Effects of amphetamine, morphine and dizocilpine (MK-801) on spontaneous alternation in the 8-arm radial maze

BEHAVIOURAL BRAIN RESEARCH ELSEVIER

Behavioural Brain Research 81 (1996) 53-59

Research report

Effects of amphetamine, morphine and dizocilpine (MK-801 ) on spontaneous alternation in the 8-arm radial maze Sabine M. H61ter 1,,, Thomas M. Tzschentke, Werner J. Schmidt Department of Neuropharmacology, Zoological Institute, University of Tfibingen, Mohlstr. 54/1, D-72074 Tfibingen, Germany Received 6 December 1995; revised 1 March 1996; accepted 1 March 1996

Abstract

The induction of psychomotor activation, behavioural sensitization and of perseverative behaviours, resulting in reduced behavioural variability, have been proposed to be common properties of drugs of abuse. The present investigation tested whether these drug effects could be measured using spontaneous alternation in an 8-arm radial maze. Behavioural effects of repeated treatment with amphetamine (2 and 4 mg/kg, i.p.), morphine (1.25 and 10 mg/kg, i.p.) and the non-competitive NMDA receptor antagonist, MK-801 (0.1 and 0.2 mg/kg, i.p.), on spontaneous alternation were evaluated in this paradigm. All drugs induced psychomotor activation. Sensitized as well as reduced locomotor activity could be observed after repeated treatment depending on drug and dose. Analysis of the sequences of arm entries revealed that all drugs induced perseverative locomotor patterns, but the pattern induced by amphetamine and morphine differed qualitatively from the pattern induced by MK-801. Keywords: Addiction; Amphetamine; Behavioural sensitization; Locomotion; MK-801; Morphine; Perseveration: Radial arm maze

1. Introduction

Addictive drugs have been presumed to share several behavioural effects, such as psychomotor stimulation[28] and behavioural sensitization, after repeated intermittent exposure [9]. The stimulant as well as the sensitizing drug actions have been proposed to be important for the development of addiction [20,28]. It has been speculated that drug-induced perseveration is another common property of drugs of abuse [15]. Loh and co-authors studied the acute effects of reinforcing and non-reinforcing drugs on the foraging pattern of rats in a continuously rebaited 8-arm radial maze. In order to detect and quantify drug-induced perseveration, two summary measures were calculated, an arm bias and a directional bias. The higher the bias scores, the less varied was the behaviour. This procedure revealed that acute administration of the reinforcing drugs amphetamine, heroin and nicotine, but not of the non-

* Corresponding author. 1Present address: Max-Planck Institute of Psychiatry, Clinical Institute, Kraepelinstr. 2, D-80804 Munich, Germany. E-mail: [email protected] 0166-4328/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved PII S01 66-4328 ( 9 6 ) 0 0 0 4 3 - 5

reinforcing drugs scopolamine or haloperidol, resulted in reduced behavioural variability. This might be due to the effect that behaviour that is ongoing at the time of drug onset is reinforced so that this behaviour is shown more frequently at the expense of other behavioural categories. Such an effect had previously been described for amphetamine, a psychomotor stimulant and functional dopamine agonist, increasing doses of which lead to "increasingly higher rates of activity, but in a decreasing number of response categories" [16]. This may account for 'habits' associated with drug-taking behaviour and might as well be an important aspect of the addictive process [ 15,17]. Dopaminergic mechanisms are involved in perseverative behaviours [19] as well as in the phenomena of psychomotor stimulation and behavioural sensitization. The neurochemical changes underlying behavioural sensitization involve the same pathways that have been implicated in the positive reinforcing and psychomotor stimulating effects of these drugs, i.e., the mesocorticolimbic dopamine system [24]. If it was characteristic of addictive drugs to reduce behavioural variability and to promote perseverative tendencies, this should be measurable in different kinds

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Sabine M. Hglter et al./Behavioural Brain Research 81 (1996) 53-59

of behaviour. Therefore the aim of the present study was to test whether drug-induced perseveration can also be observed in non-reinforced behaviours, i.e., when rats are spontaneously alternating in the 8-arm radial maze without food reinforcement. Spontaneous alternation refers to the tendency of rats to explore novel places sequentially and in succession [6], thus in a radial arm maze, rats tend to visit one arm, and then an adjacent arm. Because we wanted to know if repeated drug treatment had any effect on the parameters of interest, rats were tested on 5 consecutive treatment days. Amphetamine and morphine were used for this purpose because they are prototypic drugs of abuse and their reinforcing effects can primarily be attributed to their actions on dopaminergic neurotransmission [5,11,25]. We further tested the effects of MK-801, a non-competitive N M D A receptor antagonist with psychomotor stimulant actions in rodents [1,2,12,26] because its abuse potential has been discussed [3,8,14].

2. Materials and methods

2.1. Animals Male Sprague-Dawley rats (Interfauna, Tuttlingen, Germany), weighing 200-290 g at the start of the experiments, were used in this study. They were housed in groups of 4-8 per cage (macrolon, 56.6 × 35 x 19 cm) in a colony room which was maintained under constant temperature and humidity on a 12-h light/dark cycle (light phase 06.00-18.00 h). Food was restricted to 12 g per animal per day and water was freely available. Rats were allowed at least 2 weeks of habituation to the colony rooms before the start of the experiments which were conducted between 08.00 and 17.00 h.

2.2. Apparatus The 8-arm radial maze used in this study was constructed from plywood sealed with a brown synthetic surface. The arms (70× 17 x 35 cm) extended from a central octagonal platform measuring 50 cm in diameter. The maze was positioned in the centre of the floor of the testing room and a video camera was fixed to the ceiling above the maze to monitor the animals' activity.

2.3. Procedure Prior to the beginning of the experiments, rats were allowed to habituate to the maze for 2 days. On the first day, all animals of a cage were placed on the central platform of the maze and allowed to explore the maze together for 15 rain. On the second day, each rat was allowed to explore the maze individually for 5 min. After this habituation phase rats were assigned randomly to

one of the treatment groups and the experiment began. On 5 consecutive treatment days, rats were placed individually onto the central platform 30 min after the intraperitoneal injection of either amphetamine (2 or 4mg/kg), morphine (1.25 or 10mg/kg), MK-801 (0.1 or 0.2 mg/kg) or saline. Rats were allowed to move freely within the maze (spontaneous alternation) for 10 min and the experimenter recorded the sequence of arm entries via the video system. Locomotion into an arm was counted as arm entry only when the animal had entered the arm with all 4 paws.

2.4. Data analyses The number of arm entries was taken as a measure for forward locomotion. In order to evaluate perseverarive tendencies, two summary measures were calculated using the sequence of arm entries made in each trial (adapted from Loh et al. [15]): (a) Arm bias. A summary score of arm bias was calculated as: X/~ [arm,/number of arm entries] z, where arm, is the number of entries into a particular arm. This measure reflects the distribution of arm entries into specific arms. A higher arm bias score indicates a higher frequency of entries into a fewer number of arms, which represents an uneven distribution of locomotor activity across the maze. The minimum value that can be obtained is 0.35355 when each arm is visited once (i.e., the minimum bias value for any arm is 1 in 8), reflecting a uniform distribution of arm entries, whereas a maximum score of 1.0 would indicate perseverative re-entry into a single arm. (b) Angle bias. When leaving an arm, a rat has the option to either re-enter that arm (0 ° turn) or enter any of the remaining 7 arms, representing 4 different angles of turn (45 °, 90 °, 135 ° or 180 ° turn). A summary score reflecting the distribution of the angles of turn was calculated as: X/~ [turn,/number of turns] 2, where turn, is the number of turns made at a particular angle. A higher angle bias score indicates a higher frequency of turns made at fewer different angles. Angle bias scores range from 0.44721 to 1.0. Frequencies of angles of turn were compared as well in order to determine which particular angle of turn was preferred.

2.5. Drugs D,L-Amphetamine sulphate (Geyer GmbH, Stuttgart), morphine sulphate (Geyer, Renningen/Wuertt) and MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imin-hydrogenmaleat, Biotrend RBI,

Sabine M. HOlter et al./Behavioural Brain Research 81 (1996) 53-59

Krln) were dissolved in saline. Drug doses refer to weights of the respective salts. 2.6. Statistical analysis

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In figures, data are presented as means___ S.E.M. Data were analyzed with two-way analyses of variance (ANOVA) with repeated measures over days. The accepted level of significance was P < 0.05. When appropriate, ANOVAs were followed by Tukey's protected ttest for further analysis.

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3.1. Effects o f amphetamine on spontaneous alternation in the radial arm maze Amphetamine induced a marked increase in locomotor activity as indicated by the number of arm entries (Fig. 1A). Two-way ANOVA with repeated measures over days revealed a significant effect of treatment (F(2,66)=60.75, P<0.0001), a significant effect of day (F(4,264) = 2.55, P < 0.05) and a significant interaction between factors (F(8,264) = 9.48, P < 0.0001). Further analysis revealed that amphetamine-treated rats made significantly more arm entries than control animals on all treatment days. The locomotor stimulatory effect of amphetamine was dose-dependent from the second treatment day on, but not acutely. Furthermore, day 1 was significantly different from day 5 for all treatment groups, in detail the number of arm entries decreased in two groups (saline and amphetamine 4 mg/kg) and increased in the amphetamine 2 mg/kg group. Arm bias scores shown in Fig. 1B indicate that rats treated with the lower dose of amphetamine showed a higher frequency of entries into a fewer number of arms. Which set of arms was preferentially visited differed between individual animals. Two-way ANOVA revealed a significant effect of treatment (F(2,66)= 11.78, P<0.0001), a nonsignificant effect of day (F(4,264)=2.18, P=0.0713) and a significant interaction between factors (F(8,264)= 2.96, P <0.01). Further analysis revealed that arm bias scores of the lower dose group were significantly different from those of the vehicle group on all treatment days. For the higher dose group, this was only true for the first treatment day. Results for angle bias scores are shown in Fig. 1C. Two-way ANOVA revealed a significant effect of treatment (F(2,66)=3.50, P < 0 . 0 5 ) and a significant interaction between factors (F(8,264)=3.53, P<0.001). Post-hoc analysis revealed that treatment with the lower dose of amphetamine resulted in reduced angle bias scores in comparison to the control group on days 3-5. In order to illustrate the effects of repeated drug treatment on the locomotor pattern, the distribution of

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Fig. 1. Effects of acute and of repeated treatment with amphetamine (2 or 4 mg/kg) or saline on the number of arm entries (A), arm bias scores (B) and angle bias scores (C) during spontaneous alternation in the radial arm maze. *P<0.05, **P<0.01, significantly different from saline; ##P < 0.01, significantly different from the lower dose; n = 10-23.

the frequencies of the angles of turn on day 5 are presented in Fig. 4. Control animals (Fig. 4A) most frequently turned into adjacent arms, i.e. they preferred 45 ° turns, less frequently 90 ° turns, then 135 ° turns and 180 ° turns. They rarely re-entered the same arm (0 ° turns). This characteristic locomotor 'profile' of control rats spontaneously alternating in the radial arm maze is changed under the different repeated drug treatments as shown in Fig. 4B-D. For amphetamine treatment, 3-way ANOVA (treatment x angle x day) revealed a significant difference between frequencies of angles of turn (F(4,150) = 121.52, P < 0.0001 ), a significant interaction between angle xtreatment (F(8,150)=4.01, P<0.001) and a significant interaction between all 3 factors (F(32,600)=131.55, P<0.0001), which means that the treatment had a differential influence on the 5 possible angles of turn on different days. Post hoc comparisons revealed that rats treated with the lower dose of amphetamine (Fig. 4B) re-entered the same arm (0 ° turn) more frequently and adjacent arms (45 ° turn) less frequently than controls (Fig. 4A).

56

Sabine M. HOlter et al./Behavioural Brain Research 81 (1996) 53-59

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Fig. 2. Effects of acute and of repeated treatment with morphine (1.25 or 10 mg/kg) or saline on the number of arm entries (A), arm bias scores (B) and angle bias scores (C) during spontaneous alternation in the radial arm maze. *P<0.05, **P<0.01, significantly different from saline; #P <0.05, ~#P<0.01, significantly different from the lower dose; n=8-14.

3.2. Effects o f morphine on spontaneous alternation in the radial arm m a z e

The locomotor stimulatory effects of acute morphine administration (Fig. 2A) were less pronounced than those of amphetamine and MK-801. Two-way A N O V A with repeated measures over days for the number of arm entries of morphine-treated rats revealed a significant effect of treatment (F(2,39) = 3.81, P < 0.05), a significant effect of day (F(4,156)= 22.35, P < 0.0001) and a significant interaction between factors (F(8,156) = 7.56, P<0.0001). The lower dose of morphine produced a small increase in locomotor activity that was significantly above control levels on all treatment days. The higher dose of morphine significantly reduced the number of arm entries made on day 1, but on the following treatment days, tolerance developed to the sedative effect of this morphine dose. Further analysis revealed that day 1 was significantly different from day 5 for all treatment groups. Results for arm bias scores are shown in Fig. 2B. Two-way A N O V A revealed a significant effect

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Fig. 3. Effectsof acute and of repeated treatment with MK-801 (0.1 or 0.2 mg/kg) or saline on the number of ann entries (A), arm bias scores (B) and angle bias scores (C) during spontaneous alternation in the radial arm maze. **P<0.01, significantly different from saline; #P<0.05, ##P<0.01, significantly different from the lower dose; n= 9-12. of treatment (F(2,27)= 15.97, P<0.0001) and a significant interaction between factors (F(8,108) = 2.1, P <0.05). Further analysis revealed that arm bias scores for the higher dose of morphine were significantly above control levels on days 1, 4 and 5 and significantly above scores of the lower dose of morphine on all treatment days. Results for angle bias scores are shown in Fig. 2C. Two-way ANOVA with repeated measures over days revealed a significant effect of treatment (F(2,39)= 7.48, P<0.01), a significant effect of day (F(4,156)=10.69, P < 0.0001) and a significant interaction between factors (F(8,156)=3.48, p=0.001). Angle bias scores of morphine-treated rats were significantly lower than control levels on days 2-4. Moreover, day 1 differed significantly from days 4 and 5 for both morphine doses. The effects of repeated morphine treatment on the locomotor pattern are shown in Fig. 4C. Three-way ANOVA for the frequencies of the angles of turn with repeated measures over days (treatment x angle x day) revealed a significant difference between frequencies of angles of

Sabine M. Hrlter et al./Behavioural Brain Research 81 (1996) 53-59

turn (F(4,135) = 271.16, P < 0.0001 ), a significant interaction between treatment xangle (F(8,135)=7.87, P < 0.0001), a significant interaction between angle x day (F(16,540)=5.96, P<0.0001) and a significant interaction between all three factors (F(32,540)=4.41, P<0.0001). Further analysis showed that morphine treatment reduced the frequency of 45 ° turns. 3.3. Effects o f MK-801 on spontaneous alternation in the radial arm maze

Acute administration of MK-801 induced a dosedependent increase in the number of arm entries (Fig. 3A). This effect persisted over the 5 consecutive treatment days. Two-way ANOVA with repeated measures over days revealed a significant effect of treatment (F(2,28)=20.81, P<0.0001), a significant effect of day (F(4,112)=4.52, P < 0 . 0 1 ) and a significant interaction between factors (F(8,112)=2.33, P<0.05). Further analysis revealed that all treatment groups were significantly different from each other on each treatment day. Furthermore, for the higher dose of MK-801, day 1 was significantly different from days 4 and 5. For the lower dose of MK-801, day 1 was significantly different from day 2. Arm bias scores did not differ significantly across treatment groups (Fig. 3B). Treatment with the higher dose of MK-801 induced an increase in angle bias scores (Fig. 3C). Two-way ANOVA revealed a significant effect of treatment (F(2,28) = 4.19, P < 0.05) and a significant interaction between factors (F(8,112)= 2.32, P <0.05). Post hoc tests revealed that angle bias scores for the higher dose of MK-801 differed significantly from those of the two other groups on days 4 and 5. Threeway ANOVA with repeated measures over days (treatment x angle x day) revealed a significant difference between frequencies of angles of turn (F(4,140)= 125.2, P < 0.0001 ), a significant interaction between treatment x angle (F(8,140)= 8.34, P < 0.0001 ), and a significant interaction between all 3 factors (F(32,560)= 1.61, P<0.05). Further analysis showed that treatment with MK-801 dose-dependently reduced the frequency of 45 ° turns. The higher dose of MK-801 induced an increase in the frequency of 90 ° and 135 ° turns. There was no significant effect on the frequency of 0 ° and 180 ° turns. These results are demonstrated in Fig. 4D.

4. Discussion All 3 substances changed the locomotor pattern of rats spontaneously alternating in an 8-arm radial maze and induced perseverations, but in different ways. Amphetamine treatment resulted in increased arm bias scores representing an uneven distribution of locomotor activity across all 8 arms, i.e. the animals' activity was preferentially focussed on a sector of the maze.

57

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Fig. 4. Distribution of the frequencies in % of the angles of turn under each treatment on the fifth treatment day. (A) saline, (B) amphetamine (2 mg/kg), (C) morphine (10 mg/kg), (D) MK-801 (0.2 mg/kg), n = 7-12.

Interestingly, with repeated drug injections only treatment with the lower dose continued to be effective in this regard. However, the way rats alternated between the arms of that sector of the maze, reflected by angle bias scores, was rather more evenly distributed than in control animals that preferred to alternate between adjacent arms (45 ° turns). Amphetamine treated rats frequently re-entered the same arm, but not to a degree that this became a strongly preferred angle of turn. These results are consistent with previous reports of perseverative locomotor patterns induced by amphetamine in rats [ 13,15,21,22], but the present results differ from those obtained by Loh and co-authors concerning the kind of perseverative locomotor pattern. After treatment with reinforcing drugs, Loh and colleagues observed an enhancement of the initial directional bias with which the animals explored the maze for food reinforcement. They did not observe an arm bias. This difference might be due to the fact that trained maze exploration for food and non-reinforced spontaneous alternation are different behavioural qualities, because the animals enter the arms for different reasons. This difference in motivation might result in different locomotor patterns that are differentially influenced by reinforcing drugs. It has been suggested that a tendency to perseverate among a few stimuli represents a sensory or 'attentional' perseveration, whereas a turning bias represents the performance of a consistent motor pattern, i.e., a motor

58

Sabine M. Hb'lter et al./Behavioural Brain Research 81 (1996) 53 59

effect [10]. According to this hypothesis, in the present experiment, amphetamine treatment induced an attentional perseveration without inducing a motor bias, because animals perseverated among a few arms of the maze reflected by increased arm bias scores, but not in a fixed motor pattern, reflected by rather lowered angle bias scores. The morphine results can be interpreted in the same way. Morphine treatment resulted in increased arm bias scores and reduced angle bias scores, indicating an attentional perseveration without motor fixation. In contrast, the kind of perseverative locomotor pattern observed under MK-801 treatment differed from that induced by the psychostimulant and the opiate. MK-801 treatment resulted in increased angle bias scores at the higher dose and a substantial shift towards higher angles of turn without any change in arm bias scores. These results suggest that the higher dose of MK-801 induced the performance of a fixed motor programme without inducing any attentional preference. This supports a recent suggestion by Dai and Carey [4] that the hyperlocomotion induced by blockade of NMDA receptor mediated glutamatergic transmission by MK-801 becomes progressively disconnected from the guidance by exteroceptive stimuli. These authors argued, that intact glutamatergic neurotransmission mediating sensory information about the external world is important for the generation of adequate motor responses. Hence, blockade of glutamatergic transmission by MK-801 would impede this flow of information so that response mechanisms would have a diminished linkage to exteroceptive stimuli. The perseverative hyperlocomotion induced by MK-801 appears to be due to the simple driving of the motor system while sensorimotor integration is disrupted, in contrast to the effects of amphetamine [28]. Furthermore, all 3 substances tested had acute psychomotor stimulant actions that became modified by repeated treatment. Amphetamine had a pronounced stimulating effect on locomotor activity. This effect became dose-dependent from the second treatment day on with the lower dose inducing higher levels of activity than the higher dose of amphetamine. Control animals habituated to the testing procedure, whereas repeated treatment with the lower dose of amphetamine resulted in a significant increase of locomotor activity, indicating that behavioural sensitization to the stimulating effects of this drug dose had occurred. In contrast, although the acute effects of both doses were indistinguishable, repeated treatment with the higher dose of amphetamine resulted in a significant decrease of locomotor activity, indicating that behavioural tolerance to the stimulating effects of this drug dose had occurred. This might be due to the effect that for low doses of amphetamine locomotion is the predominant response, whereas for intermediate doses locomotion is interrupted by brief

episodes of stereotyped behaviours, e.g., sniffing, which gradually restricts gross whole-body locomotor activity [ 16,23 ]. Thus, reduced locomotor activity after repeated treatment might have been due to an increase in smaller repetitive movements. This is also a possible explanation for the observation that arm bias scores are not elevated under the higher dose of amphetamine either. Because smaller repetitive movements become the predominant response with repeated treatment with the higher dose of amphetamine, this might interfere with or counteract perseverative tendencies in the overall locomotor pattern that is measured by arm bias scores. The stimulant actions of morphine were less pronounced than those of amphetamine. Nevertheless, locomotor activity increased with repeated treatment for both doses, indicating the development of behavioural sensitization to the stimulating effects of the lower dose and behavioural tolerance to the acute sedative effects of the higher dose. MK-801 had a dose-dependent stimulatory effect comparable to that of amphetamine. After repeated treatment with the higher dose of MK-801 locomotor activity decreased, indicating the development of behavioural tolerance to the acute stimulatory effects of this dose. Taken together, the results presented showed that psychomotor activation, behavioural sensitization and drug-induced perseveration were measurable in spontaneous alternation in an 8-arm radial maze. Moreover, the present results suggest that the differentiation between arm bias scores and angle bias scores can be used to detect different kinds of perseverative locomotor patterns. The difference in the kind of perseverative locomotor patterns induced by the 3 substances tested in this study might be explained by the fact that the reinforcing effects of the functional dopamine agonist amphetamine as well as of the opiate morphine can primarily be attributed to their actions on dopaminergic neurotransmission [5,11,25], whereas the highly selective non-competitive NMDA receptor antagonist MK-801 acts primarily through influencing glutamatergic neurotransmission [27] and acts only indirectly and in high doses through influencing dopaminergic neurotransmission [7,18]. This might be a reason for the equivocal results in other paradigms concerning the discussion of the abuse potential and the rewarding properties of MK-801 [3,8,14]. In summary, the observation of drug-induced perseveration under non-reinforced conditions supports the speculation that this might be another common property of drugs of abuse.

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