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Normal serotonin but elevated 5-hydroxyindoleacetic acid concentration in cerebellar cortex of patients with dominantly-inherited olivopontocerebellar atrophy
84
\cmo~'h'n~'c Lc/tcr~. 144 (19921 ~4 ~f~ ~ 1992 Elsevier Scientific Publishers Ireland Ltd. All rights reserved 0304-3940/92~$ 05.00
NSL 08926
Normal serotonin but elevated 5-hydroxyindoleacetic acid concentration in cerebellar cortex of patients with dominantly-inherited olivopontocerebellar atrophy Stephen J. Kish ", Yves Robitaille b, Lawrence Schut c, Munir E1-Awar d, Melvyn J. Ball ~ and Kathleen Shannak " "Human Neurochemieal Pathology Lab, Clarke Institute of Psychiatry, Toronto (Canada), ~:Montreal Neurological Institute, Quebec (CanadaL ~University ofMinnesota, Minneapolis and United Hospital, St. Paul, MN (USA), JDepartment q/Neurology, UniversiO, of Pittsburgh, Pittsburgh, PA (USA) and "Departments of Neurology and Pathology, Oregon Health Sciences University. Portland, OR (USA) (Received 11 May 1992: Revised version received 5 June 1992: Accepted 8 June 1992)
Key words: Serotonin; Inferior olive; Cerebellum; Climbing fibre; Cerebellar ataxia; Olivopontocerebellar atrophy; 3-Acetylpyridine Beas-Zarate and coworkers (Eur. J. Pharmacol., 198 (1991) 7 14) recently reported markedly reduced concentration of presynaptic serotonin neurotransmitter markers in cerebellum of rodents which had suffered destruction of the inferior olivary-cerebellar (climbing fibre) projections by the neurotoxin 3-acetylpyridine; these experimental animal data suggested that serotonin might be one of the neurotransmitters released by climbing fibres. We measured the concentration of serotonin and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in autopsied cerebellar cortex of 14 patients with dominantly-inherited olivopontocerebellar atrophy (OPCA) who all had near-total degeneration of the inferior otivary climbing fibres. As compared with the controls, mean concentration of serotonin in cerebellar cortex of the OPCA patients was normal whereas 5-HIAA levels l+79%, P<0.02) and "turnover' ratio 5-HIAA/serotonin (+ 148%, P<0.05), on average, were significantly elevated. These data do not support the notion that serotonin is a predominant neurotransmitter of the human climbing fibre. However, the markedly elevated serotonin turnover ratio suggests the possibility of increased serotonergic neuronal activity, which might alter, and perhaps improve, the functioning of the preserved cerebellar cortical neurones in OPCA.
The mammalian cerebellar cortex receives serotonincontaining afferents which innervate all of the three (molecular, Purkinje cell, granule cell)cortical layers [11]. Although these serotonergic neurones are generally considered to arise predominantly from pontine raphe nuclei and other nuclei of the medullary and pontine reticular formation (cf. ref. IlL Beas-Zarate and coworkers [1] recently provided evidence that serotonin might be one of the neurotransmitters of the climbing fibres, which originate in the inferior olive and terminate in cerebellar cortex. In this regard, this group reported a total depletion of serotonin itself, absence of calcium-dependent serotonin release, as well as marked (-60%) reduction of serotonin uptake, in cerebellar slices of rodents who had received 3-acetylpyridine, a neurotoxin which destroys the inferior olivary-cerebellar climbing fibres. In order to examine the relationship between cerebellar serotonin Correspondence." S.J. Kish, Human Neurochemical Pathology Laboratory, Clarke Institute of Psychiatry, 250 College Street, Toronto. Ont., Canada M5T 1R8. Fax: (1) (416) 979-7871.
and the climbing fibre in the human we examined the concentration of serotonin and its major metabolite 5hydroxyindoleacetic acid (5-HIAA) in autopsied cerebellar cortex of 14 patients with end-stage dominantly-inherited olivopontocerebellar atrophy (OPCA), who all had a near total loss of the inferior olivary cells. We reasoned that if the climbing fibres provide a substantial serotonergic innervation to the human cerebellar cortex, as suggested by the Beas-Zarate study, the cerebellar cortical concentration of serotonin should be markedly reduced in OPCA. In addition, information on the behaviour of cerebellar serotonin in OPCA could have clinical implications in view of the neuromodulatory action of this substance in mammalian cerebellum [7,10] as well as the observations of improved clinical status~ in some cerebellar ataxia patients, following treatment with 5-hydroxytryptophan, the precursor of serotonin [12]. Autopsied cerebellar cortex (outer aspect of superior semilunar Iobule) was obtained from 14 end-stage patients with the clinical diagnosis of OPCA (clinical signs of imbalance, limb ataxia, dysarthria and dysphagia) and
85 positive family history (pedigree S, n=9); pedigree Se, n=2; single patients from pedigrees C, D, and An; for description of pedigrees and some neuropathological details see ref. 6) and 10 control subjects who died without evidence of neurological or psychiatric disease. At autopsy, one half-brain was placed into formalin fixative for histopathological evaluation whereas the other halfbrain was immediately frozen at -80°C. The mean ages (controls: 37.1 _+ 5.3 years; OPCA: 40.1 + 2.6; mean + S.E.M.) and intervals between death and freezing of the brain (controls: 12.6 + 2.0 h; OPCA: 9.1 + 1.6) did not differ significantly (Student's two-tailed t-test, P>0.05). Gross inspection of the formalin-fixed half-brain revealed, in all of the cases, a severe degree of cortical cerebellar atrophy which involved both the vermis and lateral lobes. Microscopic neuropathologic analysis confirmed the diagnosis of OPCA with extensive, near-total loss of the inferior olivary cells with gliosis in all patients, together with moderate to severe neuronal loss and gliosis in basal pontine nuclei and cerebellum. The lateral cerebellar hemispheres and vermis showed a severe loss of Purkinje cells with reactive changes of Bergmann's glia, but without or only mild focal cell loss in the granule cell layer. The dorsal raphe nuclei, also examined in all patients, showed no evidence of specific qualitative or structural changes on routine and modified Bielschowsky stains; these nuclei were not, however, subjected to a quantitative morphometric study. Serotonin and 5HIAA in perchloric acid extracts were determined by the HPLC-electrochemical procedure of Felice et al. [4]. As shown in Fig. 1, mean levels of serotonin in the OPCA cerebellar cortex were not significantly different from the control values (P>0.05, Student's two-tailed ttest). Concentration of 5-HIAA, on average, was significantly elevated (+79%, P<0.02) in the OPCA patients. Similarly, the mean molar ratio 5-HIAA/serotonin, an estimate of serotonin 'turnover', was significantly (P<0.05) elevated by 148% in the OPCA patients. The results of experimental animal studies have implicated several substances as neurotransmitters/neuromodulators of the climbing fibres, including aspartate and glutamate (see ref. 13), adenosine [3], and more recently, as mentioned above, serotonin [1]. In human OPCA patients (including patients from pedigrees S and C examined in the present study) having severe inferior olivary cell loss, the observations, beginning with the early pioneering studies of Thomas Perry, of markedly reduced levels of cerebellar cortical aspartic acid [2, 5, 8, 9] are consistent with the possibility that aspartic acid might be one of the neurotransmitters of the human climbing fibre. This study represents, to our knowledge, the first examination of the behaviour of serotonin in cerebellum of patients with OPCA.
50
10
40
8
CONTROLS
30
E ~ opcA
o
O)
4
a0
i
,°t 0
L
_
_
~
~L~-~
....
SEROTONIN 5 - H I A A
~
.....
5-HIAA/SEROTONIN
Fig. 1. Serotonin, 5-HIAA (5-hydroxyindoleaceticacid), and ratio 5HIAA/serotonin in cerebellar cortex of 14 patients with dominantly inherited olivopontocerebellaratrophy (OPCA) and ten control subjects. Values represent mean _+ S.E.M. *P<0.05, "'P<0.02, Student's two-tailed t-test.
Our first major observation, the normal concentration of serotonin in OPCA cerebellar cortex despite extensive, near-total inferior olive cell loss, suggests that serotonin in human cerebellar cortex is unlikely to be derived substantially from inferior olivary-cerebellar climbing fibre innervation or be a predominant neurotransmitter of the human climbing fibre. Nevertheless, our observation that serotonin concentration, expressed per mg tissue, was not elevated in the atrophic (see above) cerebellar cortex (as occurs in some animal models of cerebellar degeneration [11]), as would be expected if there were total preservation of serotonergic afferents in the presence of tissue shrinkage, does suggest that some, probably modest, loss of serotonergic innervation, or retraction of afferents has occurred in OPCA cerebellum. The finding, in the rodent cerebellum, of near total depletion of serotonin and other presynaptic markers following climbing fibre lesion by the neurotoxin 3-acetylpyridine [1] contrasts markedly with our human data and may indicate a species difference between the human and the rodent, The possibility also has to be considered, however, as suggested by Beas-Zarate and colleagues, that in their experimental animal study, 3-acetylpyridine, in addition to lesioning the inferior olivary cells, might have damaged some extra-olivary pontomedullary cells, including raphe nuclei, which could provide a serotonergic innervation to the cerebellum. In our OPCA patients no histopathologic abnormalities were observed in the dorsal raphe nucleus (other raphe nuclei not systematically assessed). Our second major observation, the markedly elevated cerebellar concentration of 5-HIAA (+79%) and serotonin metabolite/neurotransmitter turnover ratio (+ 148%) is interesting and suggests the possibility of in-
86
creased activity of serotonergic neurones innervating the cerebellar cortex in OPCA. Elevated serotonin metabolite and turnover ratio (with normal neurotransmitter levels) of a somewhat less magnitude (+37 to +63%) has also been observed, in our laboratory, in three striatal subdivisions of the same patients examined in the present investigation [6], suggesting that the degenerative process in OPCA leads to a general activation of some lower brain stem (probably raphe) serotonergic neurones. The functional consequences of increased cerebellar serotonergic activity in the human are not known. Although serotonin appears, in experimental animal studies, to have no prominent action on spontaneous neuronal activity of cerebellar cortical neurons, it is known to modulate the effects of both excitatory and inhibitory neurotransmission [7, 10] and thus may serve an important biasing role in cerebellum [10]. Symptomatic improvement of some patients with cerebellar ataxias by the serotonin precursor 5-hydroxytryptophan [12], perhaps by the above mechanism, suggests that above-normal serotonergic activity in OPCA cerebellum, as implied by our biochemical data, might actually represent a beneficial phenomenon. Our human neurochemical data suggest the need for further experimental investigations to understand the role of the serotonin neurotransmitter system in both normal and lesioned cerebellum.
3
4
5
6
7
8
9
10
11
This study was supported by US NIH NINDS Grant NS26034 to S.K. who is a Career Scientist of the Ontario Ministry of Health.
12
1 Beas-Zarate, C., Morales-Villgran, A., Tapia-Arizmendi, G. and
Feria-Velasco, A., Effect of 3-acetylpyridine on serotonin uptake and release from rat cerebellar slices, Eur. J. Pbarmacol., 198 (1991) 714. 2 Bebin, E.M., Bebin, J., Currier, R.D., Smith, E.E. and Perry, T.L.,
13
Morphometric studies in dominant olivopontocerebellar atrophy: comparison of cell losses with amino acid decreases, Arch. Neurol., 47 (1990) 188 192. Do, K.Q., Vollenweider, F.X., Zollinger, M. and Cuenod. M., Effect of climbing fibre deprivation on the K~-ew~ked release of endogenous adenosine from rat cerebellar slices, Eur..1. Neurosci.. 3 (1990) 201 208. Felice, L.J., Felice, J.D. and Kissinger, P.T., Determination of catecholamines in rat brain parts by reverse-phase ion-pair liqt, id chromatography, J. Neurochem., 31 (1978) 1461 1465. Kish, S.J., Robitaille, Y., EI-Awar, M., Gilbert, J., Deck, J., Chang, L.J. and Schut, L., Brain amino acid reductions in one family with chromosome 6p-linked olivopontocerebellar atrophy, Ann. Neurol., 30 (1991) 780 784. Kish, S.J., Robitaille, Y., EI-Awar, M., Clark, B., Schut, L., Ball, M.J., Young, L.T., Currier, R. and Shannak, K., Striatal monoamine neurotransmitters and metabolites in dominantly-inherited olivopontocerebellar atrophy, Neurology, in press. Maura, G., Carbone, R., Maddatena, G., Pestarino, M. and Raitcri, M., 5-HT2 presynaptic receptors mediate inhibition of glutamate release from cerebellar mossy fibre terminals, Eur. J. Pharmacol., 202 (1991) 185 190. Perry~ T.L., Currier, R.D., Hansen, S. and MacLean, J., Aspartatetaurine imbalance in dominantly-inherited olivopontocerebellar atrophy, Neurology, 27 (1977) 257 261. Perry, T.L., Kish, S.J., Hansen, S. and Currier, R.D., Neurotransminer amino acids in dominantly-inherited cerebellar disorders. Neurology, 31 (1981) 237 242. Strahlendorf, J.C., Lee, M. and Strahlendorf~ H.K, Serotonin modulates muscimol- and baclofen elicited inhibition ot" cerebellar Purkinje cells, Eur. J. Pharmacol., 201 (1991) 239 242. Triarhou, L.C. and Ghetti, B., Serotonin-immunoreactivity in the cerebellum of two neurological mutant mice and the corresponding wild-type genetic stocks, J. Chem. Neuroanat., 4 (1991) 421 -428. Trouillas, P., Brudon, F. and Adeleine, P., Improvement of cerebellar ataxia with levorotatory form of 5-hydroxytryptophan: a double-blind study with quantified data processing, Arch. Neurol., 45 (1988) 1217122. Vollenweider, F.X.. Cuenod, M. and Do, K.Q., Effect of climbing fibre deprivation on release of endogenous aspartate, glutamate, and homocysteate in slices of rat cerebellar hemispheres and vermis, J. Neurochem., 54 (1990) 1533 1540.
\cmo~'h'n~'c Lc/tcr~. 144 (19921 ~4 ~f~ ~ 1992 Elsevier Scientific Publishers Ireland Ltd. All rights reserved 0304-3940/92~$ 05.00
NSL 08926
Normal serotonin but elevated 5-hydroxyindoleacetic acid concentration in cerebellar cortex of patients with dominantly-inherited olivopontocerebellar atrophy Stephen J. Kish ", Yves Robitaille b, Lawrence Schut c, Munir E1-Awar d, Melvyn J. Ball ~ and Kathleen Shannak " "Human Neurochemieal Pathology Lab, Clarke Institute of Psychiatry, Toronto (Canada), ~:Montreal Neurological Institute, Quebec (CanadaL ~University ofMinnesota, Minneapolis and United Hospital, St. Paul, MN (USA), JDepartment q/Neurology, UniversiO, of Pittsburgh, Pittsburgh, PA (USA) and "Departments of Neurology and Pathology, Oregon Health Sciences University. Portland, OR (USA) (Received 11 May 1992: Revised version received 5 June 1992: Accepted 8 June 1992)
Key words: Serotonin; Inferior olive; Cerebellum; Climbing fibre; Cerebellar ataxia; Olivopontocerebellar atrophy; 3-Acetylpyridine Beas-Zarate and coworkers (Eur. J. Pharmacol., 198 (1991) 7 14) recently reported markedly reduced concentration of presynaptic serotonin neurotransmitter markers in cerebellum of rodents which had suffered destruction of the inferior olivary-cerebellar (climbing fibre) projections by the neurotoxin 3-acetylpyridine; these experimental animal data suggested that serotonin might be one of the neurotransmitters released by climbing fibres. We measured the concentration of serotonin and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in autopsied cerebellar cortex of 14 patients with dominantly-inherited olivopontocerebellar atrophy (OPCA) who all had near-total degeneration of the inferior otivary climbing fibres. As compared with the controls, mean concentration of serotonin in cerebellar cortex of the OPCA patients was normal whereas 5-HIAA levels l+79%, P<0.02) and "turnover' ratio 5-HIAA/serotonin (+ 148%, P<0.05), on average, were significantly elevated. These data do not support the notion that serotonin is a predominant neurotransmitter of the human climbing fibre. However, the markedly elevated serotonin turnover ratio suggests the possibility of increased serotonergic neuronal activity, which might alter, and perhaps improve, the functioning of the preserved cerebellar cortical neurones in OPCA.
The mammalian cerebellar cortex receives serotonincontaining afferents which innervate all of the three (molecular, Purkinje cell, granule cell)cortical layers [11]. Although these serotonergic neurones are generally considered to arise predominantly from pontine raphe nuclei and other nuclei of the medullary and pontine reticular formation (cf. ref. IlL Beas-Zarate and coworkers [1] recently provided evidence that serotonin might be one of the neurotransmitters of the climbing fibres, which originate in the inferior olive and terminate in cerebellar cortex. In this regard, this group reported a total depletion of serotonin itself, absence of calcium-dependent serotonin release, as well as marked (-60%) reduction of serotonin uptake, in cerebellar slices of rodents who had received 3-acetylpyridine, a neurotoxin which destroys the inferior olivary-cerebellar climbing fibres. In order to examine the relationship between cerebellar serotonin Correspondence." S.J. Kish, Human Neurochemical Pathology Laboratory, Clarke Institute of Psychiatry, 250 College Street, Toronto. Ont., Canada M5T 1R8. Fax: (1) (416) 979-7871.
and the climbing fibre in the human we examined the concentration of serotonin and its major metabolite 5hydroxyindoleacetic acid (5-HIAA) in autopsied cerebellar cortex of 14 patients with end-stage dominantly-inherited olivopontocerebellar atrophy (OPCA), who all had a near total loss of the inferior olivary cells. We reasoned that if the climbing fibres provide a substantial serotonergic innervation to the human cerebellar cortex, as suggested by the Beas-Zarate study, the cerebellar cortical concentration of serotonin should be markedly reduced in OPCA. In addition, information on the behaviour of cerebellar serotonin in OPCA could have clinical implications in view of the neuromodulatory action of this substance in mammalian cerebellum [7,10] as well as the observations of improved clinical status~ in some cerebellar ataxia patients, following treatment with 5-hydroxytryptophan, the precursor of serotonin [12]. Autopsied cerebellar cortex (outer aspect of superior semilunar Iobule) was obtained from 14 end-stage patients with the clinical diagnosis of OPCA (clinical signs of imbalance, limb ataxia, dysarthria and dysphagia) and
85 positive family history (pedigree S, n=9); pedigree Se, n=2; single patients from pedigrees C, D, and An; for description of pedigrees and some neuropathological details see ref. 6) and 10 control subjects who died without evidence of neurological or psychiatric disease. At autopsy, one half-brain was placed into formalin fixative for histopathological evaluation whereas the other halfbrain was immediately frozen at -80°C. The mean ages (controls: 37.1 _+ 5.3 years; OPCA: 40.1 + 2.6; mean + S.E.M.) and intervals between death and freezing of the brain (controls: 12.6 + 2.0 h; OPCA: 9.1 + 1.6) did not differ significantly (Student's two-tailed t-test, P>0.05). Gross inspection of the formalin-fixed half-brain revealed, in all of the cases, a severe degree of cortical cerebellar atrophy which involved both the vermis and lateral lobes. Microscopic neuropathologic analysis confirmed the diagnosis of OPCA with extensive, near-total loss of the inferior olivary cells with gliosis in all patients, together with moderate to severe neuronal loss and gliosis in basal pontine nuclei and cerebellum. The lateral cerebellar hemispheres and vermis showed a severe loss of Purkinje cells with reactive changes of Bergmann's glia, but without or only mild focal cell loss in the granule cell layer. The dorsal raphe nuclei, also examined in all patients, showed no evidence of specific qualitative or structural changes on routine and modified Bielschowsky stains; these nuclei were not, however, subjected to a quantitative morphometric study. Serotonin and 5HIAA in perchloric acid extracts were determined by the HPLC-electrochemical procedure of Felice et al. [4]. As shown in Fig. 1, mean levels of serotonin in the OPCA cerebellar cortex were not significantly different from the control values (P>0.05, Student's two-tailed ttest). Concentration of 5-HIAA, on average, was significantly elevated (+79%, P<0.02) in the OPCA patients. Similarly, the mean molar ratio 5-HIAA/serotonin, an estimate of serotonin 'turnover', was significantly (P<0.05) elevated by 148% in the OPCA patients. The results of experimental animal studies have implicated several substances as neurotransmitters/neuromodulators of the climbing fibres, including aspartate and glutamate (see ref. 13), adenosine [3], and more recently, as mentioned above, serotonin [1]. In human OPCA patients (including patients from pedigrees S and C examined in the present study) having severe inferior olivary cell loss, the observations, beginning with the early pioneering studies of Thomas Perry, of markedly reduced levels of cerebellar cortical aspartic acid [2, 5, 8, 9] are consistent with the possibility that aspartic acid might be one of the neurotransmitters of the human climbing fibre. This study represents, to our knowledge, the first examination of the behaviour of serotonin in cerebellum of patients with OPCA.
50
10
40
8
CONTROLS
30
E ~ opcA
o
O)
4
a0
i
,°t 0
L
_
_
~
~L~-~
....
SEROTONIN 5 - H I A A
~
.....
5-HIAA/SEROTONIN
Fig. 1. Serotonin, 5-HIAA (5-hydroxyindoleaceticacid), and ratio 5HIAA/serotonin in cerebellar cortex of 14 patients with dominantly inherited olivopontocerebellaratrophy (OPCA) and ten control subjects. Values represent mean _+ S.E.M. *P<0.05, "'P<0.02, Student's two-tailed t-test.
Our first major observation, the normal concentration of serotonin in OPCA cerebellar cortex despite extensive, near-total inferior olive cell loss, suggests that serotonin in human cerebellar cortex is unlikely to be derived substantially from inferior olivary-cerebellar climbing fibre innervation or be a predominant neurotransmitter of the human climbing fibre. Nevertheless, our observation that serotonin concentration, expressed per mg tissue, was not elevated in the atrophic (see above) cerebellar cortex (as occurs in some animal models of cerebellar degeneration [11]), as would be expected if there were total preservation of serotonergic afferents in the presence of tissue shrinkage, does suggest that some, probably modest, loss of serotonergic innervation, or retraction of afferents has occurred in OPCA cerebellum. The finding, in the rodent cerebellum, of near total depletion of serotonin and other presynaptic markers following climbing fibre lesion by the neurotoxin 3-acetylpyridine [1] contrasts markedly with our human data and may indicate a species difference between the human and the rodent, The possibility also has to be considered, however, as suggested by Beas-Zarate and colleagues, that in their experimental animal study, 3-acetylpyridine, in addition to lesioning the inferior olivary cells, might have damaged some extra-olivary pontomedullary cells, including raphe nuclei, which could provide a serotonergic innervation to the cerebellum. In our OPCA patients no histopathologic abnormalities were observed in the dorsal raphe nucleus (other raphe nuclei not systematically assessed). Our second major observation, the markedly elevated cerebellar concentration of 5-HIAA (+79%) and serotonin metabolite/neurotransmitter turnover ratio (+ 148%) is interesting and suggests the possibility of in-
86
creased activity of serotonergic neurones innervating the cerebellar cortex in OPCA. Elevated serotonin metabolite and turnover ratio (with normal neurotransmitter levels) of a somewhat less magnitude (+37 to +63%) has also been observed, in our laboratory, in three striatal subdivisions of the same patients examined in the present investigation [6], suggesting that the degenerative process in OPCA leads to a general activation of some lower brain stem (probably raphe) serotonergic neurones. The functional consequences of increased cerebellar serotonergic activity in the human are not known. Although serotonin appears, in experimental animal studies, to have no prominent action on spontaneous neuronal activity of cerebellar cortical neurons, it is known to modulate the effects of both excitatory and inhibitory neurotransmission [7, 10] and thus may serve an important biasing role in cerebellum [10]. Symptomatic improvement of some patients with cerebellar ataxias by the serotonin precursor 5-hydroxytryptophan [12], perhaps by the above mechanism, suggests that above-normal serotonergic activity in OPCA cerebellum, as implied by our biochemical data, might actually represent a beneficial phenomenon. Our human neurochemical data suggest the need for further experimental investigations to understand the role of the serotonin neurotransmitter system in both normal and lesioned cerebellum.
3
4
5
6
7
8
9
10
11
This study was supported by US NIH NINDS Grant NS26034 to S.K. who is a Career Scientist of the Ontario Ministry of Health.
12
1 Beas-Zarate, C., Morales-Villgran, A., Tapia-Arizmendi, G. and
Feria-Velasco, A., Effect of 3-acetylpyridine on serotonin uptake and release from rat cerebellar slices, Eur. J. Pbarmacol., 198 (1991) 714. 2 Bebin, E.M., Bebin, J., Currier, R.D., Smith, E.E. and Perry, T.L.,
13
Morphometric studies in dominant olivopontocerebellar atrophy: comparison of cell losses with amino acid decreases, Arch. Neurol., 47 (1990) 188 192. Do, K.Q., Vollenweider, F.X., Zollinger, M. and Cuenod. M., Effect of climbing fibre deprivation on the K~-ew~ked release of endogenous adenosine from rat cerebellar slices, Eur..1. Neurosci.. 3 (1990) 201 208. Felice, L.J., Felice, J.D. and Kissinger, P.T., Determination of catecholamines in rat brain parts by reverse-phase ion-pair liqt, id chromatography, J. Neurochem., 31 (1978) 1461 1465. Kish, S.J., Robitaille, Y., EI-Awar, M., Gilbert, J., Deck, J., Chang, L.J. and Schut, L., Brain amino acid reductions in one family with chromosome 6p-linked olivopontocerebellar atrophy, Ann. Neurol., 30 (1991) 780 784. Kish, S.J., Robitaille, Y., EI-Awar, M., Clark, B., Schut, L., Ball, M.J., Young, L.T., Currier, R. and Shannak, K., Striatal monoamine neurotransmitters and metabolites in dominantly-inherited olivopontocerebellar atrophy, Neurology, in press. Maura, G., Carbone, R., Maddatena, G., Pestarino, M. and Raitcri, M., 5-HT2 presynaptic receptors mediate inhibition of glutamate release from cerebellar mossy fibre terminals, Eur. J. Pharmacol., 202 (1991) 185 190. Perry~ T.L., Currier, R.D., Hansen, S. and MacLean, J., Aspartatetaurine imbalance in dominantly-inherited olivopontocerebellar atrophy, Neurology, 27 (1977) 257 261. Perry, T.L., Kish, S.J., Hansen, S. and Currier, R.D., Neurotransminer amino acids in dominantly-inherited cerebellar disorders. Neurology, 31 (1981) 237 242. Strahlendorf, J.C., Lee, M. and Strahlendorf~ H.K, Serotonin modulates muscimol- and baclofen elicited inhibition ot" cerebellar Purkinje cells, Eur. J. Pharmacol., 201 (1991) 239 242. Triarhou, L.C. and Ghetti, B., Serotonin-immunoreactivity in the cerebellum of two neurological mutant mice and the corresponding wild-type genetic stocks, J. Chem. Neuroanat., 4 (1991) 421 -428. Trouillas, P., Brudon, F. and Adeleine, P., Improvement of cerebellar ataxia with levorotatory form of 5-hydroxytryptophan: a double-blind study with quantified data processing, Arch. Neurol., 45 (1988) 1217122. Vollenweider, F.X.. Cuenod, M. and Do, K.Q., Effect of climbing fibre deprivation on release of endogenous aspartate, glutamate, and homocysteate in slices of rat cerebellar hemispheres and vermis, J. Neurochem., 54 (1990) 1533 1540.