Psychopharmacology (1993) t t 0: 427-436 Psychopharmacology © Springer-Verlag 1993

Interactions between chronic haloperidol treatment and cocaine in rats: an animal model of intermittent cocaine use in neuroleptic treated populations Patricia A. LeDuc and Guy Mittleman

Department of Psychology, Memphis State University, Memphis, TN 38152, USA

Received May 21, 1992 / Final version August 24, 1992

Abstract. This experiment investigated the possibility that rats maintained on chronic haloperidol treatment would show increased behavioral responsiveness to cocaine, sim- ilar to that observed in human stimulant abusers who are chronically treated with neuroleptics. Thus, the effects on locomotion and stereotyped behavior of intermittent in- jections of cocaine were investigated in female rats receiv- ing chronic haloperidol treatment. Daily injections of haloperidol (0.2 mg/kg, IP) or vehicle were administered for 6, 12 or 18 days prior to the start of testing with cocaine and were then continued throughout cocaine testing. All rats received four doses of cocaine (0.0, 3.0, 7.5, or 15.0 mg/kg, IP) in random order with an intervening vehicle day between successive drug days. The four dose sequence of cocaine was repeated a total of four times. Initial cocaine administration produced dose dependent increases in locomotion and stereotyped behavior. When the sequence of cocaine doses was repeated, differences among treatment groups emerged. Groups treated with haloperidol exhibited heightened locomotion in response to cocaine and with repeated injections, showed a higher rate of behavioral sensitization than control animals. These differences in the behavioral response to cocaine were maintained for at least 2 months following termin- ation of daily haloperidol treatment. In order to examine the mechanisms underlying this heightened responsive- ness to cocaine, apomorphine-induced locomotion (dose range, 0 250 gg/kg, SC) was determined. Regardless of dose, rats treated with haloperidol showed different tem- poral patterns of locomotion in response to apomorphine suggesting that the increased response to cocaine was related to changes in dopaminergic receptor sensitivity.

Key words: Haloperidol - Cocaine - Apomorphine Stereotypy - Locomotor activity - Sensitization - Rat

The neuroleptic haloperidol is often used in the treatment of stimulant-induced psychosis, schizophrenia, and

Correspondence to: G. Mittleman

Tourette's disease. The therapeutic efficacy of this drug is related to its antagonistic effects on dopamine (DA) sys- tems. Haloperidol affects DA systems by competitively binding to DA receptors, thus blocking neurotransmis- sion (Carlsson 1978). When used acutely to counteract stimulant intoxication, occupancy of postsynaptic re- ceptors by haloperidol blocks the effects of increased synaptic DA caused by administration of indirect agonists such as amphetamine and cocaine (Groves and Rebec 1976; Ellinwood and Kitbey 1977). In humans, this block- ade is manifest as a decrease in physiological and be- havioral indices of arousal (Schnoll et al. 1984). In rats, such acute blockade markedly attenuates the elevations in locomotion and stereotypy that typically occur in re- sponse to stimulant administration (Randrup et al. 1963; Bhattacharyya et al. 1979).

While acute treatment with haloperidol is effective in treating occurrences of stimulant intoxication, chronic daily administration is needed to produce and maintain clinical efficacy in the treatment of schizophrenia and Tourette's syndrome. Prolonged treatment with haloperi- dol can induce pre- and postsynaptic changes in dopamin- ergic neural systems. Presynaptically, reductions in the number of spontaneously active DA neurons in the sub- stantia nigra and ventral tegmental area have been ob- served following chronic neuroleptic administration (Chiodo and Bunney 1983; White and Wang 1983). Intra- cellular recordings show that these neurons have signific- antly more depolarized membrane potentials than con- trols, leading to a state of depolarization block (Bunney and Grace 1978; White and Wang 1983). Postsynapticalty, chronic haloperidol administration can induce dopamine receptor proliferation (Wilmot and Szczepanik 1989). The functional expression of these changes has also been examined in animals by recording locomotion and stereo- typy in response to DA agonists. In rats, chronic haloperi- dol treatment can enhance locomotion and stereotypy in response to acute administration of amphetamine and cocaine (Rastogi et al. 1983; Csernansky et al. 1990).

In comparison to the therapeutic effectiveness of halo- peridol in treating acute stimulant intoxication, abuse of stimulants in populations maintained on haloperidol or

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similar neuroleptics appears to result in a profound in- crease in symptoms, suggesting that chronic treatment with haloperidoI can augment, rather than reduce, the effects of drugs such as cocaine. Mesulam (1986) described the effects of cocaine use by a Tourette's patient who had been taking haloperidol for 10 years. The patient experi- enced violent jerking in all limbs as well as motor and vocal tics immediately following cocaine inhalation. These markedly exacerbated symptoms persisted for approxim- ately 3-5 h and occurred despite the fact that daily medic- ation had been taken. Similar symptom exacerbation has been reported in cases of schizophrenic patients who abuse stimulants (e.g. Janowsky and Davis 1976; Dixon et al. 1991). In addition, Richard et al. (1985) reported that in hospitalized schizophrenics, relapsing occurred more often in patients who abused stimulants, and that antipsy- chotic medication did not prevent the relapses. In this context it should also be noted that schizophrenics have higher rates of stimulant use than the general population (Mueser et al. 1990) and also tend to use stimulants more often than other groups of psychiatric patients (Schneier and Siris 1987).

As stimulant abuse in patients receiving chronic neuroleptic treatment can markedly exacerbate symp- toms, and chronic, intermittent stimulant use produces a progressive enhancement of many of the behavioral drug effects known as reverse tolerance or behavioral sensitiza- tion (Randrup et al. 1963; Ellinwood 1967; Segal and Mandell 1974; Post 1981; Richard et al. 1985; Mesulam 1986; Robinson and Becker 1986), it seems likely that an interaction between intermittent stimulants and chronic neuroleptic treatment may have additive effects. Many studies that have investigated the effects of chronic neuro- leptic treatment withdraw the drug days prior to be- havioral or neurochemical measurements (Halperin et al. 1983; Blaha and Lane 1987; Lane and Blaha 1987; Prosser et al. 1988). Additionally, following chronic treatment with neuroteptics such as haloperidol, only the acute effects of agonist challenge are typically examined (Rebec et al. 1982; Seeger et al. 1982; Dewey and Fibiger 1983). It is therefore possible that the behavioral and neurochemi- cal changes observed in neuroleptic treated animals fol- lowing withdrawal of the drug, or after an acute stimulant challenge, may not be comparable to the effects seen in humans when chronic neuroleptics and chronic stimulant abuse are combined. As recently indicated by Gawin (1991), most animal models of stimulant use do not reflect human abuse patterns. By not investigating multi-dose binges or using multiple cocaine-free days to examine abstinence periods common among human abusers, ani- mal models have limited their generalizability.

This experiment investigated the interaction between chronic haloperidol treatment and long term intermittent cocaine administration. One purpose of this experiment was to determine if chronic treatment with haloperidol produced a heightened response to the initial administra- tion of cocaine or whether the behavioral response was significantly enhanced following repeated exposure to cocaine. In order to better approximate human patterns of abuse, haloperidol was not withdrawn prior to cocaine administration and multiple doses of cocaine as well as multiple cocaine-free days were used. Secondly, as noted

above, the duration of neuroleptic treatment (e.g. acute versus chronic) is an important factor influencing both neural and behavioral changes (Bunney et al. 1973; Bunney and Grace 1978; Bunney 1984). Thus, in this study, daily injections of haloperidol were administered for 6, 12 or 18 days prior to testing with cocaine in order to determine if treatment length influenced the behavioral response to this drug. Thirdly, the permanence of in- creases in the behavioral response to cocaine was investig- ated following withdrawal of haloperidol. Finally, to in- vestigate the mechanisms underlying the observed be- havioral changes, the direct agonist apomorphine was used to behaviorally assess pre- and postsynaptic receptor changes during neuroleptic treatment and following with- drawal.

Materials and Methods

Subjects

Thirty-two mature (300 gin) female Long Evans rats (Charles River, Raleigh, NC) served as subjects. The animals were housed in pairs under a light-dark 12:12 h schedule with free access to food and water (lights on: 0630 hours).

Activity testing

Locomotor activity was tested in a bank of eight individual 25 x 40 x 18 cm clear Plexiglas cages. Two infrared photocell beams bisected the length of each cage 3 cm above the floor, 12 cm from the front and back of each cage. For each cage, interruptions of either photocell beam were registered incrementally by a microcomputer and counted as front beam breaks or rear beam breaks. Cage crosses, calculated from the photocell counts, were used as the measure of locomotion. A cross was defined as a trip along the length of the cage and comprised two alternating beam interruptions (e.g. front-rear). Cage crosses were summed in 10 rain time bins during the locomotion tests.

Stereotypy rating

Behavioral stereotypy was rated by an observer blind to the treat- ment condition for one minute (per rat) every 15 min during each cocaine and apomorphine test session. The rats were rated for stereotypy using a rating scale initially described by Maclennan and Maier (1983) : 0 = inactive; 1 = intermittent locomotor activity; 2 = continuous locomotor activity; 3 = intermittent stereotypy; 4 = continuous stereotypy over a wide area; 5 = continuous stereo- typy in a restricted area; 6 = pronounced stereotypy in a restricted area; 7 = intermittent stereotyped licking or biting directed at the floor or walls; 8 = continuous stereotyped licking or biting.

Procedure

Pre-drug baseline. Baseline locomotor activity was collected in 50 min sessions on two consecutive days. All animals were injected (IP) with lactic acid vehicle (1 ml/kg) immediately prior to testing.

Haloperidol Baseline. Rats were randomly divided into four groups that received daily injections (IP) of either lactic acid vehicle, (group t) or haloperidol (groups 2, 3 and 4), 12 h prior to testing. Groups 2, 3 and 4 received daily injections of haloperidol (HAL; 0.2 mg/kg in lactic acid vehicle, pH 4.5) for 6, t2 or t8 days, respectively, prior to periodic administration of cocaine. Thus, the groups were de-

signated: (1) Control, (2) HAL-& (3) HAL-12 and (4) HAL-18. Haloperidol baseline locomotor activity was recorded in 50 min sessions on 18 consecutive days. Figure 1 indicates the schedule of neuroleptic treatment and provides an overall description of the sequence of drug testing.

Cocaine testing. After receiving lactic acid or 6, 12 or 18 days of haloperidol, all rats received IP injections (1 ml/kg) of cocaine hydrochloride (Sigma) in 0.9% saline vehicle. Drug doses (0.0, 3.0, 7.5, 15.0 mg/kg) were scheduled in a Latin square design with an intervening saline day between successive cocaine test days. This sequence of four doses of cocaine, requiring 8 test days, was repeated four times for a total of 32 days. Rats were placed in the activity cages immediately after cocaine or saline injections. On cocaine test days, the recording of locomotor activity commenced immediately after administration of the drug. As described earlier, cage crosses were cumulated in 10 rain time bins during these 50 rain test sessions. A test session of 50 rain was selected as, in pilot studies, this length of time most closely coincided with the duration of behavioral activation produced by this dose range of cocaine. Cocaine-induced stereotypy was recorded, using the scale described above, at 1 min intervals every 15 min of the sessions. Thus, stereotyped behavior was rated at 0, 15, 30 and 45 min post-injection. As indicated in Fig. t, daily haloperidol or vehicle injections were continued throughout the 32 days of testing with cocaine.

Apomorphine testing. Following completion of the four, 8 day se- quences of cocaine, locomotor activity and stereotypy in response to apomorphine (Sigma) were determined. Doses of the drug (0.0, 50, 100 or 250 pg/kg in 0.05% ascorbic acid solution) were presented in random order on successive test days. Cage crosses, summed over 10 rain bins, and stereotypy ratings, determined at 15 rain intervals, were collected during 60 rain sessions on each day of apomorphine testing. Test sessions of 60 min were used because, at the highest dose of apomorphine (250 ~tg/kg), pilot studies indicated that rats showed clear indications of behavioral activation that persisted for 1 h post-injection. Daily haloperidol and vehicle injections were continued throughout these 4 days of apomorphine administration.

Haloperidol withdrawal. At the conclusion of the drug sequences described above, daily haloperidol injections were discontinued. In order to assess changes associated with short term neuroleptic withdrawal, 10 days following haloperidol cessation animals were subject to one, four-dose sequence of cocaine followed by one, four dose sequence of apomorphine, as described above. Fifty-six days after haloperidol cessation animals were again tested with one

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sequence of cocaine followed by another sequence of apomorphine in order to examine the effects of long term neuroleptic withdrawal (see Fig. 1).

Data analysis

Cage crosses were subjected to repeated measures analysis of vari- ance (ANOVA; Winer 1962). Six separate ANOVAs were used to examine group differences in drug induced locomotor activity. These analyses were performed on cage crosses obtained during (1) pre- drug baseline, (2) hatoperidol baseline, (3) cocaine-induced loco- motion during haloperidol treatment, (4) apomorphine-induced locomotion during haloperidol treatment, as well as (5) cocaine and (6) apomorphine-induced cage crosses following cessation of halo- peridol.

Four separate ANOVAs were used to analyze stereotypy ratings obtained on cocaine and apomorphine test days. ANOVAs were performed on ratings collected on (t) cocaine test days during haloperidol treatment, (2) cocaine test days following haloperidol withdrawal, (3) apomorphine test days during haloperidol treat- ment, and (4) apomorphine test days after haloperidol cessation.

Cocaine-induced locomotion during haloperidol treatment was subjected to a four-factor ANOVA. The factors were Group (Con- trol, HAL-6, HAL-12 and HAL-18), Determinations (four, 8-day sequences of the drug), Dose (0.0, 3.0, 7.5 and 15.0 mg/kg) and Time Bins (five, 10-min bins). These same factors were used to analyze cage crosses collected after haloperidol was withdrawn. In this analysis, data obtained from the two sequences of cocaine injections 10 and 56 days after haloperidol withdrawal were compared with the last sequence of drug prior to hatoperidol withdrawal. Thus, three determinations were used for this analysis (Determinations 4, 5 and 6).

Stereotypy ratings from the cocaine test days during haloperidol treatment and following haloperidol withdrawal were subjected to separate ANOVAs. All factors and their levels were identical to the cage cross analyses except that Time Bins had four levels (0, 15, 30 and 45 min).

Locomotor activity and stereotypy ratings collected on apomor- phine test days were also evaluated using repeated measures ANOVAs. The factors used to analyze apomorphine-induced loco- motion were Group (4 levels), Determinations (1, 2 and 3), Dose (0.0, 50, 100 and 250 gg/kg), and Time Bins (six, 10-rain bins). These same factors were used to analyze stereotypy ratings except that the number of levels of Time Bins changed to 5 (0, 15, 30, 45 and 60 rain).

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Simple main effects tests were used to examine the interaction of variables. When appropriate, Dunnett's 't' tests were used to analyze drug effects in comparison to control.

Results

Predrug baseline

Analysis of locomotor activity prior to haloperidol treat- ment revealed that there were no initial group differences during the predrug baseline tests.

Haloperidol baseline

Analysis of the initial 18 days of haloperidol or vehicle treatment indicated that the groups did not differ in locomotor activity prior to the start of cocaine testing [F(3,28) = 0.931, P = 0.45]. However, all rats displayed a significant decline in locomotor activity across these 18 test days [F(17,476) = 7.417, P < 0.001].

Effects of initial exposure to cocaine

Figure 2 (determination 1) illustrates the effects of the first sequence of cocaine injections on locomotor activity.

Rats in all groups displayed dose-dependent increases in cocaine-induced locomotion [F(3,84) = 70.635, P < 0.001]. While there were no group differences in the level or time course of cage crosses, at the high dose of cocaine all groups treated with haloperidol tended to show higher locomotor activity levels for the first 30 rain of the test session in comparison to controls. Similar to the pattern of locomotor activity, all groups displayed dose- dependent increases in stereotyped behavior [F(3,84) = 246.37, P < 0.001]. There were no significant differ-

ences in cocaine-induced stereotypy among groups (data not shown).

Effects of repeated exposure to cocaine (sensitization)

In agreement with previous reports, intermittent injec- tions of cocaine resulted in a progressive increase in locomotor activity and behavioral stereotypy (Post and Rose 1976; Ho et al. 1977). As shown in Fig. 2, sensitiza- tion to cocaine is evident when the time course of the locomotor response to the first cocaine determination is compared with that produced during determination 4 (determinations 2 and 3 are not shown). Analysis conduc- ted across determinations 1 through 4 indicated that cocaine-induced activity levels increased significantly

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Fig. 2. Cocaine-induced locomotor activity in rats. Determinations 1 and 4 occurred while animals re- ceived daily injections of haloperidol or vehicle. Data from determinations 2 and 3 are not shown. Deter- minations 5 and 6 indicate cocaine-induced locomo- tion 10 (determination 5) and 56 (determination 6) days after cessation of haloperidol or vehicle injec- tions. The dashed line indicates when daily hatoperi- dol injections were terminated. Each symbol on the graphs is the average number of cage crosses in 10 min for each treatment group (N per group = 8). Filled circle = vehicle, hollow square = rats treated with haloperidot for 6 days prior to the start of coc- aine tests, hollow triangle = rats treated with haloper- idol for 12 days prior to the start of cocaine tests, hollow diamond = rats treated with haloperidot for 18 days prior to the start of cocaine tests. The numbers above each 10 min interval indicate how many groups differed significantly from control (Dunnett's t-test, P < 0.05 or less). SED between groups, across determinations ranged from 7.15 to 9.60. See Meth- ods for additional details

[F(3,84) = 21.02, P < 0.001] and that the groups re- sponded differently to the different drug doses [F(9,84) = 2.22, P < 0.03]. Simple main effects tests were conduc-

ted to further specify these group differences. These tests indicated that rats in the control group showed increases in the time course of locomotor activity over the four determinations [F(36,252) = 1.84, P < 0.005]. As shown in Fig. 2, increases in the time course of cocaine-induced locomotion in this group were most apparent at the two highest doses of the drug (7.5 and 15.0 mg/kg). Thus, with repeated injections of these doses there were sequential increases in locomotor activity during the first time bin that were followed by a monotonic decline in locomotion throughout the remainder of the test sessions. Rats treated with daily haloperidol showed a similar pattern of pro- gressive enhancements in activity. However, with repeated injections of cocaine (3.0 and 7.5 mg/kg) the difference between haloperidol treated and control rats increased during the first 10 min post-injection and extended later into the test sessions (comparing determinations 1 and 4). Following repeated injections of the highest dose of coc- aine (15.0 mg/kg) the difference in locomotion between the Experimental and Control rats was maintained throughout the test sessions.

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Repeated injections of cocaine also produced signific- ant increases in overall stereotypy across determinations [F(3,84) = 6.12, P < 0.001] although there were no group differences in the level or time course of stereotypy (data not shown). This enhancement was most apparent at the lowest dose of cocaine (3.0 mg/kg). Rats in all groups displayed intermittent locomotion (average rating of 2) during determination 1. By determination 4 average ratings increased to approximately 3, which is indicative of intermittent stereotyped behavior.

Effects o f initial exposure to apomorphine

As shown in Fig. 3 (determination 1), the temporal pat- tern of locomotion among the treatment groups differed in a dose-related fashion [F(45,420)= 2.34, P < 0.001]. At the vehicle dose, all haloperidol groups displayed significantly higher levels of activity than controls during the first 10 rain of the test session. After this time, group differences were no longer discernible. In comparison to the vehicle injection, striking group differences were ap- parent following all doses of apomorphine. At the lowest dose (50 gg/kg), control animals exhibited a marked and

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Fig. 3. Apomorphine-induced locomotor activity in rats. Determination 1 occurred while animals received daily injections of hatoperidol or vehicle. Determinations 2 and 3 indicate apomorphine-induced locomotion 18 (de- termination 2) and 64 (determination 3) days after cess- ation of haloperidol or vehicle injections. The dashed line indicates when daily haloperidol injections were termin- ated. Each symbol on the graphs is the average number of cage crosses in 10 rain for each treatment group (N per group = 8). Filled circle = vehicle, hollow square = rats treated with haloperidol for 6 days prior to the

start of cocaine tests, hollow triangle = rats treated with haloperidol for 12 days prior to the start of cocaine tests, hollow diamond = rats treated with haloperidol for t8 days prior to the start of cocaine tests. The numbers above each 10 min interval indicate how many groups differed significantly from control (Dunnett's t-test, P < 0.05 or less). SED between groups, across deter- minations ranged from 2.61 to 3.17

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typical suppression of locomotion throughout the 60 min session. Similar suppression of locomotion did not occur in haloperidol treated groups. In contrast, these animals displayed immediate increases in locomotion that persis- ted throughout the first half of the test session. At this dose, increases in locomotor activity were directly related to the length of haloperidol treatment prior to drug testing. Thus, the HAL-18 group exhibited the largest increase in locomotion while HAL-6 animals exhibited the smallest. The dose of 100 gg/kg caused an initial suppression of activity in all groups which lasted through- out the first 20 min of the session. However, group differ- ences appeared 30 min post-injection. All haloperidol groups displayed significantly larger increases in locomo- tion than control animals, which persisted for 10 min. At the highest dose of apomorphine (250 lag/kg), increases in activity levels throughout the last half of the test session were also directly related to the length of initial treatment with haloperidol (0, 6, 12 or 18 days). At this dose, the HAL-18 animals exhibited the largest increases while the controls displayed the smallest increase in activity.

As can be seen in Fig. 4 (determination 1), when initially administered apomorphine, dose-dependent group differences were also observed in the time course of

stereotypy [F(36,336)= 1.52, P = 0 . 0 3 ] . The largest group differences occurred following the high dose of apomorphine (250 pg/kg). At 60 min post-injection, ani- mals in the control group exhibited discontinuous locom- otion (average rating = 1). In comparison, haloperidol groups at the same time point showed behaviors ranging from continuous locomotion to intermittent stereotypy (average rating = 2 3).

Effects o f cocaine after haloperidol withdrawal

Locomotor activity from the final cocaine sequence dur- ing daily haloperidol administration (determination 4) was compared with the two subsequent sequences (deter- minations 5 and 6) which began 10 and 56 days, respect- ively, after cessation of haloperidol treatment (Fig. 2). Regardless of group, significant changes in the locomotor response to cocaine were observed across the three deter- minations [F(2,56) = 6.33, P < 0.004]. During determina- tion 4, all groups averaged 64.8 (SE = 1.13) cage crosses (all doses combined). Locomotor activity increased to 79.9 (SE = 1.03) during determination 5, and then returned to pre-cessation levels in determination 6 (average cage cros-

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Fig. 4. Apomorphine-induced stereotypy in rats. Deter- mination 1 occurred while animals received daily injec- tions of haloperidol or vehicle. Determinations 2 and 3 in- dicate apomorphine-induced stereotypy 18 (determination 2) and 64 (determination 3) days after cessation of halo- peridol or vehicle injections. The dashed line indicates when daily haloperidol injections were terminated. Each symbol on the graphs is the average stereotypy rating of each treatment group (N per group = 8). All rats were ra- ted for behavioral stereotypy for 1 min, at 15 min inter- vals. Filled circle = vehicle, hollow square = rats treated with haloperidot for 6 days prior to the start of cocaine tests, hollow triangle = rats treated with haloperidol for 12 days prior to the start of cocaine tests, hollow diamond = rats treated with haloperidol for 18 days prior to the

start of cocaine tests. The numbers above each 15 min in- terval indicate how many groups differed significantly from control (Dunnett's t-test, P < 0.05 or tess). SED be- tween groups, across determinations ranged from 0.34 to 0.48

sess 61.6; SE = 0.92). As clearly illustrated in Fig. 2, during the final cocaine determination the level of loco- motor activity in all groups remained significantly higher than that observed during determination 1, indicating that the increases in cocaine-induced activity were long- lasting [F(1,28) = 35.3, P < 0.001].

Although fluctuations in the level of cocaine-induced locomotion were observed over determinations 4, 5 and 6, dose-dependent differences among groups were preserved [F(9,84) = 2.71, P = 0.008]. Specifically, when adminis- tered the middle (7.5 mg/kg) or high dose (15.0 mg/kg) of cocaine all haloperidol groups continued to exhibit heightened locomotion in comparison to controls at 10 and 56 days following cessation of daily haloperidol injec- tions.

Stereotypy ratings in all groups increased significantly 10 days (determination 5) following the cessation of daily treatment with haloperidol (data not shown), and were then maintained at this level during the final determina- tion [F(2,56) = 5.54, P = 0.005]. Not surprisingly, in all groups the level of stereotyped behavior during deter- mination 6 remained significantly higher than that ob- served during determination 1, indicating that the in- creases in cocaine-induced stereotypy were long-lasting [F(1,28) = 32.54, P < 0.001].

Effects of apomorphine after haloperidol withdrawal

Apomorphine-induced locomotion during daily haloperi- dol treatment was compared with that obtained 18 and 64 days following haloperidol termination. Regardless of group, significant changes in the level of locomotor activ- ity were observed across the three determinations [F(2,56) = 6.36, P < 0.004]. During determination 1, all groups

averaged 10.8, (SE = 1.63) cage crosses (all doses com- bined). This level of locomotor activity was maintained during determination 2 (average cage crosses = 10.5; SE = 1.62), and then tended to decline during determination

3 (average cage crosses = 9.0; SE = 1.40). In addition to this change in activity levels common to all groups, group differences in the time course of locomotor activity were also observed [F(30,280) = 1.60, P = 0.01]. When exam- ining the activity levels of animals at the 50Mg/kg dose, Fig. 3 clearly shows that the suppression of locomotor activity seen in control animals remained consistent across determinations. In comparison, the immediate in- crease in apomorphine-induced locomotion observed dur- ing determination 1 in the haloperidol treated groups was no longer present at 18 (determination 2) and 64 (deter- mination 3) days after haloperidol cessation. The pattern of locomotor activity in control animals following the middle dose (100 gg/kg) also remained consistent over determinations. Analysis indicated that although group differences were largely maintained over determinations, the large increase in locomotor activity seen in all haloper- idol groups in determination 1 (30-40 min post-injection) was less pronounced and tended to occur 10 min earlier in the test interval after the neuroleptic was withdrawn. Similarly, at the 250 gg/kg dose (Fig. 3) the clear relation- ship between initial treatment length and increased Io- comotor activity observed during determination 1 was

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largely preserved after haloperidol withdrawal (determin- ations 2 and 3), although group differences were some- what reduced due to increases in locomotion in the con- trol group.

Apomorphine-induced stereotypy during haloperidol treatment (determination 1) and following cessation of the drug (determination 2 and 3) was compared (Fig. 4). Although all groups continued to display dose dependent increases in apomorphine-induced stereotypy [F(6,168) = 40.325, P = 0.001], no significant group differences in

the level or time course of stereotyped behavior following haloperidol withdrawal were observed. However, all groups exhibited significant changes in the time course of stereotypy across the three determinations [F(24,672) = 12.64, P = 0.001]. During determination 3, at the low-

est dose of apomorphine (50 gg/kg), all groups exhibited an increase in stereotyped behavior at 15 and 30 rain post- injection in comparison to the same time points of deter- mination 1. At the middle dose (100 lag/kg), following haloperidol termination, stereotypy levels of all groups decreased at 15 and 30 min post-injection when compared to the same time points during determination 1 (Fig. 4). At the high dose (250 lag/kg) increases in stereotyped behavior occurred across determinations. When com- pared to determination 1, at 15 and 30 min post-injection, all groups displayed higher levels of stereotyped behavior during determinations 2 and 3.

Discussion

The main results of this experiment indicated that after repeated administration of cocaine, animals maintained on daily haloperidol exhibited a consistently enhanced behavioral response to cocaine. Additionally, these results provide indications of the neurophysiological site medi- ating the enhanced response to cocaine in neuroleptic treated animals.

When initially administered cocaine (determination t ), haloperidol treated animals exhibited dose-dependent increases in activity levels similar to those of controls. Previous studies have shown that following chronic neuroleptic treatment, acute administration of apomor- phine or amphetamine can significantly elevate activity and stereotypy above control levels (Tarsy and Baldessarini 1974; Dustan and Jackson 1976; Smith and Davis 1976; Rebec et al. 1982). However, in these studies the neuroleptic was withdrawn for 2-10 days prior to behavioral assessment. These apparently conflicting res- ults may thus be accounted for by this methodological difference although it is possible that had still larger doses of cocaine been used, initial group differences in locomo- tor or stereotyped behavior might have been observed.

With repeated injections of cocaine (determinations 2-4), haloperidol treated animals exhibited significant increases in the amount (3.0 and 7.5 mg/kg) and duration (15.0 mg/kg) of locomotor activity in comparison to controls. This result indicates that when chronic haloperi- dol treatment was combined with repeated cocaine ad- ministration, neuroleptic treated animals exhibited signi- ficantly more rapid behavioral sensitization of locomotor activity. In comparison to the group differences in locom-

434

orion, both control and haloperidol treated animals show- ed similar and significant increases in stereotyped be- havior when repeatedly administered cocaine. Together, these results indicate that chronic treatment with haloper- idol does not block behavioral sensitization to concurren- tly administered cocaine and in the case of locomotion, actually facilitates its development.

Following short- (10 days) or long-term (56 days) withdrawal of haloperidol, differences in cocaine-induced locomotion between the Experimental and Control groups were maintained. Importantly, these results indi- cate that in addition to facilitating the sensitization of cocaine-induced locomotion, long-term maintenance of heightened locomotor and stereotyped responses was not altered by the termination of chronic haloperidol injec- tions.

The finding of no apparent difference between halo- peridol treated and control groups in the rate of sensitiza- tion of stereotyped behavior can be interpreted in a number of different ways. First, it may not be surprising in light of the relatively low doses of cocaine that were used. Other studies have used considerably larger doses of this drug to produce high levels of stereotypy (40 mg/kg and higher; Kuczenski et al. 1991). Alternatively, the lack of group differences may provide important clues about the neurophysiological substrate involved in cocaine-induced sensitization. As it is readily acknowledged that in rats, locomotion and stereotyped behavior elicited by cocaine and amphetamine are the result of increased dopaminer- gic neurotransmission in the mesolimbic and nigrostriatal dopamine systems, respectively (Randrup and Munkvad 1967; Costall and Naylor 1975; Creese and Iversen 1975; Kelly et al. 1975; Ho et al. 1977; Scheel-Kruger et al. 1977), this result suggests that at the doses used, the combination of chronic haloperidol and intermittent cocaine predom- inantly affected mesolimbic dopaminergic substrates. Ad- ministration of apomorphine prior to haloperidol with- drawal (determination 1) provided evidence consistent with this possibility.

In agreement with previous reports, a low dose of apomorphine (50 gg/kg) induced hypolocomotion in con- trol animals, presumably by reducing dopamine release (Imperato et al. 1988). In comparison, haloperidol treated rats exhibited increases in locomotor activity that were directly proportional to the length of initial treatment (determination 1). As it has been suggested that this reduction in activity in control rats occurs as a function of presynaptic autoreceptor stimulation (Skirboll et al, 1979) and that hatoperidol as well as other neuroleptics infused directly into the nucleus accumbens produces a similar antagonism of the activity reducing effects of apomor- phine (Van Ree et al. 1982; Radhakishun and Van Ree 1987), these results suggest that following co-administra- tion of haloperidol and cocaine, presynaptic receptors in the nucleus accumbens became less sensitive to apomor- phine.

The results of the initial administration of apomor- phine also support the finding that higher doses of this drug (t00 and 250 lag/kg) increase locomotion in normal controls rats (DiChiara et al. 1976). Increases in locomo- tor activity were also observed in the haloperidol treated

groups, but to a much greater degree than was seen in controls. Similar to the low dose of apomorphine, in- creases in locomotion were related to the length of halo- peridol treatment. As high doses of apomorphine affect primarily postsynaptic DA receptors (Skirboll et al. 1979), these results are suggestive that treatment with haloperi- dol induced changes in postsynaptic DA receptors such that they were more sensitive to the locomotor stimu- lating effects of apomorphine.

In contrast to the striking group differences in locomo- tor activity levels, apomorphine administration produced few differences in stereotyped behaviors among the treat- ment groups. While the high dose (250 gg/kg) produced longer lasting effects on apomorphine-induced stereotypy in all haloperidol groups, the overall level of these be- haviors did not differ from those of control animals. This lack of apparent group differences in stereotyped behavior following either cocaine or apomorphine, together with the consistent group differences in the locomotor response to these drugs, provides additional support for the conclu- sion that the combination of chronic haloperidol and intermittent cocaine predominantly affected mesolimbic dopaminergic substrates.

The relationship between the response to cocaine and apomorphine was further assessed following short- (18 days) and long-term (64 days) neuroleptic withdrawal. In comparison to the relative stability of group differences in cocaine-induced locomotion, the behavioral response to apomorphine changed at both of these time points. Injec- tions of 50 gg/kg apomorphine induced hypolocomotion in the experimental groups which was indistinguishable from that of controls. The hypolocomotion observed in control animals remained stable with repeated adminis- tration of apomorphine, demonstrating that the initial group differences in locomotion (determination 1, 50 lag/kg) were due to either chronic haloperidol treat- ment or a combination of haloperidol and cocaine, but not to long term cocaine administration alone. Thus, one possible interpretation of these results is that alterations in presynaptic sensitivity in haloperidol treated groups returned to control levels following termination of daily treatment. However, as haloperidol treated groups main- tained a heightened locomotor response to cocaine during this time, it seems unlikely that such putative, presynaptic changes were related to the maintenance of these group differences.

In contrast to this shift toward control levels seen at the lowest dose of apomorphine following termination of haloperidol treatment, group differences among Experi- mental and Control rats were largely preserved following administration of 100 and 250 gg/kg apomorphine even though control animals tended to exhibit increases in locomotion at the highest dose. The persistence of this heightened locomotor response in haloperidol treated groups corresponded to their maintenance of enhanced responsiveness to cocaine. These results thus provide behavioral evidence consistent with the possibility that increases in postsynaptic sensitivity to the locomotor stimulating effects of apomorphine were related to the observed differences between rats treated with chronic haloperidol and animals in the control group. Not sur-

435

prisingly, similarities in stereotypy induced by apomor- phine between the Experimental and Control groups persisted tbllowing termination of the neuroleptic.

It is also possible that the pattern of apomorphine- induced locomotion in haloperidol treated rats reflected only increases in postsynaptic receptor sensitivity. If this is indeed the case the immediate increases in locomotion observed at the lowest dose of apomorphine during deter- mination t may be viewed as similar to that occurring in later time bins following higher doses of this drug, but not masked by simultaneously occurring stereotypy (Lyon and Robbins 1975). However, this possibility seems un- likely given that only the group differences in apomor- phine-induced locomotion following high doses (100 and 250 ~tg/kg) were maintained following hatoperidol termin- ation, while the low dose differences were not. These results thus appear to be consistent with different mech- anisms underlying, respectively, the low and high dose patterns of apomorphine-induced locomotion observed in haloperidol treated rats across determinations 1-3. The pattern of locomotion elicited by apomorphine, both before and after neuroleptic termination, additionally sug- gested that the heightened responsiveness of haloperidol treated groups is at least partially mediated by en- hancements in postsynaptic receptor sensitivity.

It should also be noted that changes in the pharma- cokinetic properties of one or more of the administered drugs, caused by the combined drug treatment, may have contributed to the behavioral differences between halo- peridol treated and control groups. For example, Westerink and Horn (1979) demonstrated, in rats, that simultaneous administration (IP) of haloperidol and apomorphine resulted in significantly reduced brain levels of apomorphine, in comparison to animals that had re- ceived apomorphine alone (but see also, Kehr et al. 1975). The contribution of potential changes in the pharma- cokinetics of any of the administered drugs to the current results is unknown. However, it seems unlikely that a simple pharmacokinetic explanation could account for the complex behavioral effects observed in the present study, including the group differences in drug-induced locomotion as welt as the relative paucity of group differences in simultaneously obtained stereotyped behavior.

These results have direct relevance to understanding the heightened behavioral response to abused substances observed in psychiatric populations. They clearly indicate that when chronic treatment with haloperidol is combined with a regimen of cocaine use that approximates human patterns of abuse, the result is a marked enhancement of the behavioral effects of this psychostimulant. Equally as important, these results show that the behavioral response increases more rapidly than that observed following re- peated exposure to cocaine alone. As the behavioral re- sponse to stimulants is related to the rewarding properties of these drugs (Hill 1970; Rylander 1971; Wise and Bozarth 1987; Di Chiara and Imperato 1988; Pettit and Justice 1989; and for discussion see Robbins et al. t990) these results are suggestive that populations treated with chronic neuroleptics may be at a considerably higher risk for drug abuse.

Acknowledgements. This research was supported by a Center of Excellence grant from the State of Tennessee to the Psychology Department at Memphis State University and grant number 1R29DA07517-01 from N.I.D.A. to G.M.P.A.L. was supported by a Robert N. Vidulich award from the Psychology Department.

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