Haloperidol-induced vacuous chewing in rats: suppression by α-methyl-tyrosine

European Journal of Pharmacology, 211 (1992) 415-419

4

© 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00

EJP 52278

Haloperidol-induced vacuous chewing in rats: suppression by a-methyl-tyrosine M a r c o D i a n a , M a r i a Collu, A n n a M u r a a n d G i a n Luigi G e s s a 'B.B. Brodie' Department of Neuroscience, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy

Received 13 August 1991, revised MS received 13 November 1991, accepted 19 November 1991

Chronic treatment of rats with haloperidol (1 mg/kg twice daily for 4 weeks) induced repetitive vacuous chewing movemer (VC), that persisted for over 72 h after haloperidol withdrawal. Haloperidol-induced VC were inhibited by the s.c. administrati~ of the specific dopamine D 1 receptor antagonist, SCH 23390 (0.025-0.100 mg/kg), in a dose-dependent manner, and were total suppressed by an acute challenge with haloperidol (2 mg/kg i.p.) and by the dopamine synthesis inhibitor, a-methyl-tyrosil (AMT) (200 mg/kg i.p.). In AMT-treated rats, VC were reinstated by the administration of the selective D l agonist, SKF 3835 The results support the hypothesis that chronic haloperidol-induced VC are mediated by dopamine acting selectively upon I receptors. Vacuous chewing; Haloperidol (chronic); Tardive dyskinesia; Dopamine D j receptors

1. Introduction H u m a n tardive dyskinesia (TD) caused by chronic neuroleptic administration is characterized by involuntary movements of the lips, high frequency jaw movements and protrusions of the tongue (Clyne and Juhl, 1976; Klawans, 1973). Often this symptomatology becomes manifest when antipsychotics are reduced or withdrawn and is masked either when neuroleptic administration is reinstated or when the dose is significantly increased (Fann et al., 1982). Despite a rather high incidence in patients treated with antipsychotic medication, the pathogenesis of T D remains a matter of conjecture, According to a generally accepted hypothesis, T D is sustained by an increased dopaminergic (DA-ergic) activity in the striatum. This hypothesis is mainly based on animal studies showing that long-term treatment with neuroleptics results in D A receptor supersensitivity to the action of D A agonists and is associated with a persistent augmentation of the D 2 receptor number (see Tarsy and Baldessarini, 1977). However, it has been objected that such supersensitivity develops after a brief period of neuroleptic treatmerit whereas much longer treatments are needed for the occurrence of TD. In a search for an animal model of TD, there have been several reports that long-term treatment of rats

Correspondence to: M. Diana, 'B.B. Brodie' Department of Neuroscience, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy.

with neuroleptics induces an increase in spontaneo orofacial movements which emerge after w e e k s months of treatment. These tnovements have be~ termed, among others, vacuous chewing movemer (VC) because they are not directed onto any physic material (Waddington, 1990). Since VC, in appearanc resemble the bucco-lingual masticatory syndrome TD, they have been proposed as a model of the hum~ syndrome (see Waddington 1990). However, there is much controversy in literature to whether VC can be considered as a model of TI tardive dystonia, neuroleptic-withdrawal, dyskines etc. (Waddington, 1990). Moreover, the few studi that attempted to define the relationship between \ and abnormalities of DA-ergic function have provid, only inconclusive results (Waddington et al., 1983; S et al., 1989). The present study was aimed at further clarifyi the possible role of D A in VC induced by long-teJ treatment with haloperidol. We considered that clarifying the role of D A in t genesis of VC might also help in determining th~ relevance as a model of T D or other neuroleptic-i duced movement disorders in man.

2. Materials and methods Male S p r a g u e - D a w l e y CD rats (Charles Riv Como, Italy) with an initial weight of 250-350 g we housed in groups of six to eight per cage in a room

416 24°C and 60% relative humidity and maintained on a 12-h l i g h t / d a r k cycle. Food and water were available ab libitum. The rats were treated with haloperidol at the dose of 1 m g / k g i.p. twice daily at 9:00 a.m. and 9:00 p.m., for the times indicated under Results. The controls received an equal volume of saline (1 m l / k g i.p.). Rats were placed singly in Plexiglass cages (30 × 25 × 45 cm) once every 3 days from 11:00 to 12:00 a.m., with standard rat litter on the floor and allowed 1 h habituation before each behavioral observation of 30 min. Scoringwas performed by an observer blind to the treatment. The number of episodes of vacuous chewing was quantified during the 30 min observation, Each episode consisted in bursts of three to five masticatorymovements, lasting 2 - 5 s. Bursts were interspersed among variable periods of s or min duration without chewing movements. Masticatory movements were characterized by vertical and lateral jaw movements and occasional tongue protrusion in the absence of any chewable material in the rat's mouth. Due to the long habituation period, exploratory behavior during the observation period was almost absent, Haloperidol was obtained from commercially available ampoules (Serenase, Lusofarmaco, Italy) and diluted to a final volume of 1 m g / m l . The following drugs were used: SCH 23390 (R-(+)-8-chloro-2,3,4,5tetrahydro-3-methyl-5-phenyl-lH-3-benzazepine-7-ol) (RBI, Natick MA, U.S.A.); SKF 38393 (7,8-dihydroxy1-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine) (RBI). Solutions of drugs were made fresh in sterile saline and were injected s.c. 2 h after the last haloperidol administration. Behavioral observation began 15 min after treatment, a-Methyl-para-tyrosine methyl esther (AMT) (Sigma, St. Louis MO, U.S.A.) was injected i.p. 2 h after the last haloperidol administration and the animals were observed starting 15 min after treatment for up to 4 h. The statistical significance of the data was analysed using the Kruskal-Wallis non parametric analysis of variance (Zar, 1984). Specific comparisons between test groups were evaluated with the M a n n - W h i t n e y U-test (Mann and Whitney, 1947) where appropriate.

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Fig. 1. Time course of VC emergence following chronic haloperk administration(HAL) (N = 18) (1 mg/kg i.p., twice daily). Cont~ rats (N = 9) received corresponding injections of saline (SA] *,**.*** P = 0.002, < 0.002, < 0.0001, respectively, vs. St (Mann-Whitney U-test).

dose of 1 m g / k g (fig. 3). Furthermore, haloperidol-i duced VC were antagonized by the s.c. administrati( of the selective D~ receptor blocker, SCH 23390, in dose-dependent manner, the minimal effective do being 50 t z g / k g (fig. 4). Haloperidol-induced VC were completely su pressed by the i.p. administration of 200 m g / k g of tl catecholamine synthesis inhibitor, A M T (fig. 5). F( lowing the latter compound, a significant reduction VC occurred within 30 min after treatment and were totally suppressed from 60 min up to 4 h aft treatment. S.c. administration of 10 m g / k g of the selective I receptor agonist, SKF 38393, reinstated the VC whfl had been suppressed by A M T administration (fig. On the other hand SKF 38393 did not further increa VC in chronic haloperidol-treated rats (who had n

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Fig. 2. Persistence of VC after withdrawal from chronic h a l o p e r i ( (HAL). HAL-treated rats (N = 12) received haloperidol as report in fig. 1 for 3 weeks. Control rats (SAL) (N = 11) received cor spondingsaline injections. * P < 0.001 with respect to SAL (Man Whitney U-test).

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Fig. 3. Suppression of chronic haloperidol-induced VC by an acute challenge with haloperidol. Rats (N = 16) were treated with haloperidol 1 m g / k g i.p., twice daily for 28 days. Two hours after the last morning treatment, half the rats received an acute challenge with haloperidol, 2 m g / k g i.p. The other half received an i.p. injection of saline. Control rats (N = 9) received corresponding i.p. injections of saline. * P < 0.01 with respect to chronic hal + saline.

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SCH 23390 (#g/Kg) Fig. 4. Inhibition of haloperidol-induced VC by The D x antagonist SCH 23390. The rats were treated chronically with haloperidol as indicated in fig. 1. After one m o n t h of daily treatments, 2 h following the last morning dose, different groups of animals received SCH 23390 at the doses indicated. Chronically saline treated rats also received SCH 23390. The n u m b e r of cases was N = 9 and N = 9 for the 0 group; N = 4 and N = 4 for the 25 group; N = 6 and N = 6 for the 50 group and N = 4 and N = 4 for the 100 group. All numbers are for SAL and H A L respectively (see legend of fig. 1). * P < 0.01

(Mann-Whitney U-test). received AMT) and failed to elicit VC in rats chronically treated with saline (fig. 5).

4. Discussion In line with previous reports, we observed a slow and gradual increase in chewing movements during chronic administration of haloperidol, a slow reduction of this phenomenon after withdrawal and suppression of this symptomatology after increasing the dose of haloperidol (Stoessl et al., 1989; Ellison et al., 1988; Gunne et al., 1982; 1986).

AMT + SALINE

ANT + SKF

Fig. 5. Suppression of haloperidol-induced VC by A M T (200 m g / ] i.p. ** P < 0.001 vs. saline + saline ( M a n n - W h i t n e y U-test). Re statement of VC by the administration of the D 1 receptor agon SKF 38393 ( A M T + SKF). * P < 0.01 vs. A M T + saline; (Man Whitney U-test). The n u m b e r of cases was N = 9 for saline +sali] N = 8 for saline + SKF; N = 8 for A M T + saline; N = 5 for AMq SKF. Symbols as in fig. 1.

However, the emergence of increased VC in o study showed a time course similar to that observed Rupniak et al. (1985) but shorter than reported other studies (Stoessl et al., 1989; Ellison et al., 19~ and much longer than in the study of Rupniak et (Rupniak et al., 1986; Waddington, 1989; a~ Waddington, 1990, for reviews), The reason for tl discrepancy is not known. However it is known tl~ neuroleptic-induced orofacial movements vary, C pending on several factors such as the route of admJ istration, treatment schedule, testing environment a: even definition of the observed phenomenon (Wa dington, 1990). For instance, an inverse correlati between oral activity and gross motor behavior observed (Levy et al., 1987), and dose dependence x~ reported (Johanson et al., 1987) for haloperidol-J duced VC. Because of these inconsistencies, we have clea defined the orofacial movements observed, have hab uated the animals to the testing environment for a Io period (60 min) in order to reduce exploratory beh~ ior to a minimum and have used both a dose and schedule of haloperidol administration adequate reach high and persistent drug concentrations in t brain. Finally, we have observed the animals durin~ longer period (30 min) than in previous studies. C study has not definitely resolved the problem of t relevance of VC as an animal model of neuroleptic-: duced TD, dystonia, or other neuroleptic-induc movement disorder in man. Yet our results have p] vided further information on the role of DA in t mediation of the orofacial movements. The major fir ing of our study is that haloperidol-induced VC suppressed by the tyrosine hydroxylase inhibitor, A/~ suggesting that the activity of endogenous dopamine necessary for the expression of this behavioral s~.

418

drome. Moreover, the finding that AMT-suppressed VC are reinstated by the administration of the specific D 1 receptor agonist, SKF 38393, and that haloperidolinduced VC are inhibited by the D 1 receptor blocker, SCH 23390, supports the contention that D l receptor stimulation might underlie neuroleptic-induced orofa-

cial movements (Rosengarten et al., 1983). The f a c t t h a t t h e d o s e o f S K F 38393 (which r e i n stated VC in A M T - t r e a t e d rats) was ineffective to further increase these movements in haloperidoltreated rats or in saline-treated animals is puzzling. A possible explanation is that, since haloperidol inhibits O 2 preferentially to D l receptors, D 1 receptors are maximally stimulated by endogenous D A during chronic haloperidol treatment so that SKF 38393 can add little to it. On the other hand, the ineffectiveness of SKF 38393 given to control animals might be due to the fact that the stimulant effect of the O~ agonist is counteracted by endogenous D A acting antagonistically o n O 2 r e ceptors. Accordingly, it has been reported that D n agonists can induce orofacial m o v e m e n t s m o r e reliably in untreated animals when D 2 receptors are simultaneously blocked (Molloy et al., 1986; Molloy and Waddington, 1988; Murray and Waddington, 1989; Rosengarten et al., 1986; Johanson et al., 1987). The gradual and relatively slow emergence of VC (in relation to the animal's life-span), their relative persistence after treatment withdrawal, their suppression after increasing neuroleptic dosage, all suggest that the observed symptomatology might constitute a relevant model for T D in patients chronically treated with neuroleptics. Since our results have shown that VC are extremely sensitive to SCH 23390, a clarification of this problem might be offered by testing the efficacy of SCH 23390 directly in patients with TD. It is pertinent to mention that the acute intramuscular injection of 1 mg of SCH 23390 has recently been found to be effective to suppress the abnormal m o v e m e n t s in one patient with Huntington's chorea (Gessa et al., 1991), a condition that is considered to be associated, like TD, with increased DA-ergic activity in the basal ganglia (Tolosa and Sparber 1974).

Acknowledgement The expert technical assistence of Mr. Stefano Aramo is gratefully acknowledged,

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