the inter-component interval (Conditions 9–11). This figure shows that at the lowest doses clozapine, administered on its own, had inconsistent effects on responding. For example, two rats displayed very little change in responding (Rats 61 and 63), two rats displayed a decrease in responding in one component (Rats 62 and 66) and the other two rats displayed an increase in responding in both components (Rats 64 and 65). Also, there was no consistent difference in the degree of disruption to responding in the left-lever component versus the right-lever component at the 2.0 mg/kg dose [t(5) = 0.84, P \0.05]. At the 5.0 mg/kg dose there was a more consistent pattern of change in responding across rats. In four of the six rats (Rats 61 – 64) there was an overall decrease in responding relative to baseline in both components. For all four of these subjects, the degree of disruption was greater in the right-lever component. Overall there was a significant difference between the proportion of baseline responding in the left- versus right-lever components [t(5)= 4.23, P B 0.01]. The highest dose of clozapine (10.0 mg/kg) produced the most consistent effects of clozapine on responding across rats. At this dose there was a consistent decrease in responding across all subjects in both components (with 11 out of 12 cases showing a proportion of baseline responding value less than 1.0). Also, for every subject the degree of disruption, relative to baseline, was greatest for responding in the right-lever component [t(5) = 3.60, PB 0.01]. Therefore, when clozapine was administered on its own there was a dose-dependent decrease in overall responding. When overall re-
sponding was reduced (for four subjects at 5.0 mg/kg and all subjects at 10.0 mg/kg), the extent of disruption was always greater in the component associated with the smallest overall amount of reinforcement. When clozapine was administered concurrently with VT 15-s food delivered during the inter-component interval, there was a consistent decrease in responding in both components compared to when clozapine was administered alone at the corresponding dose (33 out of 36 cases). As with haloperidol, when clozapine was administered concurrently with inter-component food delivery, the effects of disruption were generally additive. That is, clozapine plus response-independent food produced greater disruption to overall responding compared to when clozapine was administered alone at the corresponding dose (paired t-tests were all significant at PB 0.05 for both left- and right-lever components at all dose levels). Furthermore, the extent to which right-lever component responding was more disrupted than left-lever component responding was greater when clozapine was administered concurrently with inter-component food delivery than when clozapine was administered alone.
4. Discussion The present findings demonstrated that both haloperidol and clozapine disrupted behavior in a manner similar to that observed when responseindependent food is presented between target components on a multiple schedule. That is, both drugs caused a decrease in responding (haloperidol at all doses and clozapine at the two highest doses) and did so to a relatively greater degree in the component associated with the smallest overall amount of food reinforcement. The greater effect of these drugs on behavior associated with relatively low reinforcement further extends the generality of Nevin’s claim that behavioral resistance to change is dependent on stimulus-reinforcer contingencies (Nevin, 1992). That is, responding in the presence of stimuli associated with the lowest overall amount of rein-
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forcement is less resistant to disruption irrespective of the relative strength of the responsereinforcer relationship maintaining responding.
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In the present case, responding in the component associated with the highest baseline response rate (but lowest overall amount of rein-
Fig. 3. Proportion of baseline responding in the left-lever (unfilled bars) and right-lever (filled bars) components as a function of the dose of clozapine (administered alone or concurrently with response-independent food delivered between components) for each subject and the group as a whole. Proportions were calculated by dividing the number of responses made in a component for the single probe session of each condition by the number of responses made in the immediately preceding baseline session during which food was not delivered between components.
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forcement) was the least resistant to disruption from haloperidol or clozapine. Therefore, both drugs acted as a disruptor in the same manner as other forms of disruption such as prefeeding subjects prior to the session (Nevin et al., 1990), reducing the maintaining reinforcement schedule to extinction (Nevin, 1974; Nevin et al., 1983, 1990) and the delivery of response-independent food outside of the target components (Nevin, 1974; Nevin et al., 1983; Harper and McLean, 1992; the current experiment). The present findings were consistent with those of Egli et al. (1992), who found that the extent of behavioral disruption from opioid drugs was dependent on the dose level (greater doses led to greater disruption) and rate of reinforcement maintaining responding (responding changed less in a component associated with a higher reinforcer rate). What Egli et al. (1992) did not assess was whether it was the baseline rate of reinforcement per se that determined relative resistance to drug-induced disruption or whether it was the baseline rate of responding that was critical. However, such a determination of the independent variable which controls resistance to drug effects is important, because different views exist about which aspects of baseline conditions are important in determining the extent of change. For example, Nevin and colleagues have asserted that resistance to change is dependent upon baseline stimulus-reinforcer contingencies. However, several authors have claimed that the extent of behavioral disruption caused by some drugs (e.g. pentobarbital and D-amphetamine) is dependent upon baseline response rates (Sanger and Blackman, 1976; Lucki and DeLong, 1983; Rees et al., 1985). The present study used a schedule arrangement that established the highest response rate in the component associated with the lowest overall amount of reinforcement, thus allowing for the separation of stimulus-reinforcer versus responsereinforcer contingencies (see Nevin et al., 1990). As a consequence, the present findings suggest that haloperidol and clozapine (as with the opioid drugs used by Egli et al. 1992) can be considered to disrupt behavior in a manner analogous to the disruption that occurs follow-
ing alterations in the environmental or reinforcement context. Furthermore, these results demonstrate that the extent of disruption is dependent upon baseline stimulus-reinforcer contingencies rather than the baseline response rate which is established via the response-reinforcer contingencies. With respect, specifically, to the effects of haloperidol, the present results are in contrast to the findings of Cohen (1986). Cohen failed to demonstrate that haloperidol produced a greater decrease in responding in the component associated with the longest delay to reinforcement. There are several differences between the present study and Cohen’s that may have contributed to these disparate findings. Firstly, the method of drug administration was different across the two studies. However, the route of administration is unlikely to be a critical difference because both studies demonstrated that haloperidol caused a sizable decrease in responding, although the doses tended to be lower in the Cohen study than used here. Another difference is that Cohen attempted to establish a differential resistance to change across two components by using a chained random interval RI 30-s RI 30-s schedule (in which the first component was signaled by a flashing houselight and the second component was signaled by a steady houselight). Because food reinforcers were only delivered after the second component, the first component was associated with a greater delay to reinforcement (and therefore, responding should have displayed less resistance to disruption), whereas, in the present study, a differential resistance to change was established across two randomly alternating components that were spatially separated (left versus right lever) by associating each with a different overall rate of food delivery. One possible way to account for the difference between the effects of haloperidol in the present study versus Cohen (1986) concerns the effects that drugs as disruptors may have on discrimination performance in the two different procedures. Generally, disruptors are thought of as devaluing the experimental reinforcer (relative to other ‘background’ reinforcers; see, for example, Nevin
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et al., 1990). However, drugs may, in addition, degrade stimulus control by component stimuli. If one of haloperidol’s effects was to reduce stimulus control, then responding would increase in the component in which responding was relatively lower during baseline training, whereas responding would decrease in the component in which responding was relatively higher during baseline. If, in addition, haloperidol was to cause an overall decrease in responding then its relative effects across components would be confounded by this disruption to stimulus control. Essentially, in Cohen’s study, responding in the component maintained by the lower rate of reinforcement (which also showed the lowest baseline rate of responding) could appear to be as equally resistant to haloperidol as responding in the more highly reinforced component (which showed the highest baseline rate of responding). However, in the present study, the component associated with the higher overall amount of reinforcement displayed the lowest baseline rate of responding. Under this situation, reduced stimulus control on its own could have enhanced responding in the richer component and reduced responding in the leaner component, thereby enhancing the apparent difference between components in terms of resistance to change. Although neither the present study nor the Cohen (1986) study directly assessed the effects of haloperidol on stimulus control, an examination of the responses made on the left and right levers during the inter-component interval suggests that stimulus control was not degraded at the doses used here. If the stimulus control exerted by the light stimuli had been degraded, then subjects would exhibit more indiscriminate responding and therefore would show an increase in inappropriate lever pressing during the intercomponent interval (e.g. responding on the left lever during the inter-component interval). Contrary to this possibility, an examination of the responses made during the inter-component interval indicated that there was no increase of these inappropriate responses during any session of disruption. It is possible that the lack of differential resistance to change to haloperidol in the Cohen (1986) study occurred because the stimulus con-
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trol across components was poorly established during baseline training (irrespective of any possible effect of haloperidol itself on stimulus control). There was some evidence that rats were discriminating between components in that they displayed a greater response rate in the component that immediately preceded reinforcement. However, this difference only demonstrates that rats were responding more quickly the more time that elapsed and the closer they got to receiving reinforcement. What is not known is whether the rats in Cohen’s study were discriminating between the stimuli signaling components. Because rats responded on only one lever and the stimuli signaling components were all in one location, it may have been that there was a great deal of overlap in the stimulus-reinforcer contingencies responsible for establishing the degree of resistance to change in each component. Nevin (1992) has argued that resistance to change depends on the correlation of reinforcement with both the component stimuli and response location (however, see also McLean et al., 1996). Therefore, if rats were not discriminating between components in Cohen’s study, then it would not be expected that they were exposed to a relatively stronger stimulus-reinforcer relationship in the component that was closest to reinforcement. In such a case, haloperidol would have had an equivalent effect on responding in each component. Despite the possibility that the method Cohen used to assess behavioral resistance to haloperidol may not have provided an adequate test of resistance to change, there is other evidence that suggests that not all drugs may act as a disruptor in the way that haloperidol and clozapine were found to in the present study. In experiments 2 and 3 of Cohen (1986), D-amphetamine, CCK-8 (cholecystokinin) and sodium pentobarbital caused an equivalent decrease in responding in both components of a multiple schedule, irrespective of the rate of reinforcement associated with each component. The inability of these drugs to produce a differential resistance to change across components was in contrast to the effects of changing the reinforcer rate to extinction for several sessions in the same study. Thus, although haloperidol and clozapine (in the present study)
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and opioids (in Egli et al., 1992) may disrupt responding in a manner analogous to other forms of behavioral disruption (such as reducing the reinforcer rate to extinction or response-independent food), there may be a variety of drugs which are not best characterized in this way. A task for future research is to determine what are the defining characteristics of drugs which act as disruptors in the way conceived of in Nevin’s resistance to change research (Nevin, 1974, 1992) . Such an examination may help determine the neurochemical pathways involved in establishing behavioral resistance to change. The results from the current study suggest that, in addition to both clozapine and haloperidol influencing dopamine activity in the brain (albeit at different receptor sites), they are also similar in terms of their disruptive effects on reinforced responding. Both drugs acted to decrease responding in the same way as observed when response-independent food was delivered between components. That is, these drugs caused a proportionally greater decrease in responding in the component associated with the smaller overall amount of reinforcement. Note, however, that although the drugs were qualitatively similar, haloperidol tended to result in greater overall disruption and a larger extent of disruption in the right-lever component versus the left-lever component (even when compared to a relatively very high dose of clozapine). This differential quantitative effect of the two drugs may be associated with their different specific sites of action in the brain. Haloperidol is considered to have a greater affinity for the dopamine D2 receptor site, whereas clozapine is an atypical neuroleptic that has greater affinity for serotonin (5-HT2), D1 and D4 receptors over the D2 site (Ellenbroek et al., 1991 Van Tol et al., 1991; Gingrich and Caron, 1993). Thus, although the neurotransmitter dopamine has been generally implicated in the reinforcement process, it may be that the action of dopamine at the D2 site plays a particularly important role in terms of the establishment and maintenance of response-reinforcer contingencies. Consistent with this conclusion a recent study using similar methods to those reported here found that the specific D2 agonist quinpirole
caused decreases in responding consistent with those observed following haloperidol delivery in the present study (Harper, 1999). Therefore, reducing dopamine activity at the D2 site may degrade the contingency maintaining the absolute level of responding, but leave the stimulus-reinforcer contingency relatively intact (i.e. the conditions responsible for behavioral resistance to change). One implication of this conclusion is that, consistent with Nevin and colleague’s claim (Nevin et al., 1990; Nevin, 1992), response rate and resistance to change are independent aspects of overall response strength and are established through different processes.
Acknowledgements The author wishes to thank all the people working in the VUW School of Psychology animal laboratory for their help. This research was supported with financial assistance from the VUW Internal Grants Committee.
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