~ ) Pergamon

Neuroscience Vol. 73, No. 1, pp. 121-130, 1996 Copyright © 1996 IBRO. Published by Elsevier ScienceLtd Printed in Great Britain S0306-4522(96)00036-X 0306-4522/96 $15.00 + 0.00

IMPAIRMENTS OF MOVEMENT INITIATION A N D EXECUTION I N D U C E D BY A BLOCKADE OF DOPAMINE D1 OR D2 RECEPTORS ARE REVERSED BY A BLOCKADE OF N-METHYL-D-ASPARTATE RECEPTORS W. H A U B E R University of Stuttgart, Institute of Biology, Department of Animal Physiology, Pfaffenwaldring 57, D-70550 Stuttgart, Germany A~traet--The effects of a dopamine D t or D 2 receptor blockade on initiation and execution of movements were examined using a simple reaction time task for rats. The task demands stimulus-triggered rapid initiation of locomotion to get a food reward. Time and force parameters of the transition from stance to gait were recorded allowing a detailed and separate analysis of the initiation and initial execution of locomotor initiation. Systemic administration of the preferential dopamine D2 antagonist haloperidol (0.1; 0.15 mg/kg, i.p.) caused a delayed movement initiation, as indicated by an increase in reaction time. In addition, movement execution was slowed, as measured by an increase in movement time, a decrease in the rate of development and in the maximum of the accelerative force component. Systemic administration of the selective dopamine D~ antagonist 7-chloro-8-hydroxy-3-methyl-l-phenyl-2,3,4,5-tetrahydro-lH-3benzazepine t~ydrochloride (SCH-23390) (0.15 mg/kg, i.p.) induced a similar pattern of impairments as haloperidol. Dizocilpine, an antagonist of the N-methyl-D-aspartate subtype of glutamate receptors in a dose which was largely ineffective when given alone (0.08 mg/kg, i.p.) reversed impairments of movement initiation and execution that were induced by the high dose of dopamine D~ or D~ antagonists (0.15 mg/kg, i.p., respectively). It is concluded that dopamine D~ and D 2 receptors are both involved in movement initiation and execution processes, which control the onset and speed of a conditioned movement, as shown here for locomotor initiation of rats. According to our results, the processes related to movement initiation and execution may be mediated by separate neuronal mechanisms, as there were no correlations between impairments of movement initiation and execution, regardless of the treatment animals received. The reversal of SCH 23390- and haloperidol-induced impairments by dizocilpine suggests a functionally antagonistic involvement of dopamine DI/D z and N-methyl-D-aspartate receptors in the control of movement initiation and execution. The results further imply that neuroleptics blocking dopamine D~ receptors probably induce similar extrapyramidal side effects as classical neuroleptics blocking dopamine D2 receptors. Copyright © 1996 IBRO. Published by Elsevier Science Ltd. Key words: movement initiation, movement execution, dopamine D~/D 2 receptors, glutamate, N-methyl-

o-aspartate receptors, rat.

A delayed response initiation and an increased response duration are major symptoms observed after a blockade of dopaminergic transmission. These deficits may account for many of the different m o t o r impairments induced by dopamine antagonists in rodents, e.g., akinesia, catalepsy, ~3 attenuated active avoidance responding, 3° deficient reaction time performance 2'23,36 and further disturbances of operant responding) z'14'15'17'35 A disturbed initiation and a slowed execution of movements have been linked predominantly to a disruption of the nigrostriatal dopamine system, since striatal infusion of dopamine antagonists or 6-hydroxydopamineAbbreviations: MT, movement time; NMDA, N-methyl-D-

aspartate; PF, peak force; RFD, rate of force development; RT, reaction time; SCH 23390, 7-chloro-8-hydroxy-3-methyl- 1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine hydrochloride. 121

induced depletion of striatal dopamine impairs response initiation in reaction time tasks. 22 Furthermore, lesions of the nigrostriatal dopamine system in experimental animals after 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine administration 34 or in Parkinson's disease x9 lead to severe motor disturbances characterized by deficits in reaction times (RT) and movement times (MT). The involvement of dopamine D~ and D 2 receptors in movement initiation and m o v e m e n t execution is poorly understood at present. D o p a m i n e D 2 receptors have been implicated consistently in both processes, because administration of dopamine D~ antagonists to rats impairs R T performance 3'23 and interferes with the execution of different movements. 1s,23 In comparison, little is known about the contribution of dopamine D~ receptors to motor control in operant tasks. Recent studies revealed that

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blockade of dopamine D l receptors with low doses of the dopamine D~ antagonist SCH 23390 did not affect the R T performance, 3 and had only moderate effects on the duration of limb m o v e m e n t in rats) 6 These results suggest functional differences between dopamine D 1 and D 2 receptors and indicate a preferential involvement of dopamine D2 receptors in m o t o r control. Functional differences between dopamine D~ and D2 receptors are of interest for several reasons. First, if a blockade of dopamine D~ receptors induces less pronounced m o t o r impairments than a blockade of dopamine D2 receptors, the use of dopamine D~ antagonists as neuroleptics may be associated with a reduced risk of extrapyramidal side effects. Secondly, differential impairments induced by a dopamine D 1 or D2 receptor blockade would have functional implications for direct and indirect striatal output pathways ~ which are important for the expression of striatal m o t o r functions and dysfunctions after a dopaminergic hypofunction. These two separate pathways are both modulated by striatal dopamine, however, their relative functional significance remains to be established. 8 If dopamine D 1 and D 2 receptors are segregated on the direct and indirect pathways as recently proposed, 18 an analysis of the participation of dopamine D~ and D2 receptors to movement initiation and execution may reveal possible functional differences of these pathways. In this study the relative contributions of dopamine D~ and D2 receptors to the initiation and execution of a rapid m o t o r response in rats were examined. D o p a mine receptors were blocked by the selective dopamine DI antagonist S C H 23390 or the preferential dopamine D2 antagonist haloperidol and an R T task was used which allows a detailed and separate analysis of m o v e m e n t initiation and execution. 21 The task demands stimulus-triggered rapid initiation of locomotion to receive a food reward. Time and force parameters of the transition from stance to gait were recorded, allowing for a precise characterization of drug effects on initiation and initial execution of this response. Dopaminergic and glutamatergic transmitter systems via N-methyl-o-aspartate ( N M D A ) glutamate receptor subtypes seem to interact in a functionally opposite way in m o t o r control. F o r instance, N M D A antagonists reverse impairments of spontaneous motor activity or catalepsy induced by dopamine antagonists or dopamine depletion. 33 The interaction of these transmitter systems with regard to the initiation and execution of complex movements is less well characterized. In recent studies the N M D A antagonist dizocilpine reversed deficient initiation 3'23'26 and execution 23 of movements induced by dopamine D2 antagonists, and there is some evidence that these m o t o r effects are brought about by glutamatergicdopaminergic interactions in the caudate-putamen. 6 Little is known about dopamine D ~ - N M D A receptor interactions in the control of movements and possible

similarities to dopamine D 2 - N M D A receptor interactions. Therefore we further investigated whether impairments of movement initiation and execution induced by a dopamine DI or D 2 receptor blockade are reversible by co-administration of the N M D A antagonist dizocilpine. EXPERIMENTAL PROCEDURES

Animals Male Spragu~Dawley rats (Interfauna, Tuttlingen, Germany) were housed in groups of three to four in a temperature-controlled colony room (23 +_2°C) with a 12 h light/dark cycle (lights on at 6.00 a.m.). They were gradually food-deprived by restricting standard laboratory rat chow (Altromin, Lage, Germany) to 11 g/rat/day. Water was continuously available. The weight range of the animals was 191-245 g at the beginning and 212-327 g at the end of the experiments. Apparatus The experiment was carried out in a modified runway as previously described. 21,22 The apparatus consists of a start box and a runway terminating in a goal box. The entrance to the runway can be locked with a remote controlled guillotine door situated, between start box and runway. The entrance is monitored by an infrared photocell beam (IDEC, Hamburg, Germany) horizontally mounted directly behind the guillotine door. A combined light (10 W)/tone (0.8 kHz, 40 dB) stimulus signalled the simultaneous opening of the front door. Below the start box a force platform was mounted to measure forces that an animal emitted during an operant response. The synchronization of stimulus presentation and front door opening was controlled by an interface (CED 1401, Cambridge, U.K.). This device also used an A/D converter for sampling force transducer output and photobeam signal (sampling rate: 1000 Hz). Data from each run was recorded and evaluated off-line, using appropriate software. Several measurements were taken from each run. RT was defined as latency between stimulus presentation and photobeam interruption. Only runs with RT in a range of 100-1000ms (termed as "correct runs") were evaluated to exclude inadequate responses, e.g., anticipatory responses. MT was defined as latency from photobeam interruption to the unloading of the force platform indicating that an animal left the start box. The force-time waveforms of the anterioposterior (horizontal) force component reflecting the animal's propulsion (and retropulsion) were also evaluated, and two drug-sensitive parameters were taken from force-time waveforms: peak force (PF), i.e., the maximum of the accelerative force, and the rate of force development (RFD), measured as a linear interpolation between time points of the last baseline crossing of the force-time waveform before RT and the PF value. Since drugs used here affect the rate of responding, the number of incorrect runs needed to complete 10 correct runs was counted. Ten incorrect runs were allowed as a maximum for each animal/session. Once 10 incorrect runs/animal per session were reached, the session was stopped and the ratio between the total of possible correct runs and performed correct runs per session was given as per cent success. The performance in the number of correct runs reached was compared with a corresponding number of control runs. Behavioural procedure The rats were trained for rapid initiation of locomotion in response to the stimulus to receive a food reward (two 45 mg food pellets; Noyes, Lancaster, U.K.), A gradually food-deprived rat was placed in the start box facing the closed guillotine door which blocks the entrance to the

D~ or D2 receptor blockade impairs initiation and execution of movements runway. After a variable delay (1-3 s) the stimulus signalled the simultaneous opening of the front door. A trained rat rapidly initiated locomotion, moved through the runway to the goal box and received the food reward in a baited cup. The rat was placed back in the start box for a new run once the pellets were eaten or 15 s had elapsed. After individual habituation to the baited apparatus, animals were trained one session/day. A session consisted of I0 consecutive runs. When rats had less than 5% incorrect runs/session they were tested for pre-experimental baseline stability for three consecutive days (criterion: nonsignificant changes of each parameter analysed by a one-way analysis of variance (ANOVA) with days as factor). Thereafter the experiment was started. Animals were used as their own controls due to pronounced interindividual baseline differences of the parameters. The experimental design was as follows: The animals were tested on three consecutive days each week. On each of these days two separate sessions with l0 runs/animal were performed. The first day, animals received two training sessions ("training day") which were not recorded. The second day ("control day") animals were tested in two sessions with saline injections, respectively. On the third day ("test day") animals were tested in a session with saline administration followed by a session with drug administration. Drug effects were detected by comparing performances in saline and drug sessions for a given test day. Since no significant performance differences were detected between saline sessions on control days (see Results), this procedure allowed a highly sensitive detection of drug effects. To avoid potential order effects of repeated injections, drug/dose combinations were assigned randomly to drug sessions.

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Drugs Haloperidol (Janssen, Neuss, Germany) was diluted in physiological saline and administered 30 min before the test. Dizocilpine (RBI, Cologne, Germany) was dissolved in saline and administered 30min before the test. R(+)SCH-23390 (R(+)-7-chloro-8-hydroxy-3-methyl- 1-phenyl2,3,4,5-tetrahydro-IH-3-benzazepine hydrochloride) (RBI, Cologne, Germany) was dissolved in physiological saline and administered 20 rain before the test. Drug doses refer to the respective salt. All drugs were administered intraperitoneally in volumes of 1 ml/kg. Saline injections (1 ml/kg, i.p.) served as controls.

Statistics Data from sessions of separate control and test days were analysed using a one-way ANOVA with days as factor followed by Tukey's protected t-test (two-tailed). Comparisons of data from saline/saline sessions of a given control day and from saline/drug sessions of a given test day were made using a paired t-test (two-tailed). The number of incorrect runs in saline and drug sessions and the success rates in saline and drug sessions were compared using the Mann-Whitney U-test (two-tailed). P _