Effects of Drugs Acting on Cerebral 5-Hydroxytryptamine Mechanisms on Dopamine-Dependent Turning Behaviour in Mice
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Br. J. Pharmac. (1976), 56, 77-85 EFFECTS OF DRUGS ACTING ON CEREBRAL 5-HYDROXYTRYPTAMINE MECHANISMS ON DOPAMINE-DEPENDENT TURNING BEHAVIOUR IN MICE J.A. MILSON Department of Pharmacology, University of Bristol Medical School, Bristol BS8 1TD C.J. PYCOCK Department of Neurology, Institute of Psychiatry, Denmark Hill, London SE5 8AF I The effects of drugs acting on cerebral 5-hydroxytryptaminergic mechanisms on drug-induced turning behaviour in mice with unilateral destruction of nigro-striatal dopaminergic nerve terminals have been studied. 2 Administration of L-tryptophan (400 mg/kg) or 5-hydroxytryptophan (200 mg/kg) increased brain 5-hydroxytryptamine and decreased the turning induced by both apomorphine (2 mg/kg) and amphetamine (5 mg/kg). 3 Parachlorophenylalanine (3 x 500 mg/kg) decreased brain 5-hydroxytryptamine and increased both apomorphine and amphetamine-induced circling behaviour. 4 Varying the protein content of dietary intake significantly altered brain 5-hydroxytryptamine and tryptophan levels, spontaneous locomotor activity and amphetamine-induced circling behaviour in these mice. 5 Systemic administration of methysergide (0.5-4 mg/kg), lysergic acid diethylamide (0.025- 0.2 mg/kg), cyproheptadine (2.5-20 mg/kg) or clomipramine (0.6-20 mg/kg) produced no consistent effect on drug-induced turning behaviour. 6 The results suggest that circling behaviour due to striatal dopamine receptor stimulation is depressed by an elevation of brain 5-hydroxytryptamine and enhanced by a reduction in brain 5- hydroxytryptamine. 7 The possible physiological relationship between dopamine and 5-hydroxytryptamine neurones in the basal ganglia is discussed. Introduction Recent behavioural studies have stressed an inter- terminals of the intact side and cause the animal to relation between 5-hydroxytryptamine'and the cate- circle towards the damaged'side. cholamine transmitters in the brain (Had£ovic & The basal ganglia is an area of the brain also rich in Ernst, 1969; Modigh, 1973a, 1974; Weiner, Goetz, terminals of 5-hydroxytryptamine neurones (Fuxe, Westheimer & Klawans, 1973; Jacobs, 1974; Jacobs, Hokfelt & Ungerstedt, 1968; Bak, Choi, Hassler, Eubanks & Wise, 1974). In rodents, an increase in Usunoff & Wagner, 1975). The close anatomical dopamine receptor activity in one striatum as relation between these two transmitter systems compared with the other causes the animal to turn in suggests a functional dependence; indeed 5-hydroxy- circles away from the side of higher activity (Anden, tryptamine has been shown to activate the release of Dahlstrom, Fuxe & Larsson, 1966; Ungerstedt, dopamine in the rat striatum (Besson, Cheramy, Feltz 1971). In rats with unilateral nigro-striatal degenera- & Glowinski, 1969) while dopamine receptor tion, but intact striatal dopamine receptors, directly stimulation increases cerebral 5-hydroxytryptamine acting dopamine agonists, such as apomorphine, turnover (Grabowska, Antkiewicz, Maj & Michaluk, induce circling away from the side of the lesion, 1973). because, it is suggested, the denervated receptors have In this study we have attempted to investigate the become supersensitive (Ungerstedt, 1971). Indirectly modulating role 5-hydroxytryptamine may exert on acting dopamine agonists, such as amphetamine, striatal dopamine function using the rotating mouse cause release of dopamine from the nigro-striatal model of von Voigtlander & Moore (1973), a system 78 J.A. MILSON & C.J. PYCOCK that directly involves the dopaminergic neurones of morphine (2 mg/kg) and 30 min after amphetamine the striatum. The effect of administering precursors of (5 mg/kg). The number of counts in one minute was 5-hydroxytryptamine such as tryptophan and 5- recorded for each group of mice and compared to the hydroxytryptophan, of p-chlorophenylalanine, an control values. inhibitor of tryptophan hydroxylase, and agents A further hour after counting, 10 mice from each of believed to block the 5-hydroxytryptamine receptor, the three groups were randomly selected and killed, has been studied on amphetamine and apomorphine- together with a group of 10 control animals, in order induced turning behaviour in mice with unilateral to determine brain 5-hydroxytryptamine levels. lesions of the nigro-striatal dopamine terminals. For other pharmacological manipulations, groups of 20 mice were marked into subgroups of four for an incomplete Latin square design in order to randomize the distribution of drugs. Mice were tested on three Methods separate days so that 12 observations were accumulated for each dose of drug. A saline-injected Animals control group was run on each occasion. Methy- sergide, in a dose range 0.5-4 mg/kg and cypro- Unilateral destruction of nigrostriatal dopamine heptadine, in a dose range 2.5-20 mg/kg, were terminals in male Swiss S strain mice was achieved by administered 15 min before amphetamine and 30 min direct injection of 6-hydroxydopamine in a dose of before apomorphine. Lysergic acid diethylamide 16 ,ug dissolved in 4 gl 0.9% w/v NaCl solution (LSD) was administered in a dose range (saline) containing 0.2 mg/ml ascorbic acid, into the 25-200 jig/kg 5 min before amphetamine and 20 min right striatum of a mouse under ether anaesthesia. The before apomorphine. technique used was that described by von Voigtlander In other experiments the effect of clomipramine in a & Moore (1973), as modified by Pycock, Tarsy & dose range 0.6-20 mg/kg was investigated on Marsden (1976) for free hand injection. Mice were submaximal turning in mice induced by 1.5 mg/kg tested 2 days after operation with dexamphetamine amphetamine. As before an incomplete Latin square sulphate (5 mg/kg) and those animals turning tightly design was used, and animals were tested on three towards the lesioned side were selected and tested at separate days. Clomipramine was administered intra- 10 days with apomorphine hydrochloride (2 mg/kg). peritoneally 30 min before amphetamine. Mice now turning away from the side of the lesion In a final series of experiments, the effect of a were selected for the following experiments. varying diet on the rate of turning induced by amphet- amine was studied. Twenty mice were fed for two weeks on laboratory pellets (Dixons, Diet 41B). Behavioural testing Throughout these experiments water was available ad lib. At the end of this period the mice were tested Three groups of 20 mice were used to investigate the on three separate days with amphetamine (5 mg/kg) effect of systemic administration of 5-hydroxytrypto- and divided into two equal groups so that the net phan (200 mg/kg), L-tryptophan (400 mg/kg) and p- turning rates of each group were the same. One group chlorophenylalanine methyl ester (3 x 500 mg/kg) on was fed high-protein (25%) pellets (Oxoid, breeding amphetamine and apomorphine-induced circling diet) while the other received a low protein diet behaviour. Ten mice from each group were randomly composed of apple and potato. The groups were then selected, marked and tested with apomorphine while tested weekly with amphetamine. Prior to amphet- the remainder were marked and tested with amine testing in the third week, spontaneous activity amphetamine. This enabled control turning rates of of the two groups was recorded in an Animex Activity each group of mice to be determined. This procedure recorder (LKB Farad Electronics). Following this was repeated after 48 h when all control rates were third amphetamine testing the diet of the two groups found to be within 10% of those obtained previously. was reversed, so that the low protein diet animals were On -the following day the 20-mouse groups were now fed high protein pellets and vice versa. Animals injected intraperitoneally with 5-hydroxytryptophan were tested again at weekly intervals with amphet- or L-tryptophan. The third group was injected three amine, and locomotor activity was recorded during times at 24 hourly intervals with p-chlorophenyl- the third week. At the end of this period mice from alanine. Amphetamine and apomorphine was both diet groups were fed their normal diet of administered to appropriate mice 30 min after 5- laboratory pellets (Diet 41B) and after one week the hydroxytryptophan or L-tryptophan and 16 h after the turning rate induced by 5 mg/kg amphetamine was final injection of p-chlorophenylalanine. After observed. To complete the experiment, the 20 mice injection of stimulant, all mice were placed in were randomly split into two groups again, fed the individual plastic boxes, measuring 12 x 12 x 8 cm. high and low protein diets for two weeks and then The number of complete revolutions made during a killed for brain biogenic amine and tryptophan one-minute period was recorded 15 min after apo- estimation. 5-HT AND TURNING BEHAVIOUR 79 a Apomorphine b Amphetamine 150r 150 0 0 125[ 125 100 L 100 -0) a2) C 75 i 75 50 P 50 0 T r 5 4- R H cP RI H 0 25 Y IT I^ 25 Y T *I c AI p a) C p 0 cJ tltn 25 25 ** U 50 a) 50 75 75 2 cc 100 c 1.2 100 I .0 125 ** 125 U) 2 L"I.0 150 a)1o.5 150 ** 0 ** 0 175 175 0 200 200 T ** Figure 1 Effect of pretreatment of unilateral striatal lesioned mice with p-chlorophenylalanine (3 x 500 mg/kg) (PCPA), L-tryptophan (400 mg/kg) (Tryp), and 5-hydroxytryptophan (200 mg/kg) (5-HTP) on forebrain 5-hydroxytryptamine (5-HT) levels and on (a) apomorphine (2 mg/kg) and (b) amphetamine (5 mg/kg)-induced turning behaviour. C denotes control group of animals, and results are expressed as a percentage of control. Mean turning rates for control group were 7.6 + 0.9, 30 min after amphetamine and 8.9 + 0.7, 1 5 min after apomorphine. Percentage means are shown for 10 observations of each drug. Vertical lines show s.e. mean. * Denotes statistical significance at the level P < 0.05.