Neuroscience Letters, 163 (1993) 31 35 31 © 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved 0304-3940193/$ 06.00

NSL 09980

Chronic CY 208-243 treatment of MPTP-monkeys causes regional changes of dopamine and GABAA receptors

C61ine Gagnon a, Baltazar Gomez-Manci l la b, Paul J. B6dard b, Th6r6se Di Paolo *a

"School of Pharmacy, Laval University, Que., Canada G1K 7P4 Department of Moh,cular Endocrinolog3!, CHUL Research Center, Laval University Medical Center. Ste-Foy, Que., Canada GI V 4G2

bCentre de Recherche en Neurobiologie, H6pital de l'EnJimt-JOsus, Que.. Canada G1J 1Z4 Department of Pharmacology, Laval University, Faculo' of Medicine, Que., Canada GIK 7P4

(Received 30 December 1992; Revised version received 11 June 1993: Accepted 11 August 1993)

Key words: CY 208 243; Dopamine; Dopamine Dt receptor; Dopamine D 2 receptor; GABA,, receptor; MPTP-monkey: Striatum

Four monkeys were rendered parkinsonian by N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) i.v. administration and then treated chroni- cally with increasing doses of the D~ agonist CY 208 243 (0.05, 0.1 and 0.5 mg/kg). All animals showed a dose-dependent improvement of their parkinsonian signs after the chronic CY 208-243 treatment; however, half of them developed peak-dose dyskinesias. Dopamine levels were more decreased in the striatum of MPTP-monkeys with dyskinesias compared to those without dyskinesias. [3H]SCH 23390 and [3H]SKF 38393 binding to D~ receptors were in general similar in the striatum of both groups of MPTP-monkeys except [3H]SKF 38393 binding which was lower in the posterior putamen of dyskinetic compared to non-dyskinetic monkeys reflecting decreased coupling of this receptor to G proteins. [3H]spiperone and [3H]N-n-propylnorapomorphine binding to D2 receptors in the striatum tended in general to be higher in dyskinetic compared to non-dyskinetic monkeys, and this reached statistical significance in the posterior caudate labelled with [3H]n-propylnorapomorphine. [3H]muscimol binding to GABA A receptors was significantly higher in the posterior caudate of dyskinetic compared to non-dyskinetic monkeys. The extent of striatal DA denervation, decreased D~, elevated D 2 and GABA A receptors, as well as the decrease of the D i D 2 receptor ratio in the posterior striatum may be involved in the appearance of dyskinesias after chronic CY 208 243 treatment.

Long-term treatment with L-3,4-dihydroxyphenylalan- ine (L-DOPA), the precursor of dopamine (DA), induces important side effects such as dyskinesias in Parkinsoni- ans [2] and in MPTP-monkeys [4]. L-DOPA-induced dyskinesias seem to be related to the severity of the ni- grostriatal damage [5] and the chronic treatment itself [9]. Administration of certain D 2 agonists, in MPTP- monkeys previously treated chronically with L-DOPA, reproduces dyskinesias similar to those induced by L- DOPA [16]. However, de novo chronic bromocriptine (D2 agonist) treatment relieves parkinsonian symptoms in MPTP-monkeys without inducing dyskinesias [13, 14]. At low doses, chronic treatment with SKF 38393, a D~ agonist, has little therapeutic action on parkinsonian symptoms in patients and monkeys [6, 13] and does not induce dyskinesias [13]. However, SKF 38393, at a higher dose (15 mg/kg), induces dyskinesias in hemipark- insonian MPTP-monkeys previously treated chronically with apomorphine [8]. CY 208 243 (CY), another D~ ag- onist, reverses akinesia and rigidity in MPTP-monkeys

*Corresponding author, Fax: (1) (418) 654-2761.

and in parkinsonian patients [21]. Dyskinesias are seen in some parkinsonian patients treated with high doses (40 rag) of CY [21].

Susceptibility to develop dyskinesias may be related to relative changes of D~ versus D2 DA receptors following chronic L-DOPA or DA agonist treatments. To test this hypothesis, MPTP-monkeys were treated chronically with CY; half of them developed dyskinesias following this treatment. To seek the underlying biochemical dif- ferences implicated in these behaviors, we compared spe- cific binding to D~, D2 and ?'-aminobutyric acid (GABA) GABA A receptors and DA concentrations in the brains of these monkeys. Agonist and antagonist ligands for D1 and Dz receptors were used in order to assess total recep- tor density as well as the high affinity agonist site binding which reflects coupling of the receptor to G proteins.

Four female, ovariectomized monkeys (Macacafascic- ularis) weighing around 3.0 kg and of approximately the same age were used in this study. They were rendered parkinsonian by N-methyl-4-phenyl-l,2,3,6-tetrahydro- pyridine (MPTP) (Aldrich Chemical) i.v. administration at a dose of 0.3 mg/kg. They received several injections at

32

weekly intervals until the parkinsonian signs were stable (akinesia, flexed posture, rigidity and intermittent pos- tural tremor). The total dose varied from 1 to 6 rag.

CY 208-243 (CY) ((-)-4,6,6a,7,8,12b-hexahydro-7- methyl-indolo [4,3-ab] phenanthridine, Sandoz, Switzer- land) treatment at doses of 0.05, 0.1 and 0.5 mg/kg s.c., daily, in one dose, was started at least 1 month after the last injection of MPTP. The two lower doses were admin- istered s.c. for 1 week and the highest dose (0.5 mg/kg) for 2 weeks. Animals were placed in individual observa- tion cages. Gross locomotor activity was recorded con- tinuously by photocells placed in each cage, giving a count every 15 min and the total for each period of 24 h. Disability scores and dexterity at picking food as well as dyskinesias at peak effect of the drug were assessed daily as described [15].

At least 2 weeks after the end of the chronic CY treat- ment, the MPTP-monkeys were sacrificed by an over- dose of pentobarbital. The forebrain was cut sagitally in two and both halves were placed in isopentane (-40°C) and then frozen at -80°C for determination of [3H]spiperone (O 2 antagonist) and [3H]SCH 23390 (D~ antagonist) binding by autoradiography as we previ- ously described [14]. [3H]SKF 38393 (D~ agonist) and [3H]N-n-propylnorapomorphine ([3H]NPA, D 2 agonist) binding were also performed in alternate coronal sec- tions as described [7, 11]. Brain slices were cut into co- ronal sections (20 pm) on a cryostat (-18°C) and slices were thaw-mounted onto gelatin and chrome alum- coated slides. Brain slices were preincubated, for 15 min at room temperature, in a Tris-HC1 buffer (containing in raM: Tris 50, NaC1 120, KC1 5, CaCI2 2, MgC12 1, 0.1% ascorbic acid and EDTA 1, pH 7.40-7.45) for [3H]NPA binding (66 Ci/mmol) and a Tris-HC1 (50 mM Tris, pH 7.40-7.45) buffer for [3H]SKF 38393 (44 Ci/mmol) bind- ing. Sections were then incubated (60 min at room tem- perature) with 1 nM of [3H]NPA or 2 nM of [3H]SKF 38393 as reported [7, 11]. Non-specific binding was de- termined in adjacent sections with addition of 10 pM (+)-butaclamol (D2) or SKF 38393 (DO. Sections were rinsed for 10 min twice in the appropriate cold (4°C) Tris-HC1 buffer and then for 10 s in distilled water. For antagonist ligands, a phosphate buffer and a concentra- tion of 1 nM of each ligand was used in the incubation medium; non-specific binding was determined with 1 ¢tM (+)-butaclamol (D2) or SCH 23390 (DI). In the [3H]spi- perone assay, ketanserin (50 nM) was added to the incu- bation medium to block 5-HT2 serotonin receptors. [3H]muscimol (GABA A agonist) binding was done on al- ternate coronal sections essentially as described [18]. Sec- tions were preincubated three times for 10 min in a 50 mM Tris-citrate buffer (pH = 7.1). Then, they were incu- bated (40 min at room temperature) with 20 nM of

[3H]muscimol. Non-specific binding was determined in adjacent sections with the addition of 0.1 mM GABA. Sections were rinsed for 1 rain in the cold Tris-citrate buffer described previously and then for 10 s in distilled water. For all the ligands, sections were dried overnight at room temperature. The slide-mounted tissue sections were then exposed to [3H]-sensitive films (Hyperfilm RPN-31, LKB) along with a set of tritium standards ([3H]-microscale, Amersham) for 3 weeks at -20°C for DA agonist ligands and for 15 days for DA antagonist ligands and [3H]muscimol. Films were developed and au- toradiograms analyzed by densitometry as previously described [14].

Specific binding to DA and GABAA receptors was evaluated at four rostrocaudal coordinates (A22.0, AI8.1, A16.4 and A9.6) [20]. Specific binding values of caudate and putamen were measured at each coordinate (n = 10 14 slices) for each monkey, in each hemisphere separately. Then the mean of right and left hemisphere values was calculated for each monkey, at each coordi- nate. Finally, values for each monkey were averaged at each coordinate for each group: two dyskinetic and two non-dyskinetic MPTP-monkeys. Ratios of specific bind- ing for each ligand ([3H]SCH 23390/[3H]spiperone ratio, ...) were calculated for the striatum of each monkey. Data were grouped for each monkey in anterior (A22.0 and A18.1 coordinates) and posterior striatum (A16.4 and A9.6 coordinates), since results obtained in these sub-regions were similar. Finally, ratios from each mon- key were averaged for each group in each brain area studied.

Striatum from alternate coronal sections (n = 3-18 slices per structure) were dissected for DA determination by HPLC with electrochemical detection [t 0].

All animals became progressively akinetic following MPTR After 1 month, there was a slight recovery but all appeared significantly slower with a hunched posture typical of the parkinsonian syndrome. At this point, all had an identical score of 6 (maximum disability = 10) on the Parkinsonian disability scale [15]. The highest dose of CY increased motility and dexterity, respectively, on av- erage by 258% and 48% over the baseline MPTP state and decreased the disability score by 74%. These results were significant (ANOVA for repeated measures fol- lowed by a Dunnet's a posteriori test). At the end of the 30-day treatment with CY half of the animals had devel- oped dyskinesia.

DA levels were lower (P < 0.05, two-tail student t-test) in the striatum of dyskinetic (11.1 4-0.2 ng/mg of pro- tein) compared to non-dyskinetic MPTP-monkeys (27.7 + 2.7 ng/mg of protein) and both were lower than in intact animals (DA, 108 + 18 ng/mg of protein, n = 8) from our previous studies [10, 12-15].

In general, D 2 receptor binding using agonist or antag- onist ligands tended to be higher in caudate and putamen of dyskinetic compared to non-dyskinetic monkeys and this reached statistical significance in the posterior cau- date labelled with [3H]NPA (Table I). D~ receptors la- belled with agonist or antagonist ligands were similar in both groups of MPTP-monkeys except in the posterior putamen where dyskinetic monkeys had lower [3H]SKF 38393 but not [3H]SCH 23390 binding compared to non- dyskinetic animals. [3H]muscimol binding was similar in the anterior striatum of both groups of MPTP-monkeys whereas in the posterior striatum it was higher in dyski- netic compared to non-dyskinetic monkeys.

Comparison of our previous specific [3H]SCH 23390 binding values for 3 intact monkeys obtained under simi- lar assay conditions (anterior striatum 599 + 33 and pos- terior striatum 531 + 72 fmol/mg of tissue, unpublished results) with the present results (Table I) suggests that D~ receptors decreased in the anterior and posterior stria- turn of all CY-treated MPTP-monkeys, compared to in- tact monkeys. In contrast [3H]spiperone specific binding to D e receptors of all CY-treated MPTP-monkeys were closer to control intact monkeys values (n = 3, anterior striatum 321 + 27 and posterior striatum 299 + 29 fmol/ mg of tissue, unpublished results).

In the anterior striatum, only the [3H]muscimol/ [3H]NPA ratio was decreased in dyskinetic compared to non-dyskinetic animals (Table II). In the posterior stria- turn, the DI/D2 specific binding ratio was decreased in dyskinetic compared to non-dyskinetic monkeys, as

33

measured with agonist or antagonist ligands: the D~/D2 binding ratio was lower in CY-treated MPTP-monkeys compared to intact controls (n = 3, [3H]SCH 23390/ [3H]spiperone: anterior striatum 1.88 + 0.06 and poste- rior striatum 1.93 + 0.11, unpublished results), dyski- netic monkeys displaying a greater decrease. This is likely due to the CY treatment since we have observed overall no change of the DI/D2 receptor binding ratio in the striatum between intact controls and untreated MPTP monkeys (intact: DI/D2 = 1.87 + 0.03 (n = 4) and MPTP: DI/D2 = 1.96 + 0.06 (n -- 3) (refs. 4 and 14: and unpublished results). The GABAA/DI receptor specific binding ratio, as evaluated with D~ agonist or antagonist ligands, was 50% higher in posterior striatum of dyski- netic compared to non-dyskinetic monkeys.

In the present study, as in our previous experiment [15], CY improved parkinsonian symptoms of MPTP- monkeys: however, half of them developed peak-dose dyskinesias. DA levels were decreased to a greater extent in the striatum of dyskinetic compared to non-dyskinetic animals. The MPTP-monkeys, more affected by MPTP toxicity were thus more susceptible to develop dyskine- sias with a DA agonist specific for one type of DA recep- tor. This agrees with the observation that extensive ni- grostriatal damage is required for L-DOPA-induced dyskinesias in squirrel monkeys [5]. A decrease > 90% of striatal DA is required for induction of D e receptor su- persensitivity in striatum of MPTP-monkeys [12]. This may explain why in the present study only dyskinetic MPTP-monkeys with lower striatal DA levels, had in-

TABLE 1

A U T O R A D I O G R A P H Y OF D~. D. and GABAA R E C E P T ORS BINDING IN STRIATUM OF DYSKINETIC A N D N O N - D Y S K I N E T I C

M P T P - M O N K E Y S T R E A T E D C H R O N I C A L L Y WITH CY 208 243

Results shown are mean -+ s tandard error of two monkeys in each group expressed in fmol/mg of tissue.

Receptor Ligand Anterior striatum

Caudate Putamen

Non- dyski- Dyski- %:' Non- dyski- Dyski-

netic netic netic netic

Posterior striatum

Caudate Putamen

%~ Non- dyski- Dyski- %~' Non- dyski- Dyski- %"

netic netic netic netic

D~ receptor

[3H]SKF 38393 190-+ 19 175 _+ 12 92 204 + 10 194_+_ 5 95

[~H]SCH23300 430_+49 455_+10 106 393_+34 453_+20 115

D 2 receptor [3H]NPA 308 _+ 30 377 _+ 15 122 330 _+ 10 422 _+ 37 128

[3H]spiperone 236 _+ 33 250 _+ 2 106 241 _+ 12 217 _+ 27 121

GABA A receptor [3H]muscimol 523 _+ 56 515 _+ 44 104 528 _+ 38 577 -+ 52 109

l(19_+ 6 102_+ 7 94 136_+ 5 101 _+ 7* 74

399_+ 18 385_+25 96 365_+ 4 358_+ 5 98

362 -+ 26 474-+ 2* 131 402 -+ 17 535 -+ 73 133

217_+34 286_+ 18 132 267_+ 14 347_+36 130

362+_22 558_+ 5* 154 4 3 9 + 5 1 565+-22 129

'~Percent of respective values for non-dyskinetic animals. *P < 0.05 compared to non-dyskinetic MPTP-monkeys by Student 's t-test (two-tail).

34

creased D2 receptors. In contrast, D1 receptors seemed less affected by the degree of striatal DA toss, since D~ receptor densities as reflected by [3H]SCH 23390 binding were similar in the two groups of MPTP-monkeys; the D1 receptor changes observed here were probably more influenced by the D1 agonist treatment than by the lesion since [3H]SCH 23390 binding was decreased compared to values obtained for intact monkeys. However, the fact that only the better-denervated dyskinetic group showed a decrease in Dl agonist binding sites suggests that this change, as dyskinesia itself, is dependent upon an inter- action between denervation and treatment.

The high-affinity agonist state of D1 receptors, which adopt this conformation when they are associated with the GTP-binding protein involved in the transduction process, was recently shown to be dependent on en- dogenous DA levels [17]. Indeed, this site is decreased in the striatum of 6-OHDA-lesioned rats and restored by preincubation with DA while [3H]SCH 23390 binding is unchanged. This is in agreement with the present find- ings of decreased [3H]SKF 38390 and unchanged [3H]SCH 23390 binding in the posterior putamen of dyskinetic monkeys with more extensive DA depletion. This suggests that in absence of DA, the D~ receptor is less coupled to its GTP-binding protein, thus hindering the transduction process.

A common mechanism mediating ballism, chorea in Huntington's disease and L-DOPA-induced dyskinesias has been proposed [9] where a disorder of the subtha- lamic nucleus (STN) may be central to the generation of choreic movements. Indeed, a lesion of the STN induces dyskinesias both in humans and monkeys [23, 24]. Hence, DA agents may cause preferential inhibition of putaminal neurons that project to the external segment of the globus pallidus, causing an overactivity of the GABA external pallidal segment neurons which project to the STN [9]. In the putamen, DA has an inhibitory action on cells projecting to the external segment of the globus pallidus (indirect pathway) and an excitatory ef- fect on those projecting to the internal segment (direct pathway) [1]. In cats, efferent neurons of the striatum projecting to the globus pallidus mainly have D2 recep- tors, whereas those projecting to the entopeduncular nu- cleus and substantia nigra mainly have D~ receptors [3]. In monkeys and humans, the internal segment of the globus pallidus is the homologue of the entopeduncular nucleus in rats and cats.

Chronic CY treatment led to a decrease of D~/D2 re- ceptor ratio in the posterior striatum of dyskinetic com- pared to non-dyskinetic MPTP-monkeys. This is a novel observation in animal models of Parkinson's disease and is in agreement with the report showing that tardive dyskinesias, following chronic haloperidol treatment, are

TABLE 11

RATIO OF SPECIFIC B I N D I N G OF DI, D2 A N D GABA A LI-

G A N D S IN A N T E R I O R A N D POSTERIOR STRIATUM OF

DYSKINETIC A N D N O N - D Y S K I N E T I C M P T P - M O N K E Y S

F R E A T E D C H R O N I C A L L Y WITH CY 208 243

Results shown are mean + standard error of two monkeys in each

group

Ligand Anterior str iatum Posterior striatum

Non- dyski- Dyskinetic Non- dyski- Dyskinetic

netic netic

[3H]SCH 23390/ [3H]spiperone

[3H]SKF 38393/ [3H]NPA

[3H]muscimol/ [3H]SCH23390

[3H]muscimol/

[3H]SKF38393

[3H]muscimol/

[3H]spiperone [3H]muscimol/

[3H]NPA

1.74 __+ 0.01 1.69 + 0.04

0.62 + 0.09 0.47 + 0.01

1.29 + 0.03 1.20 __+ 0.07

2.53 -+ 0.27 3.18 + 0.02

2.21 + 0.04 2.0l + 0.07

1.59 _+ 0.13 1.14_+ 0.07*

0.30 _+ 0.01 0.21 _+ 0.02*

1.06 + 0.05 1.54 + 0.12"

3.62 _+ I).48 5.48 + 0.04*

1.68 + 0.22 1.74 + 0.02

1.63 + 0.03 1.38_+ 0.04* t.05 _+ 0.09 1.18 + 0.03

*P < 0.05 compared to non-dyskinetic MPTP-monkeys by Student 's

t-test (two-tail).

associated with a decrease of the D1/D 2 ratio in rat stria- tum [19]. The preferential stimulation of increased D2 receptors in the posterior striatum of dyskinetic MPTP- monkeys, by endogenous DA, may favor the indirect pathway and increase inhibition of the STN neurons, therefore inducing dyskinesias. Increased density of D2 receptors seem to be important for appearance of dyski- nesias since the less denervated MPTP-monkeys with normal D2 receptor levels in the posterior striatum, had no dyskinesias. We have shown that chronic treatment with bromocriptine relieves parkinsonian symptoms without inducing dyskinesia in MPTP-monkeys [13]; the important decrease of striatal D2 receptors in these mon- keys may explain the absence of dyskinesia [14].

Thus the therapeutic effects of DA agonists in parkin- sonian patients and in MPTP-monkeys may be due to stimulation of both D~ and D 2 receptors, whereas ap- pearance of dyskinesias may result from the imbalance between striatal D~ and D2 receptors. Treatment with DA agonists and the resulting DA receptor imbalance would cause the preferential stimulation of striatal GABA neurons of the indirect pathway, projecting to the external segment of the globus pallidus, and inhibition of STN neurons. Indeed, an increase of regional cerebral glucose utilization is observed in the STN of unilateral 6-hydroxydopamine lesioned rats treated with L-DOPA [22], suggesting increased activity of pallidal neurons

35

p r o j e c t i n g to the S T N . S t r i a ta l G A B A A r e c e p t o r s were

inc reased in the w e l l - d e n e r v a t e d M P T P - m o n k e y s c o m -

p a r e d to the a n i m a l s less d e p l e t e d o f D A . In the less

a f fec ted an ima l s , s t i m u l a t i o n o f D2 r e c e p t o r s by en-

d o g e n o u s D A m a y h a v e a f fec ted s t r ia ta l G A B A levels

a n d p r e v e n t e d the G A B A A r e c e p t o r increase .

In c o n c l u s i o n , M P T P - m o n k e y s t r ea t ed c h r o n i c a l l y

wi th the D~ agonis t , CY, m a y d e v e l o p dysk ines ias .

Dysk ines i a s a p p e a r e d in M P T P - m o n k e y s wi th the g rea t -

est s t r ia ta l D A loss c o n f i r m i n g the i m p o r t a n c e o f dener -

va t ion . D y s k i n e t i c M P T P - m o n k e y s had h ighe r s t r ia ta l

levels o f D~ a n d G A B A A recep to r s c o m p a r e d to n o n -

dysk ine t i c a n i m a l s a n d s imi la r D~ r e c e p t o r levels in the

a n t e r i o r s t r i a tum. In the p o s t e r i o r p u t a m e n , [3H]SKF

38393 bu t n o t [3H]SCH 23390 b i n d i n g was dec reased in

dysk ine t i c c o m p a r e d to n o n - d y s k i n e t i c m o n k e y s , sug-

ges t ing d e c r e a s e d c o u p l i n g o f this r e c e p t o r wi th G T P -

b i n d i n g pro te ins . T h e dec rease o f D I D 2 r a t io in the pos -

t e r i o r s t r i a t u m o f dysk ine t i c M P T P - m o n k e y s m a y h a v e

caused the p re f e r en t i a l s t i m u l a t i o n o f s t r ia ta l G A B A ef-

fe ren t n e u r o n s p r o j e c t i n g to the ex te rna l s e g m e n t o f the

g l o b u s pal l idus , t he re fo re inh ib i t ing S T N n e u r o n s a n d

i n d u c i n g dyskines ias .

Th i s r e sea rch was s u p p o r t e d by the P a r k i n s o n F o u n -

d a t i o n o f C a n a d a .

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