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The endogenous opioid system in Gilles de la Tourette syndrome
Medical Hypotheses19: 371-378, 1986
THE ENDOGENOUS
OPIOID
SYSTEM IN GILLES SYNDROME.
MA Gillman, R Sandyk. South African Botha Ave, 173 Louis Institute, 2192.Johannesburg. South Africa.
DE LA TOURETTE Brain Research Johannesburg.
ABSTRACT The various neurotransmitter systems postulated to be involved in the pathogenesis of Gilles de la Tourette syndrome(GTS) are described with special reference to the endogenous opioid system(EOS). Malfunction of the opioid system is proposed as the underlying disturbance in this disease causing secondary dysfunction of the other systems. Furthermore, various the symptoms of the illness are examined also in terms of dysfunction of the endogenous opioid system. INTRODUCTION. Gilles de la Tourette syndrome (GTS) is a chronic central nervous system disorder characterised by the occurance of tics, explosive vocal utteranaces and imitative phenomena problems in GTS include obsess(I) - Common concomitant ions and compulsions, sleep disorder , and aggressive behaviour (I). Intellect is usually well preserved (I). Although disturbances in a number of neurotransmitters have been put forward as possible causes of the illness, the exact pathogenesis is still unknown.This paper will discuss the possibility that all the neurotransmitter imbalances so far postulated may be secondary to an underlying dysfunction of the endogenous opioid system (EOS). NEUROCHEMICAL
EVIDENCE.
Dopamine. -_-__---
The dopaminergic supersensitivity theory has attracted attention since Seignot (2) used haloperidol major successfully in the treatment of GTS. This concept is
371
suported by the finding that postsynaptic dopamine stimulants such as methylphenidate acutely exacerbate symptoms of this illness (3). Furthermore, the low levels of homovanillic acid found in the CSF of GTS subvjects could be indicative of decreased activity of the dopaminergic system, which could lead to supersensitivity of postsynaptic receptor (4,5). The major problem with this theory is that not all cases of GTS respond favourably to neuroleptics (6). The dopaminergic system has been linked to the EOS since morphine and endogenous opioids have been shown to cause in vivo release of dopamine in the caudate nucleus (7), and dopamine enhances met-enkephalin release from the is considerable striatum in rats (8). There further evidence indicating that opioids causeactivation of dopaminergic neuronal systems It is thus (9,10,11). conceivable that malfunction of the EOS(perhaps hypoactivity) could result in hypersensitivity of postsynaptic dopaminergic receptors. Noradrenalin. -__---______ The possibility of the involvement of the nor-adrenergic system in the pathogenesis of GTS is a possibility since receptor agonist clonidine, the alpha- 2 noradrenergic appears to ameliorate the condition 2 (13,14).This effect is probably largely mediated by presynaptic inhibition of noradrenergic transmission in the locus coeruleus (15). However, other mechanisms may also be involved , since the of clonidine requires cholinergic hypotensive effects naloxone and EOS involvement since atropine (16) and (17) can block these effects. Moreover, clonidine has been shown to cause the release of beta-endorphins (18). This highlights the posssible connection between the EOS and the therapeutic effects of clonidine in GTS. In addition, since not all cases of GTS respond to clonidine (6) , the noradrenergic involvement may be a compensation for some other primary patdhology that may be related to the SOS. Serotonin
(5-HT).
with both L-tryptophan (19) and a Although trials serotonin blocker (20) have failed to provide conclusive in this evidence of the involvemlent of serotonin from GTS show low some patients suffering condition, accumulation of 5-hydroyindole acetic acid (5HIAA) in the probenicid loading (4). This latter factor CSF following to the dopamine efect (vide suspra) may is analagous indicate postsynaptic serotonin receptor supersensitivity these discrepant results may indicate in GTS. However again, that the serotoninergic involvement is compensatory to some other underlying disorder. The serotonergic system appears to be linked to the EOS, since morphine and an enkephalin analogue can cause the release of serotonin 372
(21) and beta-endorphin raises levels of serotonin and 5HIAA in the CNS (22). Furthermore, lowering of serotonin in within the brain causes an increase levels metenkephalin levels ( 23). It is thus possible that the involvement of the serotonergic system could be secondary to a malfunction of the EOS.
Acetylcholine --_--_--__--Physostigmine has been shown to increase tic production (the cholinergic antagonist) (24). However, scopolamine the therapeutic also has this effect (25). Moreover effects of clonidine may be mediated partly by cholinergic is well known in addition , that a mechanisms (16). It and exists between the dopaminergic relationship disturbancas such as cholinergic systems in motor (26).These Parkinson's disease and Huntington's chorea discrepant results may also indicate a compensatory role for the cholinergic system in the pathogenesis of GTS. Interestingly, physostigmine has been shown to cause elevation of beta-endorphin levels (27), and there is between the anatomical evidence showing contact cholinergic system and the EOS (28). It is thus possible that the therapeutic effects of cholinomimetics could be mediated by the EOS. Gamma-aminobutyric acid (GABA) _----_----_-~~~~~~~~~~~ Clonazepam has been shown in one study to ameliorate the symptoms of some patients suffering from GTS (29). This effect could possibly be mediated via potentiation of the GABA-ergic system. Since psychological factors such as stress and anxiety appear to be implicated in the production of some symptoms of GTS (I), the role of the GABAergic system may be important. Furthermore, the antianxiety and anti-stress effects of GABA have been related to opioid mechanisms. For instance, the anxiolytic effect of diazepam can be attenuated by naloxone (30). Much other work has been presented showing that GABA and GABA-ergic drugs increase the activity of the EOS (21,31). It is thus possible that hypoactivity of the EOS could result in decreased activity of the GABA-ergic system, with the production of tics. The Endogenous opioid system. -----------_--_----__--_____ From the above discussion it is clear that the EOS is related to the function of neurotransmitters which according to the latest evidence appear to be involved in the pathogenesis of GTS. Furthermore, using analgesic concentrations of nitrous oxide (an opioid agonist ) (3237) I we have shown that this agent produces a naloxone reversible reduction in the symptoms of GTS (38).This provides further evidence for the possibility that a key 373
pathogenic
factor in GTS may be a malfunction
of the EOS.
Furthermore, the butyrophenones such as haloperidol and pimozide which are useful in treating GTS have been shown to have substantial affinity for opioid receptors (39). Interestingly some of the butyrophenones have greater affinity for opioid receptors than pethidine and propoxyphene (39). Moreover, haloperiodol can potentiate morphine analgesia and prevent the development of tolerance and dependence to morphine (40). This information quite clearly supports the notion that modulation of the EOS is of crucial importance in both the pathogenesis and treatment of GTS. SYMPTOMS OF GTS AND THE EOS. Thought disorders and obsessive behaviour : GTS has been described as a "psychosis with multiple tics" (I). Overactivity of the EOS has been implicated as a possible disorder in shizophrenia (41).Stress has been shown to activate the EOS (42).We postulate that GTS is caused by malfunction of the opioid system. It is thus possible that opioid receptors become supersensitive in the course of this illness and that release of endorphins secondary to stress could conceivably cause psychotic behaviour. An obsessive-compulsive disorder is frequently reported in cases of GTS (I). This condition is probably mediated at least, to some extent by hypoactivity of the EOS, since naloxone has been shown to aggravate symptoms of this condition (43). Aggressive behaviour : As mentioned earlier, the EOs (vide supra) appears to be linked to the serotoninergic system. Subjects committing violent crimes have been shown to have lowered levels of 5-HlAAA in their CSF (44). Underactivity of the serotoninergic system maky be related to hypoactivity of the EOS, thus giving rise to aggressive behaviour.Furthermore, the EOS seems to reduce conflict behaviour.(32). Sexual behaviour : Aabnormal sexual behaiour and thoughts are often symptoms of GTS (I). The EOS has been implicated been shown in sexual behaviour (43,45) and naloxone has to increase to sexual activity (46). It is thus possible that hypoactivity of the EOS could result in disorders of sexual behaviour. CONCLUSIONS probably involving an GTS is a complex CNS disorder, alluded to above interplay of all the neurotransmitters The as well as some that have not been mentioned. by the complexity of the illness is further compounded well known waxing and waning of symptoms which often 374
characterises the disease (I). It thus appears compenstion may be periods of neurotransmitter pensation during the course of this illness.
that there and decom-
This paper presents evidence that the EOS may play a key part in the pathogenesis of GTS. It is therefore possible that further investigations into the role of the EOS in GTS may throw light on the pathophysiology of this enigmatic disorder. REFERENCES. Gilles de la Tourette of 1. Devinsky 0. Neuroanatomy involvement.Arch Neurol. syndrome.Possible midbrain 40:508-514,1983. 2. Seignot MJN. Un cas de maladie des tics de Gilles de la Tourette syndrome gueri nar le R-1625. Ann Med Psycho1 119: 578-9,196l. 3. Golden GS.Gilles de la Tourette syndrome following methylphenidate administration.Dev Child Neurol 16:7678,1974. 4
W,Caprpiolli RM,Singer Butler IJ, Korlow S,Seifert HS.Biogenic amine metabolism in Tourette syndrome.Ann Neurol. 6 : 37-39, 1979.
BA,Young JG,LCarbonari CAN. et al. 5. Cohen DJ,Shaywitz Centralbiogenic amine metaolism in children with the syndrome of chronic multiple tics of Gilles de la Tourette : Norepinephrine, serotonin and dopamine. J AM Acad Child Psychaitry 18: 320-341, 1979. 6. Shapiro AK,Shapiro E,Eisenkrafdt GJ.Treatment of Gilles de la Tourette syndrome with clonidine and 40: 1235-1240,1983. neuroleptics.Arch Gen Psychiatry 7. Chesselet MF,Cheramy A, Reisine TD, Glowinski J. Morphine and delta-opiate agonists locally stimulate in vivo dopamine release in cat caudate nucleus.Nature 291: 320-322, 1981. 8. Pasinetti G, Govoni S,Di Giovine S, Spano PF, Trabucchi M.Dopamine enhances met-enkephalin efflux from rat striatal slices. Brain Res 293: 364-367, 1984. 9. Gysling K,Wang RY. Morphine-induced activation of Dopamine neurones in the rat. Brain Res.. 277: 127, 1983.
A10 119-
lO.Ostrowski NL, Hatfield CB,Caggiula AR, The effects of low doses of morphine on the activity of dopamine containing cells and on behaviour. Life Sci. 31:23472350,1982. 375
ll.Joyce EM,Iversen SD. The effects of morphine applied locally to metencephalic dopamine cell bodies on spontaneous motor activity in the rat. Neuroscience Letters. 14: 207-212,1979. 12.Gunne LM,Jonsson J, Fuxe K.Effects of morphine intoxications on brain catecholamines neurons.Eur JPharmacol. 5: 338-342,1969. 13.Brunn RD. Clonidine treatment of Tourette Syndrome : In Freidhoff AJ, Chase TN feds): Gilles de la Tourette syndrome.New York, Raven Press, pp. 403-405. BA. Clonidine 14.Cohen DJ,Nathanson JA, Shaywitz Tourette syndrome. Lancet 2 : 551-553, 1979.
in
15.Cedarbaum JM,Aghajanian GK.Catecholamine receptors on locus coeruleus neurons : Pharmacological characterisation.Eur J Pharmacol 44: 375 - 385, 1977. of 16.Srimal RC, Gulati K, Dhawan BN.On the mechanisms central hypotensive actions of clonidine.Can J Physiol. Pharmacol 55 : 100 - 1014, 1977. 17.Farsang C, Kunos G.Naloxone reverses the antihypertensive effects of clonidine.Br J Pharmacol. 67 : 161-64, 1979. 18.Pettibone DJ, Mueller GP. Clonidine releases immunoreactive beta-endorphin from rat pars distalis.Brain Res. 221:409-414,1981. 19.Van Woert MH, Lip LC,Balis MF . Long term therapy of myoclonus and other neurologic disorders with L-5 hydroxytryptophan and carbidopa. N Engl J Med 296: 7075, 1977. 20.Shapiro AK,Shapiro E,Bruin RD, Sweet RD. Gilles Tourette syndrome. Raven Press , New York. 1978.
de la
21.Pycock CJ,Burns S,Morris R. In vitro release of 5hydroxytryptamine and gamma amino-butyric acid from rat periaqueductal gray and raphe dorsalis region produced by morphine or an enkephalin analogue. Neuroscience letters. 22: 313-317, 1981. 22.Van Loon GR. De Souza EB. Effects of beta-endorphin on brain serotonin metabolism.Life Sci 23: 971-978, 1978. A. 23.Dellaveodova L, Parenti M,Titrone F, Groppetti Interactions between serotonergic and enkephalinergic and hypothalamus.Eur J neurons in rat striatum Pharmacol , 85; 29-34, 1982. 24.Stahl
SA,Berger
PA.
Physostigmine 376
in Gilles
de
la
Tourette syndr0me.N Eng J Med. 203: 298,198O. 25.Tanner CM,Goetz CJ, Klawans HL. Cholinergic and anticholinergic effects in Tourette syndrome ; abstract 60 Programme and abstracts of the first International Gilles de la Tourette syndrome symposium.New York, May, 1981. 26.Weiner WJ, Klawans HL. Cholinergic-monoaminergic interactions within the striatum : Implications for choreiform disorders.In :Cholinergic-monoaminergic intereactions in the brain.Butche (eds) 335 -382, 1978. 27.Risch SC,Cohen RM,Janowsky DS,Kalin NH, Murphy DL. Mood and behavioural effects of physostigmine on humans are accompanied by elevations in plasma beta-endorphin and cortisol.Science ,209 : 1545-1547, 1980. 28.Sar M,Stumpf WE,Miller RJ, Chang K,Cuatrecases P Immunohistochemical localisation of enkephalin in rat brain and spinal cord.J Comp Neurol 182 : 17-38, 1978. 29.Gonce M, Barbeau A. Seven cases of Gilles de la Tourette syndrome: partial relief with clonazepam : A pilot study.Canad J Neurol Sci.4: 279-283, 1977. 30.Cooper SJ. Benzodiazepine-opiate antagonist intereactions in relation to anxiety and appetite.Trends Pharmacol SC. 4 : 456-458, 1983. 3l.Sawynok J,Labella F.GABA and Baclofen potentiate the Kfrom rat evoked release of methionine-enkephalin striatal slices. Eur J Pharmacol 63:103-110, 1981. oxide Nitrous SH,Finck AD. BA,Ngai 32.Berkowitz analgesia:reversal by naloxone and development of tolerance. J Pharmacol Exp Ther 203: 539-547, 1976. 33.Hynes MD,Berkowitz BA.Nitrous oxide stimulation of locomotor activity : Evidence for opiate-like behaioural effeclt . J Pharmacol Ex Ther . 209 : 304-308, 1979. FJ. The paradoxical 34.Gillman MA, Kok L,Lichtigfeld effects of naloxone on nitrous oxide analgesia in man. Eur J Pharmacol 161: 175-177, 1980. 35.Gillman MA,Lichtigfeld FJ.A comparison of the effects of morphine sulphate and nitrous oxide on chronic pain state im man. J Neurolog Sci. 49:41-45, 1981. 36.Yang JC,Clark WC,Ngai SH. Antagonism of nitrous oxide , 52: 414analgesia by naloxone in man.Anesthesiology 417, 1980.
377
MA. 3H naloxone displacement 37.Daras C, Cantrill :evidence for nitrous oxide as opioid receptor agonist.Eur J Pharmacol 89: 177-178, 1983. 38.Gillman MA, Sandyk R.Tourette syndrome concentrations of nitrous analgesic naloxone.Br M J 288: 114, 1984.
:
effect of oxide and
AP,Snyder SH. Butyrophenone 1,Feinberg 39.Creese influences on the opiate receptor.Eur J Pharmacol 36 : 231-236, 1976. 40.Eidelberg E, Espamer R. in brain opiate actions 192:50-56, 1975.
Dopaminergic mechanisms of .J Pharmacol Exp Ther.
41 Berger PAM,Akil H,Watson SJ, Barchas JD. Behavioral pharmacology of the endorphins.Ann Rev Med. 33:397415,19872. 42.Guillemin R,Vargo T, Rossier J et al.Beta endorphin and adreno-corticotropin are secreted concomitantly by the pituitary gland. Science 197: 1367-1369, 1977. administration in D. Naloxone 43.Insel TR, Pickar obsessive compulsive disorder. Report of 2 cases. Am J Psychiatry.140: 1219-1220, 1983. 44.Van Praag HM.Depression
.Lancet 2: 1259-1264,1982.
45.Gillman MA,Lichtigfeld FJ. The effects of nitrous oxide and naloxone on orgasm in humlan females : A preliminary report. J Sex Res 19: 49-57, 1983. 46.Gessa GI, Paglietti E .Pelllegrini B. Induction copulatory behavior in sexually inactive rats naloxone. Science 204 : 203-205, 1979 Acknowledgements. ~~~~~-_----_---_ This work was supported by a Grant from ANLO AMERICAN CORPORATION OF SOUTH AFRICA.
378
of by
THE ENDOGENOUS
OPIOID
SYSTEM IN GILLES SYNDROME.
MA Gillman, R Sandyk. South African Botha Ave, 173 Louis Institute, 2192.Johannesburg. South Africa.
DE LA TOURETTE Brain Research Johannesburg.
ABSTRACT The various neurotransmitter systems postulated to be involved in the pathogenesis of Gilles de la Tourette syndrome(GTS) are described with special reference to the endogenous opioid system(EOS). Malfunction of the opioid system is proposed as the underlying disturbance in this disease causing secondary dysfunction of the other systems. Furthermore, various the symptoms of the illness are examined also in terms of dysfunction of the endogenous opioid system. INTRODUCTION. Gilles de la Tourette syndrome (GTS) is a chronic central nervous system disorder characterised by the occurance of tics, explosive vocal utteranaces and imitative phenomena problems in GTS include obsess(I) - Common concomitant ions and compulsions, sleep disorder , and aggressive behaviour (I). Intellect is usually well preserved (I). Although disturbances in a number of neurotransmitters have been put forward as possible causes of the illness, the exact pathogenesis is still unknown.This paper will discuss the possibility that all the neurotransmitter imbalances so far postulated may be secondary to an underlying dysfunction of the endogenous opioid system (EOS). NEUROCHEMICAL
EVIDENCE.
Dopamine. -_-__---
The dopaminergic supersensitivity theory has attracted attention since Seignot (2) used haloperidol major successfully in the treatment of GTS. This concept is
371
suported by the finding that postsynaptic dopamine stimulants such as methylphenidate acutely exacerbate symptoms of this illness (3). Furthermore, the low levels of homovanillic acid found in the CSF of GTS subvjects could be indicative of decreased activity of the dopaminergic system, which could lead to supersensitivity of postsynaptic receptor (4,5). The major problem with this theory is that not all cases of GTS respond favourably to neuroleptics (6). The dopaminergic system has been linked to the EOS since morphine and endogenous opioids have been shown to cause in vivo release of dopamine in the caudate nucleus (7), and dopamine enhances met-enkephalin release from the is considerable striatum in rats (8). There further evidence indicating that opioids causeactivation of dopaminergic neuronal systems It is thus (9,10,11). conceivable that malfunction of the EOS(perhaps hypoactivity) could result in hypersensitivity of postsynaptic dopaminergic receptors. Noradrenalin. -__---______ The possibility of the involvement of the nor-adrenergic system in the pathogenesis of GTS is a possibility since receptor agonist clonidine, the alpha- 2 noradrenergic appears to ameliorate the condition 2 (13,14).This effect is probably largely mediated by presynaptic inhibition of noradrenergic transmission in the locus coeruleus (15). However, other mechanisms may also be involved , since the of clonidine requires cholinergic hypotensive effects naloxone and EOS involvement since atropine (16) and (17) can block these effects. Moreover, clonidine has been shown to cause the release of beta-endorphins (18). This highlights the posssible connection between the EOS and the therapeutic effects of clonidine in GTS. In addition, since not all cases of GTS respond to clonidine (6) , the noradrenergic involvement may be a compensation for some other primary patdhology that may be related to the SOS. Serotonin
(5-HT).
with both L-tryptophan (19) and a Although trials serotonin blocker (20) have failed to provide conclusive in this evidence of the involvemlent of serotonin from GTS show low some patients suffering condition, accumulation of 5-hydroyindole acetic acid (5HIAA) in the probenicid loading (4). This latter factor CSF following to the dopamine efect (vide suspra) may is analagous indicate postsynaptic serotonin receptor supersensitivity these discrepant results may indicate in GTS. However again, that the serotoninergic involvement is compensatory to some other underlying disorder. The serotonergic system appears to be linked to the EOS, since morphine and an enkephalin analogue can cause the release of serotonin 372
(21) and beta-endorphin raises levels of serotonin and 5HIAA in the CNS (22). Furthermore, lowering of serotonin in within the brain causes an increase levels metenkephalin levels ( 23). It is thus possible that the involvement of the serotonergic system could be secondary to a malfunction of the EOS.
Acetylcholine --_--_--__--Physostigmine has been shown to increase tic production (the cholinergic antagonist) (24). However, scopolamine the therapeutic also has this effect (25). Moreover effects of clonidine may be mediated partly by cholinergic is well known in addition , that a mechanisms (16). It and exists between the dopaminergic relationship disturbancas such as cholinergic systems in motor (26).These Parkinson's disease and Huntington's chorea discrepant results may also indicate a compensatory role for the cholinergic system in the pathogenesis of GTS. Interestingly, physostigmine has been shown to cause elevation of beta-endorphin levels (27), and there is between the anatomical evidence showing contact cholinergic system and the EOS (28). It is thus possible that the therapeutic effects of cholinomimetics could be mediated by the EOS. Gamma-aminobutyric acid (GABA) _----_----_-~~~~~~~~~~~ Clonazepam has been shown in one study to ameliorate the symptoms of some patients suffering from GTS (29). This effect could possibly be mediated via potentiation of the GABA-ergic system. Since psychological factors such as stress and anxiety appear to be implicated in the production of some symptoms of GTS (I), the role of the GABAergic system may be important. Furthermore, the antianxiety and anti-stress effects of GABA have been related to opioid mechanisms. For instance, the anxiolytic effect of diazepam can be attenuated by naloxone (30). Much other work has been presented showing that GABA and GABA-ergic drugs increase the activity of the EOS (21,31). It is thus possible that hypoactivity of the EOS could result in decreased activity of the GABA-ergic system, with the production of tics. The Endogenous opioid system. -----------_--_----__--_____ From the above discussion it is clear that the EOS is related to the function of neurotransmitters which according to the latest evidence appear to be involved in the pathogenesis of GTS. Furthermore, using analgesic concentrations of nitrous oxide (an opioid agonist ) (3237) I we have shown that this agent produces a naloxone reversible reduction in the symptoms of GTS (38).This provides further evidence for the possibility that a key 373
pathogenic
factor in GTS may be a malfunction
of the EOS.
Furthermore, the butyrophenones such as haloperidol and pimozide which are useful in treating GTS have been shown to have substantial affinity for opioid receptors (39). Interestingly some of the butyrophenones have greater affinity for opioid receptors than pethidine and propoxyphene (39). Moreover, haloperiodol can potentiate morphine analgesia and prevent the development of tolerance and dependence to morphine (40). This information quite clearly supports the notion that modulation of the EOS is of crucial importance in both the pathogenesis and treatment of GTS. SYMPTOMS OF GTS AND THE EOS. Thought disorders and obsessive behaviour : GTS has been described as a "psychosis with multiple tics" (I). Overactivity of the EOS has been implicated as a possible disorder in shizophrenia (41).Stress has been shown to activate the EOS (42).We postulate that GTS is caused by malfunction of the opioid system. It is thus possible that opioid receptors become supersensitive in the course of this illness and that release of endorphins secondary to stress could conceivably cause psychotic behaviour. An obsessive-compulsive disorder is frequently reported in cases of GTS (I). This condition is probably mediated at least, to some extent by hypoactivity of the EOS, since naloxone has been shown to aggravate symptoms of this condition (43). Aggressive behaviour : As mentioned earlier, the EOs (vide supra) appears to be linked to the serotoninergic system. Subjects committing violent crimes have been shown to have lowered levels of 5-HlAAA in their CSF (44). Underactivity of the serotoninergic system maky be related to hypoactivity of the EOS, thus giving rise to aggressive behaviour.Furthermore, the EOS seems to reduce conflict behaviour.(32). Sexual behaviour : Aabnormal sexual behaiour and thoughts are often symptoms of GTS (I). The EOS has been implicated been shown in sexual behaviour (43,45) and naloxone has to increase to sexual activity (46). It is thus possible that hypoactivity of the EOS could result in disorders of sexual behaviour. CONCLUSIONS probably involving an GTS is a complex CNS disorder, alluded to above interplay of all the neurotransmitters The as well as some that have not been mentioned. by the complexity of the illness is further compounded well known waxing and waning of symptoms which often 374
characterises the disease (I). It thus appears compenstion may be periods of neurotransmitter pensation during the course of this illness.
that there and decom-
This paper presents evidence that the EOS may play a key part in the pathogenesis of GTS. It is therefore possible that further investigations into the role of the EOS in GTS may throw light on the pathophysiology of this enigmatic disorder. REFERENCES. Gilles de la Tourette of 1. Devinsky 0. Neuroanatomy involvement.Arch Neurol. syndrome.Possible midbrain 40:508-514,1983. 2. Seignot MJN. Un cas de maladie des tics de Gilles de la Tourette syndrome gueri nar le R-1625. Ann Med Psycho1 119: 578-9,196l. 3. Golden GS.Gilles de la Tourette syndrome following methylphenidate administration.Dev Child Neurol 16:7678,1974. 4
W,Caprpiolli RM,Singer Butler IJ, Korlow S,Seifert HS.Biogenic amine metabolism in Tourette syndrome.Ann Neurol. 6 : 37-39, 1979.
BA,Young JG,LCarbonari CAN. et al. 5. Cohen DJ,Shaywitz Centralbiogenic amine metaolism in children with the syndrome of chronic multiple tics of Gilles de la Tourette : Norepinephrine, serotonin and dopamine. J AM Acad Child Psychaitry 18: 320-341, 1979. 6. Shapiro AK,Shapiro E,Eisenkrafdt GJ.Treatment of Gilles de la Tourette syndrome with clonidine and 40: 1235-1240,1983. neuroleptics.Arch Gen Psychiatry 7. Chesselet MF,Cheramy A, Reisine TD, Glowinski J. Morphine and delta-opiate agonists locally stimulate in vivo dopamine release in cat caudate nucleus.Nature 291: 320-322, 1981. 8. Pasinetti G, Govoni S,Di Giovine S, Spano PF, Trabucchi M.Dopamine enhances met-enkephalin efflux from rat striatal slices. Brain Res 293: 364-367, 1984. 9. Gysling K,Wang RY. Morphine-induced activation of Dopamine neurones in the rat. Brain Res.. 277: 127, 1983.
A10 119-
lO.Ostrowski NL, Hatfield CB,Caggiula AR, The effects of low doses of morphine on the activity of dopamine containing cells and on behaviour. Life Sci. 31:23472350,1982. 375
ll.Joyce EM,Iversen SD. The effects of morphine applied locally to metencephalic dopamine cell bodies on spontaneous motor activity in the rat. Neuroscience Letters. 14: 207-212,1979. 12.Gunne LM,Jonsson J, Fuxe K.Effects of morphine intoxications on brain catecholamines neurons.Eur JPharmacol. 5: 338-342,1969. 13.Brunn RD. Clonidine treatment of Tourette Syndrome : In Freidhoff AJ, Chase TN feds): Gilles de la Tourette syndrome.New York, Raven Press, pp. 403-405. BA. Clonidine 14.Cohen DJ,Nathanson JA, Shaywitz Tourette syndrome. Lancet 2 : 551-553, 1979.
in
15.Cedarbaum JM,Aghajanian GK.Catecholamine receptors on locus coeruleus neurons : Pharmacological characterisation.Eur J Pharmacol 44: 375 - 385, 1977. of 16.Srimal RC, Gulati K, Dhawan BN.On the mechanisms central hypotensive actions of clonidine.Can J Physiol. Pharmacol 55 : 100 - 1014, 1977. 17.Farsang C, Kunos G.Naloxone reverses the antihypertensive effects of clonidine.Br J Pharmacol. 67 : 161-64, 1979. 18.Pettibone DJ, Mueller GP. Clonidine releases immunoreactive beta-endorphin from rat pars distalis.Brain Res. 221:409-414,1981. 19.Van Woert MH, Lip LC,Balis MF . Long term therapy of myoclonus and other neurologic disorders with L-5 hydroxytryptophan and carbidopa. N Engl J Med 296: 7075, 1977. 20.Shapiro AK,Shapiro E,Bruin RD, Sweet RD. Gilles Tourette syndrome. Raven Press , New York. 1978.
de la
21.Pycock CJ,Burns S,Morris R. In vitro release of 5hydroxytryptamine and gamma amino-butyric acid from rat periaqueductal gray and raphe dorsalis region produced by morphine or an enkephalin analogue. Neuroscience letters. 22: 313-317, 1981. 22.Van Loon GR. De Souza EB. Effects of beta-endorphin on brain serotonin metabolism.Life Sci 23: 971-978, 1978. A. 23.Dellaveodova L, Parenti M,Titrone F, Groppetti Interactions between serotonergic and enkephalinergic and hypothalamus.Eur J neurons in rat striatum Pharmacol , 85; 29-34, 1982. 24.Stahl
SA,Berger
PA.
Physostigmine 376
in Gilles
de
la
Tourette syndr0me.N Eng J Med. 203: 298,198O. 25.Tanner CM,Goetz CJ, Klawans HL. Cholinergic and anticholinergic effects in Tourette syndrome ; abstract 60 Programme and abstracts of the first International Gilles de la Tourette syndrome symposium.New York, May, 1981. 26.Weiner WJ, Klawans HL. Cholinergic-monoaminergic interactions within the striatum : Implications for choreiform disorders.In :Cholinergic-monoaminergic intereactions in the brain.Butche (eds) 335 -382, 1978. 27.Risch SC,Cohen RM,Janowsky DS,Kalin NH, Murphy DL. Mood and behavioural effects of physostigmine on humans are accompanied by elevations in plasma beta-endorphin and cortisol.Science ,209 : 1545-1547, 1980. 28.Sar M,Stumpf WE,Miller RJ, Chang K,Cuatrecases P Immunohistochemical localisation of enkephalin in rat brain and spinal cord.J Comp Neurol 182 : 17-38, 1978. 29.Gonce M, Barbeau A. Seven cases of Gilles de la Tourette syndrome: partial relief with clonazepam : A pilot study.Canad J Neurol Sci.4: 279-283, 1977. 30.Cooper SJ. Benzodiazepine-opiate antagonist intereactions in relation to anxiety and appetite.Trends Pharmacol SC. 4 : 456-458, 1983. 3l.Sawynok J,Labella F.GABA and Baclofen potentiate the Kfrom rat evoked release of methionine-enkephalin striatal slices. Eur J Pharmacol 63:103-110, 1981. oxide Nitrous SH,Finck AD. BA,Ngai 32.Berkowitz analgesia:reversal by naloxone and development of tolerance. J Pharmacol Exp Ther 203: 539-547, 1976. 33.Hynes MD,Berkowitz BA.Nitrous oxide stimulation of locomotor activity : Evidence for opiate-like behaioural effeclt . J Pharmacol Ex Ther . 209 : 304-308, 1979. FJ. The paradoxical 34.Gillman MA, Kok L,Lichtigfeld effects of naloxone on nitrous oxide analgesia in man. Eur J Pharmacol 161: 175-177, 1980. 35.Gillman MA,Lichtigfeld FJ.A comparison of the effects of morphine sulphate and nitrous oxide on chronic pain state im man. J Neurolog Sci. 49:41-45, 1981. 36.Yang JC,Clark WC,Ngai SH. Antagonism of nitrous oxide , 52: 414analgesia by naloxone in man.Anesthesiology 417, 1980.
377
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