European Journal o f Pharmacology, 56 (1979) 181--182

181

© Elsevier/North-Holland Biomedical Press

Rapid communication INCREASE IN STRIATAL ACETYLCHOLINE LEVELS BY GABA MIMETIC DRUGS: LACK OF INVOLVEMENT OF THE NIGRO-STRIATAL DOPAMINERGIC NEURONS B. SCATTON * and G. B A R T H O L I N I

Research Department, Synth~labo (L.E.R.S.), 58, rue de la Glaci~re, 75013 Paris, France Received 20 April 1979, accepted 23 April 1979

The corpus striatum contains massive cholinergic innervation mainly originating from interneurons. Recent evidence has been provided that GABA-ergic neurons may indirectly affect the activity of the striatal cholinergic interneurons via changes of nigrostriatal dopaminergic neuron activity. Thus, the administration of picrotoxin, a GABAreceptor antagonist, induced an increase in striatal acetylcholine (ACh) which was abolished by a 6-hydroxydopamine (6~)H DA)-induced lesion of the nigro-striatal dopaminergic pathway (Javoy et al., 1977). In the present study we have investigated the effect of two GABA mimetic agents SL 76002 (Kaplan et al., unpublished observations; Bartholini et al., 1979) and muscimol on striatal ACh levels. We report that these GABA mimetic agents enhanced striatal ACh content and that this effect was not mediated by the nigro-striatal dopaminergic pathway. Male Charles River rats (150 g) were injected intraperitoneally with SL 76 002 (10--400 mg/kg) or muscimol (0.2--7.5 mg/kg) and were decapitated 30 min later. Striatal ACh was measured according to the modified method (Scatton and Worms, unpublished results) of Guyenet et al. (1974). Table 1 shows that intraperitoneal injection of SL 76002 or muscimol induced a doserelated increase in striatal ACh content; in contrast, choline levels were not altered. As * F r o m whom reprints should be requested at the following address: Synthdlabo (L.E.R.S.), 31 av. Paul Vaillant Couturier, 92220 Bagneux, France.

ACh-esterase activity was not affected by SL76002, its metabolites and muscimol {data not shown) the increase in ACh concentration probably reflected a decreased release of ACh. This effect is unlikely to be connected with an interaction of GABA mimetics with ACh receptors as SL 76 002, its metabolites and muscimol in a high concentration (5 × 10 -4 M) did not affect the binding of the muscarinic antagonist 3H-3~luinuclidinylbenzylate in rat brain membrane preparations (Briley et al., personal communication). TABLE 1 Effects of SL 76 002 and m u s c i m o l on striatal A C h levels. SL 76 002 or m u s c i m o l was injected i.p. to normal rats or t o rats unilaterally injected w i t h 6-OHDA (8 ~g/2 gl) in the substantia nigra 3 weeks earlier. Striatal A C h was measured 3 0 rain after decapitation. Values are m e a n s w i t h S.E.M. of results f r o m 14 d e t e r m i n a t i o n s per group. Treatment

Dose

Striatal Ach levels (nmoles/g)

(mg/kg Control SL 76 002

Muscimol

i.p.)

Normal

10 50 150 400 0.2 1 2.5 7.5

36.7 41.8 50.9 61.3 62.4 47.7 49.2 63.5 89.2

+ 1.2 + 1.7 -+ 3.01 + 3.01 + 2.21 + 3.61 + 3.51 + 3.61 -+ 4.41

6-OHDA 35.1 + 1.7

63.6 + 2.91

100.1 + 2.61

1 p < 0.001 vs. the respective c o n t r o l s (Student's t-testL

182 To determine if the effect o f GABA agonists on striatal ACh levels was mediated through dopaminergic neurons, muscimol (7.5 mg/kg, i.p.) or SL 76 002 (400 mg/kg i.p.) were injected to animals in which unilateral degeneration of the nigro-striatal DA pathway had been induced by injecting 6-hydroxydopamine (6-OHDA) ( 8 p g / 2 # l ) into the substantia nigra (Javoy et al., 1977). Three weeks after the chemical lesioning a 90% decrease in striatal DA was observed in the ipsilateral side (control side = 11.5 + 0.4; lesioned side = 1.1 + 0.2 pg/g). As shown in table 1, muscimol and SL 76 002 increased striatal ACh levels to a similar extent in the intact and in the lesioned side. The present results indicate that GABA mimetic drugs enhance striatal ACh levels independently of the integrity of the nigrostriatal DA pathway. Also, 2 weeks after unilateral hemitransection between substantia nigra and striatum, GABA mimetic agents retained their ability to increase striatal ACh levels (data n o t shown). This excludes the possibility that, in the experiments with 6~)HDA, development o f DA target cells supersensitivity had compensated the reduced dopaminergic input to-striatal ACh cells. It is suggested that striatal ACh neurons m a y receive a GABAergic inhibitory influence intrinsic to the striatum. This view is supported by our observation (in preparation)

that direct infusion of GABA or muscimol into the striatum also induced an increase in ACh levels. The exact nature of this interaction however remains to be established. It might be possible that striatal GABA-ergic interneurons or collaterals of descending GABAergic neurons influence cholinergic cells in the striatum through direct connections with, or indirectly via non

Increase in striatal acetylcholine levels by GABA mimetic drugs: lack of involvement of the nigro-striatal dopaminergic neurons.

European Journal o f Pharmacology, 56 (1979) 181--182 181 © Elsevier/North-Holland Biomedical Press Rapid communication INCREASE IN STRIATAL ACETYL...
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