Abstract. The behavioural effects of increasing doses of apomorphine and haloperidol were observedin a group of six marmosets. Behaviour was classified ...
Psychopharmacology
Psychopharmacology 66, 41-43 (1979)
9 by Springer-Verlag 1979
Interaction of Apomorphine and Haloperidol: Effects on Locomotion and Other Behaviour in the Marmoset P. R. Scraggs, H. F. Baker, and R. M. Ridley Division of Psychiatry, Clinical Research Centre, Watford Road, Harrow, Middlesex, HA1 3UJ, England
Abstract. The behavioural effects of increasing doses of apomorphine and haloperidol were observedin a group of six marmosets. Behaviour was classified quantitatively into categories: Locomotion, inactivity, checking (small head movements), social interaction and purposeful activities. Statistical analysis revealed that apomorphine had a stimulant effect on checking and locomotion which could be antagonized by haloperidol. Activities and social contact were severely reduced by both apomorphine and haloperidol. Inactivity was increased by the lowest dose of apomorphine in otherwise untreated animals. It is suggested that haloperidol antagonizes the stimulant effects of apomorphine but is synergistic to its suppressant effects, and that the low dose effect o f a p o m o r p h i n e on inactivity is mediated by a mechanism which may be different from that acted upon by haloperidol. Key words: Dopamine Marmosets
Apomorphine Locomotion -
Haloperidol Social interaction -
of several weeks, amphetamine causes a decrease in locomotion as well as other behavioural changes (Ridley et al., 1978). In other primate species, amphetamine has been reported both to increase (Isaac and Troelstrup, 1969) and decrease (Alexander and Isaac, 1965) the amount of locomotion. AP has not been studied extensively in the primate: Shintomi and Y a m a m u r a (1975) report AP-induced stereotyped behaviour in cynomolgus monkeys, although locomotion was not measured in that study. We have previously reported that propranolol and diazepam decrease locomotion in amphetaminetreated marmosets but not in otherwise untreated animals, while aceperone (an c~-noradrenergic blocker) decreases locomotion in normal marmosets but not in amphetamine-treated animals. Haloperidol reduces locomotion in either condition (Scraggs and Ridley, 1979). This interaction of drug effects implies a complex determination o f the degree of locomotion in the primate. To investigate further the role o f D A in locomotion and other behaviours we have looked at the interaction of AP and haloperidol in the marmoset.
Materials and Methods In rodents, amphetamine and apomorphine (AP) cause an increase in locomotion (Lyon and Robbins, 1975; Ernst 1967). Since amphetamine facilitates the release of dopamine (DA) and noradrenaline (NA) in rat brain (Groves and Rebec, 1976), while AP is a direct DA receptor stimulant (And6n et al., 1967), it has been suggested that these behavioural effects are mediated by DA. In the marmoset (a small New World primate) we have found that acutely administered amphetamine (Scraggs and Ridley, 1978) does not cause a change in locomotion although there is an increase in small head movements (checking). When given orally over a period
Subjects and Apparatus. The subjects were captive-born adolescent marmosets (three male, three female) weighing 250-300 g each. They were housed together in a large perspex-sided cage (70 • 70 x 80 cm), containing food, water and wooden perches, in a room with other cagedmarmosets.The averagetemperature was 24~C. The animals wereobservedthrough a small aperture 3 m from the cage. Drug Administration. Doses of 0.063, 0.25 and 0.75 mg/kg AP were made up in 0.9 % sodium chloride and injected into the thigh muscle in volumesof 0.1 - 0.2 ml. Doses of 0.03 and 0.18 mg/kg haloperidol were similarly injected. One dose of each drug (or saline control injection) was administered on alternate weekdaysto the six animals in a balanced design within and across days. On any one day, three drug combinationswereadministeredto the six animalssuch that two animals received each combination. The observer was not aware of each animal's drug combination. Animals were injected first with
0033-3158/79/0066/0041/$01.00
42
Psychopharmacology 66 (1979)
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Fig, 1. Effects of haloperidol and apomorphine on behaviour 18 - 66 min after injection of apomorphine. Ordinate shows proportion of time per five observations as ~ of total time _+ SEM: 9 Saline; [] 0.063 mg/kg, m 0.25 mg/kg, and [] 0.75 mg/kg apomorphine; 9 P < 0.05 and 9 9 P < 0.01 where each dose ofapomorphine alone was comparedwith saline control conditions; x P < 0.05, x x P < 0.01, and x x x P < 0.001 where each combined treatment of haloperidol and apomorphine was compared with each appropriate dose of apomorphine alone using a twotailed matched pair t-test (df= 5)
haloperidol (or saline) followed after 30 rain by AP (or saline). For each drug animals were injected at 1-min intervals and subsequently observed in the same order.
Observation of Behaviour. Using a metronome, behaviour occurring in each second over blocks of 50 s for each animal was classified into five mutually exclusive categories! (1) Checking (movement of the head only); (2) activities (movement of only part of the body, excluding head only, such as eating, drinking and self-grooming and other actions of unknown purpose, e.g. manipulation of objects); (3) contact (physical contact between two animals including grooming, fighting, play and sexual activity); (4) locomotion (displacement of the whole body); and (5) inactivity (no discernable movement). Readings of 50-s duration for each animal were taken once before the first injection, then at 12-rain intervals for 1 h commencing 6 rain after the second injection, followed by four further readings in the subsequent 4 h. The numbers of 1 s counts/50 s of each behavioural category indicates the strength of that behaviour at the time the reading was taken. This method of assessment of behaviour may be considered both sensitive and reliable; using this method we have previously been able to demonstrate a 2:1 difference in potency between the d- and/-isomers of amphetamine (Scraggs and Ridley, 1978) occurring consistently over time. Behavioural effects of the disomer in that study agree closely with the effects of d-amphetamine observed independently in other marmosets by R.M.R. (Ridley et al., 1979).
Results and Discussion
The dose-dependent effects of AP in haloperidol- and saline pretreated animals in the five behavioural cate-
:gories are shown in Fig. 1. The means of scores obtained in the five observations 1 8 - 6 6 rain after the second injection have been calculated to demonstrate the main effect of these drugs. The categories of activities and social contact have been combined since scores on both were low and fell during any drug treatment. Statistical comparison has been made between doses of AP and saline and between combined doses of haloperidol and AP and the appropriate AP alone condition using a two-tailed matched pair t-test in each case. Locomotion. In saline-pretreated animals AP caused a dose-dependent increase in locomotion ( P < 0.01 at 0.75 mg/kg AP). Both doses of haloperidol caused a decrease in locomotion in saline-pretreated animals (P < 0.05 at 0.03 mg/kg, P < 0.01 at 0.18 mg/kg) and, comparing each combined treatment with haloperidol and AP against the appropriate AP alone condition, an overall decrease in locomotion was also seen. Thus haloperidol not only reduced locomotion in normal animals but also antagonized AP-induced locomotion suggesting that these effects may be mediated by DA. It cannot, therefore, be inferred from the lack of effect of amphetamine on locomotion in the marmoset that this behaviour is not under dopaminergic influence in this species. It is possible that the slow release of DA by
P. R. Scraggs et al. : Apomorphine and Haloperidol: Effects on Locomotion in the Marmoset
43
amphetamine allows compensatory effects to act in preventing an increase in locomotion, or that amphetamine has other effects which counteract any potential increase in locomotion mediated by dopaminergic activity. The effect of AP on DA receptors may be too rapid or too specific to activate compensatory mechanisms. Alternatively, amphetamine and AP may exert their effect preferentially at different anatomical sites concerned with different behavioural functions in the primate while exerting more similar effects when applied systemically to the less well differentiated rodent brain.
the stimulant effect of AP and the suppressant effect of haloperidol strongly suggest that DA is involved in determining the degree of locomotion in the primate. The differing dose effects of AP and the interaction of AP and haloperidol on the various forms of behaviour measured in this study imply that, while DA may be involved in all these behaviours, the mechanisms or site of its action may differ in each case. This offers the potential of the differential control of these aspects of DA function in the primate by drug treatment.
Checking. AP caused a dose-dependent increase in checking (P < 0.01 at 0.25 and 0.75 mg/kg) while haloperidol caused a dose-dependent decrease (P < 0.05 at 0.03 mg/kg, P < 0.001 at 0.18 mg/kg). Haloperidol and AP acted antagonistically since, for each dose of haloperidol, increasing doses of AP brought about an increase in the amount of checking.
References
Activities and Contact Between Animals. Activities and social contact were reduced by AP in saline-pretreated animals (P < 0.01 at 0.25 and 0.75 mg/kg). Although the low dose of haloperidol alone did not cause a significant decrease in activities and contact, combined treatment with haloperidol and AP suppressed these behaviours a/most completely. It Would appear that AP does not reduce activities and contact merely as a consequence of stimulating checking and locomotion since blocking this stimulation with haloperidol does not restore activities and contact. Furthermore, activities and contact were reduced at the lowest dose of AP when neither locomotion nor checking were significantly increased. Inactivity. Inactivity was increased by AP alone only at its lowest dose ( P < 0.05 at 0.063 mg/kg). At tbis dose AP did not exert a significant stimulant effect on checking or locomotion although activities and contact were reduced. It is thus possible that AP exerts a suppressant effect on behaviour when given in low doses. Sedative effects of low doses of AP have been reported in rodents (di Chiara etal., 1976) and man (Corsini et at., 1977). Each dose of haloperidol caused an increase in inactivity. There is little indication of antagonism of this effect by AP. There is also no summation of the effects of the low dose of AP and haloperidol despite the increase in inactivity caused by both drugs alone. Possibly different neural mechanisms are involved in each case~ In conclusion, it may be said that despite the lack of effect of amphetamine on locomotion in the marmoset,
Alexander, M., Isaac, W~: Effects of illumination on the activity of the rhesus macaque. Psychol. Rep. 16, 311-313 (1965) And+n, N., Rubenson, A., Fuxe, K., Hokfelt, T.: Evidence for dopamine stimulation by apomorphine~ J. Pharm. Pharmacol. 19, 627-628 (1967) di Chiara, G., Proceddu, M. L., Vargui, L., Argiolas, A., Gessa, G. L. : Evidence for dopamine receptors mediating sedation in the mouse brain. Nature 264, 565-567 (1976) Corsini, G. U., Del Zompo, M., Marconi, S., Piccardi, M. P., Onali, P. L., Mangoni, A. : Evidence for dopamine receptors in the humari brain mediating sedation and sleep. Life Sci. 20, 16131618 (1977) Ernst, A. M. : Mode of action of apomorphine and dexamphetamine on gnawing compulsion in rats. Psychopharmacologia 10, 316323 (1967) Groves, M., Rebec, O. V.: Biocheraistry and behaviour: Some central actions of amphetamine and antipsychotic drugs. Am. Rev. Psychol. 27, 91-127 (1976) Isaac, W., Troelstrup, R. : Opposite effect of illumination and damphetamine upon activity in the squirrel monkey (Saimiri) and the owl monkey (Aotes). Psychopharmacologia 15, 260-264 (1969) Lyon, M., Robbins, T.: The action of central nervous system stimulant drugs: A general theory concerning amphetamine effects. Curr. Dev. Psychopharmacol. 2, 80-163 (1975) Ridley, R. M., Baker, H. E., Crow, T. J.: Behavioural effects of amphetamines and related stimulants: The importance of species differences as demonstrated by a study in the marmoset. [n: Amphetamine and related stimulants: Chemical, biological, clinical and sociological aspects, J. Caldwell ed. Ohio: CRC Press, in press, 1978 Ridley, R. M., Baker, H. F., Scraggs, P. R. : The time-course of the behavioural effects of amphetamine and their reversal by haloperidol in a primate species. Biol. Psychiatry, in press (1979) Scraggs, P. R., Ridley, R. M. : Behavioural effects of amphetamine in a small primate: Relative potencies of the D- and L-isomers. Psychopharmacology 59, 243-245 (1978) Scraggs, P. R., Ridley, R. M.: The effect of dopamine and noradrenaline blockade on amphetamine-induced behaviour in the marmoset. Psychopharmacology 62, 4 1 - 4 5 0979) Shintomi, K., Yamamura, M. : Effects ofpenfluridol and other drugs on apomorphine-induced stereotyped behaviour in monkeys. Eur. J. Pharmacol. 31, 273--280 (1975) Received April 20, 1979
