The effects of intranigral injections of picrotoxin and carbachol in cats with a lesioned nigrostriatal pathway

Neuroscience Letters, t l (1979) 197--200 © Elsevier/North-Holland Scientific Publishers Ltd.

197

THE EFFECTS OF INTRANIGRAL INJECTIONS OF PICROTOXIN AND CARBACHOL IN CATS WITH A LESIONED NIGROSTRIATAL PATHWAY S T A N I S ~ A W W O L F A R T H a, P E T E R W A N D

and KARL-HEINZ S O N T A G

Max-Planck-lnstitUte of Experimental Medicine, Hermann-Rein-Str. 3, D-3400 Gottingen (G.F.R.) and alnstitute of Pharmacology, Polish Academy of Sciences, 31--343 KrakOw

(Poland) (Received October 23rd, 1978) (Revised version received November 10th, 1978 ) (Accepted November l~th, 1978)

SUMMARY

Picrotoxin, carbachol and atropine were injected intranigrally through chronically implanted cmnnulae in cats. The drag-induced behavioural syndromes, mainly asymmetric behaviour, were analyzed. The changes in these syndromes after 6-hydroxydopamine (6-OHDA) lesion of'the substantia nigra (SN) indicate that, in addition to the dopaminergic (DA), a non-catecholaminergic (non-CA) nigral output exists, both being responsible for asyrametric behaviour. It is furti~ers,Jggestedthat 7-aminobutyric acid (GABA) receptors are present on both dol~aminergic and non-CA nigral output neurons, while acetylcholine (ACh) receptors, responsible for asymmetric behaviour, are almost exclusively located on non-CA nigral output neurons.

The substantia nigra (SN) is thought to play an important role in control of motor function. Its main output is the dopaminergic (DA) rAgrostriatalpathway which is considered to be mainly responsible for the maintenance of a cholinergic
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cannula exceeded the-outer one b y 0.1 mm~ Cats were observed and filmed separately in a room 3 X 4 m in size. A f a r an interval of at least 4 days, 10 ~g of 6-hydroxydopamine (6-OHDA) dissolved in 4 #1 of 1% ascorbic acid was injected into the right SN. 2 weeks after the administration of the neurotoxin, injections of picrotoxhl and carbachol were repeated and the intr~uigral action of both drugs was evaluated after destruction of their nigrostr]ataL ~xget points. In some experiments o n intact cats, carbachol injections into SN were combined with simultaneous contralate.r~ or preceding (10 rain) ipsilateral injections of atropine. The choLinomimetic carbachol, unilaterally injected into SN, produced contralateraL asymmetric behaviour in almost all animals before and after 6-OHDA lesions of SN. However, after lesion of SN in 2 out of 8 catssome ipsflateral asymmetric behaviour was observed. The specificity of a nigra! ACh input producing contralateral asymmetric behaviour after carbachol administration is supported by the effects of atropine. This drug, ipsilateraUy injected blocked, while when contralaterally given enhanced the effect of carbachol. The GABA antagonist picrotoxin produced contralateral asymmetric behaviour in 3 out of 5 intact animals; in 1 out of these 5 cats, however, marked ipsilateral asymmetric behaviour was observed, while one animal biphasically turned to both sides. After lesion of the nigrostriatal pathway only extremely strong ipsilateral asymmetric behaviour appeared. Shifting which was

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Fig. 2. Behavioural effects of ~ntranigral injection of picr0toxin given before (A) and after (B) a lesion of the nigrostriatal pathway with 6-OHDA. The inset shows the proposed ni gral inPut, output relations involving the relev,ant transmitters, for further details see Fig. 1.

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induced before the lesion in all 5 cats, after the lesion occurred only in 2 out of 5 animals. The results presented here indicate that a t least two kinds of neuronal inputs arLd outputsare present in the SN: GABA'ergic and cholinergic inputs, as well as D A a n d non-CA outputs, ACh receptors, responsible for the asymmetri'c behaviour, are almost exclusively present on' non-CA nigral output neurons. However, the fact that the enhancement of locomotor activity could be influenced by 6-OHDA supports the previous findings of Butcher et al. [ 4,5] and Wolfarth et al. [ 10 ], indicating that ACh receptors make synaptic connections as well with DA nigral neurons but have only weak influence on asymmetric behaviour. On the contrary, GABA receptors are present on both DA and non-CA nigral output neurons as shown by the alteration of picrotoxin-induced asymmetric behaviour following 6-OHDA lesion of SN. This conclusion is supported by the findings of Aghajanian and Bunney [1,2], who suggested a similar model resulting from their microiontophoretic studies. We suggest, therefore, that in addition to the well known DA, a non-CA nigral output is involved in eliciting asymmetric behaviour. ACKNOWLEDGEMENTS

Fellowship from Max-Planck-Gesellschaft from S. Wolfarth is gratefully acknowledged. The authors are indebted to Miss Christine Bode and Mr. H. Ropte for valuable technical help. This work was supported by the Deutsche Forschungsgemeinschaft, SFB 33. REFERENCES 1 Aghajanian, G.K. and Bunney, B.S., Dopami~ergic and non-dopaminergic neurons of the substantia nigra: differential responses to putative transmitters, J. Pharmacol. (Paris), 5 (J 974) 56--57. 2 Aghajanian, G.K. and Bunney, B.S., Dopamine "Autoreceptors": pharmacological characterization by microiontophoretic single cell record.~ng studies, Naunyn-Schrr_,i~..ieberg's Arch. Pharmacol., 297 (1977) 1--7. 3 And~n, N.-E., Rubenson, A., Fuxe, K. and H6kfelt, T., Evidence for dopamine receptor stimulation by apomorphine, J. Pharm. Pharmacol., 19 (1967) 627--629. 4 Butcher, L.L., Talbot, K. and Bilezikjian, L ~Acetylcholinesterase neurons in dopaminecontaining regions of the brain, J. Neural Trans., 37 (1975) 127 -153. 5 Butcher, L.L. and Hodge, G._~., Postnatal development of acetylcholinesterase in the caudate~putamen nucleus and substantia nigra of rats, Brain Res., 106 (1976) 2?3--240. 6 Schwartz, W.J., Gunn, R.H., Sharp, F.R. and Evarts, E.V., Unilateral electrolytic lesions of the substantia nigra cause contralateral circling in rats, Brain Res., 105 (1976) 358-361. 7 Snider, R.S. and Niemer, W.T., A stereotaxic atlas of the cat brain, The University of Chicago Press, Chicago, 1964. 8 Ungerstedt, U., Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneratiion of the nigro-striatal dopamine system, Acta physiol, scand. Suppl., 367 (1971) 69--93. 9 Woifarth, S. and Boissier, J.R., On the choice of so-called placebo solution for the intranigral nlicroinjection in the rat, Pol. J. Pharmacol. Pharm., 28 (19'76) 27--36. 10 Wo~farth, S., Dulska, E., Go]'embiowska-Nikitin, K., and Vetulani, J., A role of the polysynaptic system of substantia nigra in the ch°linergic'd°paminergic equilibrium in the central nervous system, Naunyn-Schmiedeberg's Arch. Pharmacol., 302 (1978) 123--131.