Rolipram, a selective c-AMP phosphodiesterase inhibitor suppresses oro-facial dyskinetic movements in rats

Life Sciences, Vol. 56, No. 25 pp. PL 443-447,1995 Copyright 0 1995 Elsevier Science Ltd Printed in the USA. All rights reserved CKm-32rJ5/95$950 t .@I

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ROLIPRAM, A SELECTIVE C-AMP PHOSPHODIESTERASE SUPPRESSES ORO-FACIAL DYSKINETIC MOVEMENTS Hajime Sasaki’, Kenji Hashimoto’,

INHIBITOR IN RATS

Yohko Maeda’, Toshiya Inada’, Yoshie Kitao’, Susumu Fukui’ and Masaomi Iyo’

‘Division of Drug Dependence and Psychotropic Drug Clinical Research and division of Geriatric Mental Health, National Institute of Mental Health, National Center of Neurology and Psychiatry, l-7-3, Kohnodai, Ichikawa, Japan. (Submitted February 13, 1995; accepted March 1, 1995; received in final form March 17, 1995) Abstract. Since striatal dopamine D2 receptor supersensitivity in the etiology of tar-dive dyskinesia has been suggested and dopamine D2 receptors are known to inhibit adenylate cyclase activity resulting in a decrease of cyclic adenosine 3’,5’-monophosphate (CAMP) levels, we hypothesized that an increase in CAMP levels ameliorates the condition. In the present study, 21-day haloperidol treatment (1.5 mg/kg I.P.) in rats resulted in an increase in striatal [?-I]-spiperone (D2) binding whereas [%I] SCH23390 (Dl) binding was unaltered. This haloperidol treatment also induced a significantly increase in the frequency of involuntary chewing movements and tongue protrusions, which ate considered as a model of tat-dive dyskinesia. These dyskinetic movements were suppressed by administration of rolipram (0.5 and 1.0 mg/kg I.P.), an inhibitor of the CAMP phosphodiesterase type IV. The present results suggest that selective CAMP phosphodiesterase type IV inhibitors could be putative therapeutic drugs for tardive dvskinesia. Key Words

tardive dyskinesia, CAMP, phosphodiesterase,

rolipram

Introduction Long-term administration of neuroleptics in man has the potential to cause tardive dyskinesia (TD), which is characterized by involuntary oro-facial movements (1). No reliable therapy for this disorder has yet been established, despite extensive research (2). In rats, long-term treatment with neuroleptics induces purposeless spontaneous oro-facial movements. As the characteristics of these movements and the time-course of their appearance resemble those observed in human TD, these movements have been considered as a putative model of TD (3). It has been reported that long-term administration of haloperidol, predominant dopamine D2 antagonist, increases the number of dopamine D2, but not Dl, receptors in the striata of rats (4) and stimulation of dopamine D2 receptors has been demonstrated to decrease cyclic adenosine 3’,5’-monophosphate (CAMP) levels through the inhibition of adenylate cyclase (5). It has been reported that rolipram (6), a selective Correspondence: Dr.M.Iyo, Division of Drug Dependence and Psychotropic Drug Clinical Research, National Institute of Mental Health, National Center of Neurology and Psychiatry, l-7-3, Kohnodai, Ichikawa, Chiba 272, Japan.

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CAMP phosphodiesterase (PDE) type IV inhibitor (7), increases CAMP levels in the sniatum by inhibition of CAMP metabolism. Therefore, we hypothesized that an increase in the number of striatal dopamine D2 receptors following long-term administration of neuroleptics may decrease striatal CAMP levels, which would cause oro-facial dyskinetic movements, and that rolipram may reverse the change in CAMP levels and alleviate these movements. In order to explore this hypothesis, we examined the effects of rolipram on involuntary oro-facial movements in rats daily treated with haloperidol for 21 days.

Materials and Methods &&ects

and Drups

Male Sprague-Dawley rats (320-370 g) were housed under 12-h light/dark cycle conditions. Haloperidol (1.5 mg/kg) dissolved in distilled water with the minimum possible quantity of acetic acid, or the vehicle only, was injected intraperitoneally (I.P.) into the rats once a day for 21 days. Rolipmm (Meiji Seika Kaisha, Ltd., Tokyo, Japan) was suspended in physiological sodium chloride solution containing 10% w/v Cremophor ELR ( polyethoxylated castor oil). Both [?I]-SCH23390 (80.4 Ci/mmol) and [%I-spiperone (17.5 Ci/mmol) were purchased from New England Nuclear, Boston, MA, USA. All the other chemicals used were purchased from commercial sources. Assessment of snontaneous

oro-facial movements

All behavioral testing was conducted 96 h after the final haloperidol or vehicle injection. The animals were placed singly in transparent plexiglass cages (25cm x 15cm xl2cm), and after a 30-min habituation period, the number of oro-facial movements, which consisted of chewing movements and tongue protrusions, was counted for 15 min. After this, every rat received an I.P. injection of either rolipram (0.5 or 1.0 mg/kg), or vehicle and was replaced, in its cage. We preliminarily counted the chewing movements and tongue protrusions for 50 minutes following the injection (n=3) and there was no prominent difference throughout this period (data not shown). Therefore, these movements were counted for 15 min following the injection for the assessment of the effects of rolipram. Striatal donamine Dl and D2 bindine exceriment The rats that had been challenged with 1 mg/kg rolipram were decapitated the day after the behavioral assessment and their striata were removed. The radiobinding assays for dopamine Dl and D2 receptors were performed following the Hatta’s method (8). Dopamine Dl and D2 receptors in the striatal homogenates were labeled with 1.17 nM [?I]-SCH23390 and 1.27 nM [?-I]-spiperone, respectively. The nonspecific bindings were determined by adding IOpM SCH23390 and 100 )IM (-)-sulpiride for Dl and D2 receptors, respectively. . . Statist&

analvsis

The behavioral data were analyzed using the Kruskal-Wallis and Mann-Whitney U-tests. The radioreceptor assay data were analyzed using Student t-test for unpaired data samples. Differences at peO.05 were considered to be significant.

Results Chewing movements and tongue protrusions appeared 4 days after the haloperidol injection. The frequency of chewing movements in the rats treated with haloperidol (118 f 23 counts/l5min; mean

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Movements

Chewing Movements

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r? 3

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60-

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40-

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roliPram vehicle rolipram 1.0 mgikg OS mgkg

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rolipram 1.0 mgkg

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Tongue Protrusions

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0

vehicle

roliPra vehicle rolipram rolipram 1.O mg/kg 0.5 mg/kg 1.O mg/kg

vehicle- treated

haloperidol-treated Fig. 16

The open and closed columns indicate the haloperidol-treated and control groups, respectively. #: ~~0.05; ##: p
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k SEM, n=12) was about 18 times higher than that in the control rats (6.5 + 1.5 counts/l5min,

n=12; pO.5). However, the respective [?-I]-spiperone binding values were 1186 + 107 and 879 f 50 (fmol/mg protein, mean + SEM, n=6) and, the value for the haloperidol-treated rats was 35 % higher than that for the controls (~~0.03). Discussion We selected rolipram (0.5 and 1.0 mg/kg, I.P.), a type IV PDE inhibitor to examine the effects of increased CAMP on oro-facial movements in this study, because it permeates to the brain well (10) and increases CAMP levels in the brain through inhibition of CAMP metabolism (6) without stimulating neurotransmitter receptors directly (ll), or altering the levels of dopamine release and metabolism (12), in doses range of 0.3 mg/kg to 3.0 mg/kg. It has been reported that chronic haloperidol treatment increases the maximum number of binding sites (Bmax) of [?I]-spiperone binding to D2 receptors without the dissociation constant (Kd) without alteration in Bmax and Kd of [?I]-SCH23390 binding to Dl receptors (8). Therefore, although we did not measure Bmax and Kd values, we have considered that our results of the increase in [?I]-spiperone binding after long-term administration of haloperidol may indicate an increase in the number of its binding sites to D2 receptors, whereas no change in [?I]-SCH23390 binding may indicate no change in Bmax and Kd of Dl receptors. This increase in striatal D2 receptors may have been responsible for the ore-facial movements. There are still debates about suitability of oro-facial dyskinetic movements in rats as a model of TD (3). In this study, the rats treated with haloperidol for 21 days showed significantly increased chewing movement and tongue protrusion frequencies 4 days after the final haloperidol treatment as compared with the control. These results agree with those reported previously (3) and we considered that this was an appropriate model of TD. Rolipram suppressed the oro-facial movements in the haloperidol-treated rats dose-dependently and at 1.0 mg/kg almost abolished them. Although we did not measure CAMP levels, it has been reported that chronic treatment with haloperidol suppresses activation of adenylate cyclase by dopamine in the rat striatum (13), and that ceruletide, which appears to be effective against the abnormal oro-facial movements in rats, restores the reduced CAMP level by modifying dopamine receptors (8). Rolipram has been reported to increase striatal CAMP levels 50 and 70 % at 0.3 and 3.0 mg/kg I.P., respectively (11). Therefore, the present results may support the hypothesis that increased levels of CAMP as a result of rolipram treatment suppressed the involuntary oro-facial movements.

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In man, it is not clear that supersensitivity in striatal dopamine D2 receptors is responsible for TD up to now. However, postmortem studies have suggested that chronic administration of neuroleptics increases the number of striatal dopamine D2 receptors (14) and the results of a positron emission tomography study has also suggested that the severity of TD depends on the density of striatal dopamine D2 receptors (15). Therefore, supersensitivity of striatal dopamine D2 receptors may be involved in the etiology of TD (16). Furthermore, CAMP levels in cerebrospinal fluid in the patients with TD were reported to be significantly lowered as compared with those in schizophrenics without TD (17). Therefore, rolipram may have beneficial effects in patients with TD.

However, as we administered rolipram systemically and did not measure brain CAMP levels, further studies may be necessary to establish whether the effects of rolipram on these involuntary movements are due to increased CAMP levels, especially those associated with postsynaptic Dl and D2 receptors in the striatum. Further, the studies using rats which have been treated with neuroleptics over a much longer period of time may also be necessary to confirm our hypothesis. References 1. 2.

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

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