Neurology © Springer-Verlag 1992

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J Neurol (1992) 239 : 103-104 Journal of

Neurology

Brain muscarinic cholinergic receptors in Huntington's disease

K . W . Lange 1'2., F. Javoy-Agid 3, Y. Agid 3, P. Jenner 2, and C. D . Marsden 1

1 University Department of Clinical Neurology, Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK

2pharmacology Group, Biomedical Sciences Division, King's College, London, UK

3Laboratoire de Mddicine Expdrimentale, INSERM U. 289, H6pital de la Salp~tri~re, Paris, France Received March 15, 1991 / Received in revised form May 10, 1991 / Accepted May 16, 1991

Summary. M u s c a r i n i c cholinergic r e c e p t o r s a n d choline a c e t y l t r a n s f e r a s e ( C H A T ) activity w e r e studied in post- m o r t e m brain tissue f r o m patients with H u n t i n g t o n ' s disease a n d m a t c h e d c o n t r o l subjects. I n c o m p a r i s o n with controls, r e d u c t i o n s in C h A T activity w e r e f o u n d in the h i p p o c a m p u s , b u t n o t in the t e m p o r a l c o r t e x in H u n t i n g - t o n ' s disease. Patients with H u n t i n g t o n ' s disease s h o w e d r e d u c e d densities o f the total n u m b e r of m u s c a r i n i c re- c e p t o r s a n d o f M-2 r e c e p t o r s in the h i p p o c a m p u s while the density o f M-1 r e c e p t o r s was u n a l t e r e d . Muscarinic r e c e p t o r b i n d i n g was u n c h a n g e d in the t e m p o r a l cortex.

T h e s e results indicate a d e g e n e r a t i o n in H u n t i n g t o n ' s disease of the s e p t o - h i p p o c a m p a l cholinergic p a t h w a y , b u t n o i m p a i r m e n t o f t h e i n n o m i n a t o - c o r t i c a l cholinergic system.

Key words: A c e t y l c h o l i n e - C h o l i n e a c e t y l t r a n s f e r a s e - M u s c a r i n i c r e c e p t o r s - H u n t i n g t o n ' s disease

Introduction

H u n t i n g t o n ' s disease is c h a r a c t e r i z e d clinically b y c h o r e - i f o r m m o v e m e n t s a n d progressive d e m e n t i a . D e m e n t i a in A l z h e i m e r ' s disease a n d P a r k i n s o n ' s disease a p p e a r s to be associated with d e g e n e r a t i o n o f s u b c o r t i c o - c o r t i c a l cholinergic systems [5, 7, 9]. While a c e t y l c h o l i n e - c o n - taining n e u r o n s are d a m a g e d in the basal ganglia in H u n - t i n g t o n ' s disease [2, 10], the status of the cholinergic af- f e r e n t p r o j e c t i o n s to t h e n e o c o r t e x a n d h i p p o c a m p u s is less clear. W e h a v e e x a m i n e d choline acetyltransferase ( C H A T ) activity a n d muscarinic cholinergic r e c e p t o r binding in the t e m p o r a l c o r t e x ( B r o d m a n n a r e a 38) a n d h i p p o c a m p u s in H u n t i n g t o n ' s disease.

Patients and methods

Brain tissue was obtained at autopsy from 12 patients with neuro- pathologically confirmed Huntington's disease and from 12 matched

* Present address and address for offprint requests: Universit~its- Nervenklinik, Ffichsleinstrasse 15, W-8700 Wtirzburg, Federal Re- public of Germany

control subjects with no evidence of neurological or psychiatric disease. All patients with Huntington's chorea had suffered from ad- vanced forms of the disease and had been demented according to DSM III criteria [1]. They had received neuroleptic medication up to the time of death. Controls had not received any drugs that are known to affect the central nervous system. Using washed mem- brane homogenates, saturation analysis was performed for the total number of muscarinic receptors with [ H]-quinuclidinylbenzi- 3 late, for M-1 receptors with [3H]-pirenzepine and for M-2 receptors with [3H]-oxotremorine-M. Non-specific binding was defined by atropine. Protein concentration and ChAT activity were measured by standard techniques (details from K.W.L.).

Results

I n c o m p a r i s o n with controls, r e d u c t i o n s in C h A T activity w e r e f o u n d in t h e h i p p o c a m p u s b u t n o t in the tem-

Table 1. Mean (SEM) ChAT activity and maximal receptor binding in the temporal cortex and hippocampus. * P < 0.05 (Wilco- xon's rank-sum test); ChAT activity in nmol/h/mg protein; receptor binding as Bmax in fmol/mg protein

Control Huntington's disease

No. of brains 12

Sex 2 F, l0 M

Age (years) 68.7 (2.5)

Death to brain removal (h) 28.4 (5.6) ChAT activity

- in temporal cortex 4.5 (0.3)

- in hippocampus 12.7 (0.9)

[3H] -quinuclidinylbenzilate binding

- in temporal cortex 861 (32)

- in hippocampus 364 (12)

[3H]-pirenzepine binding

[3H]-oxotremorine-M-binding

12 5F, 7M 64.2 (2.1) 30.1 (4.4)

4.2 (0.3) 8.1 (0.8)*

811 (26) 280 (12)*

580 (18) 197 (15)

194 (10) 39 (3)*

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104

poral cortex in H u n t i n g t o n ' s disease (Table 1). Patients with H u n t i n g t o n ' s disease showed reduced densites of the total n u m b e r of muscarinic receptors and of M-2 receptors m e a s u r e d by specific binding of [3H]-quinuclidinylbenzilate and [3H]-oxotremorine-M in the hippocampus while the density of M-1 receptors, as identified by specific [3H]-pirenzepine binding, was unchanged.

Muscarinic r e c e p t o r binding was unaltered in the temporal cortex. Alterations in the equilibrium dissociation constants (KD) were not observed.

Discussion

T h e reduction in C h A T activity and in muscarinic M-2 receptors, which are thought to be located mainly pre- synaptically, indicates a d e g e n e r a t i o n of the cholinergic p a t h w a y f r o m the s e p t u m to the h i p p o c a m p u s . This is s u p p o r t e d by decreased C h A T activity in septal nuclei [10]. T h e p r e s e n t results of unaltered cortical C h A T activity and putatively pre-synaptic M-2 receptors suggest that the ascending cholinergic system f r o m the substan- tia i n n o m i n a t a to the n e o c o r t e x is not d a m a g e d in H u n - tington's disease. This is consistent with previous reports showing a p r e s e r v a t i o n of neurons in the nucleus basalis of M e y n e r t [3, 6]. D e m e n t i a is associated with neuronal d a m a g e or loss in the nucleus basalis in A l z h e i m e r ' s disease and P a r k i n s o n ' s disease [8]. T h e findings in H u n - tington's disease, however, indicate that d a m a g e to this region is not a prerequisite for the d e v e l o p m e n t of dementia. T h e cognitive i m p a i r m e n t in H u n t i n g t o n ' s disease m a y be related to h i p p o c a m p a l deficits and d a m a g e to n e u r o n a l systems within the basal ganglia, although it cannot be ruled out that the d e m e n t i a might s t e m direct- ly f r o m cortical a t r o p h y [4].

Acknowledgement. This study was supported by the Medical Re- search Council and the Parkinson's Disease Society. K. W. L. was supported by the Deutsche Forschungsgemeinschaft.

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