1. The dopamine hypothesis Where did it all start? Birgit Högl Dept. of Neurology, Innsbruck Medical University, Austria

2. Arch Neurol Vol 39, Nov 1982, Letters to the Editor 5 patients, 200 mg in 4, 500-750 in 5th Bromocr. and codeine also helpful, whereas pimozide worsened RLS may result from IA of biogenic amines, or between endorphins and DA, triggered by relaxation and sleep in susceptible individuals

3. Am J Psychiatry 142:5, May 1985

5. Montplaisir 1985 l 5 generations of RLS in family l 3 underwent PSG, PLM confirmed in 2 l CSF in index patient: free dopamine and HVA increased l PSG 8 nights (3 baseline, 5 treatment: 0,5, 1, 2, 4 mg clonazepam) LP at 8 a.m. in rest: ⇑ free NA, ⇑ free DA, ⇑ HVA (all in the CSF, not in serum) l PMS in wakefulness less periodic, clonazepam helped „RLS and PLMS represent 2 clinical manifestations of the same CNS dysfunction“ Bruxism and PMS are repetitive stereotype motor behaviors in sleep“ Both conditions may appear as side effects of levodopa, suggesting increased dopaminergic activity

8. Montplaisir 1986 l 7 patients with RLS and PLM at baseline and after treatment of levodopa l Sleep and RLS improved l PMS reduced during first third, and rebound during last third of the night „These results and previous biochemical findings raise the hypothesis that RLS and PMS may...result from reduced dopaminergic activity in the CNS, perhaps resulting from decreased sensibility of postsynaptic receptors“

9. Montplaisir 1986 Refer to hypothesis of increased DA activity as potential cause of ⇑ DA and ⇑ HVA in CSF l Later treated patients with GHB („thought to block release of DA in CNS“): marked increase of RLS and PMS, followed by suppression: biphasic effect? l New hypothesis: RLS and PMS may results from decreased dopaminergic activity in the CNS l L-dopa is effective for RLS and PMS (not only RLS alone) l Effect of L-dopa on RLS and PMS and results with GHB support hypothesis that central DA may be involved in physiopathology of these conditions l In addition, homocriptine was effective, whereas pimozide worsened PLM PMS related to age, and DA binding and HVA turnover decreased in normal aging

10. Montplaisir 1986 l PMS are frequent in narcolepsy, where low DA and HVA and increased HVA turnover are found l DA mechanisms involved in RLS and PMS in various conditions. In narcolepsy, may result from ⇓ availability of DA In insomnia associated with RLS and PMS basic machanism is not a decrease in the biosynthesis or release of DA. Rather it could be impaired sensitivity of post synaptic receptors l Role of spinal dopamine cells

12. Akpinar 1987 16 RLS plus insomnia Treated with L-dopa (13), bromocriptine (2), pimozide (1) Decreased awakenings and wake times „dysfunction of dopamine system triggered by sleep, and resting and dopaminergic potentiation by drugs affect symptoms“ „To get rid of symptoms patient move the legs, walk about, eat something, rub and massage the limbs or stand up“ Patients with mild symptoms of RLS are common, but they do not seek medical advise (refers to Ekbom 1945) Severity related to number of awakenings Drug or placebo in double blind cross over trial All had upleasant sensations, many pain, 13 PMS Levodopa helpful on sleep, treatment followed 0,5 – 5 years

13. Case 1, age 56 l RLS for 23 years, also RLS in mother, sister and daughter l Severe insomnia due to sensations and nocturnal myoclonus l Pretreated with „large and combined dose of sevatives“ (barbiturate, antidepressants, benzodiazepines): RLS worsened, insomnia continued l Slight and temporary benefit from diazepam, B12 and electrical stimulations l In 1978 admitted to our hospital for sleep study. Long wakefulness and sleep stage 1. l Treatment with nitrazepam (2,5-5 mg), diazepam (5-10 mg), diphenylhydantoin (100-200 mg), carbamazepin (400-600 mg) and amytriptylin (20-100 mg) were not effective on RLS, pimozide (10- 30 mg) worsened the symptoms, cholrdiazepoxied mild help

14. l 2 years later the patient was rehospitalized suicidal due to very severe and unremitting RLS. The following drugs were tried: baclophen (15 mg), methysergide (2 mg), no result, biperiden (6-8 mg) gave some relief l 14 days later, on April 18, 1980 100 mg levodopa plus 25 mg benserazide was given 1 hour before bedtime. l „This was the first time the patient ever slept continously for 2 hours without symptoms of RLS.“ Reoccurance of symptoms with placebo l Maintenance treatment: 200/50 mg L-dopa at 10 p.m., midnight, and 125 mg at 4 a.m. Content with dosage until 1983. Than bromocriptine was added. l During MI treatment in 1973, morphine helped once

16. Akpinar 1987 (cont) l RLS disappearence with high fever may be related to activation of the body´s dopamine stores: drugs that stimulate central dopamine receptors or increased availability of dopamine at these receptors cause hypothermia (Dillmann: effects of iron deficiency on catecholamine metabolism and body temperature regulation1982)

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18. Guilleminault 1987 l PLM in elderly subjects free of RLS l 11 patients with nocturnal sleep disturbances and early morning awakening l None had narcolepsy, RLS or sleep apnea l 5 patients treated with hydroxytryptophan, 6 patients treated with levodopa and dopadecarboxylase inhibitor (additionally) l PSG monitoring at baseline and during acute and chronic treatment l Polysomnography with tibialis anterior monitoring at baseline and during first nights of treatment l 5HTP: PLMI and PLMRI unchanged up to 1500 mg l Levodopa and carbidopa: definite reduction of PLM

19. Guilleminault 1987 l Conclusions: PLM even without RLS can be improved with levodopa/carbidopa l Complete elimination of PLM and PLMR not possible l PLM tend to cluster at the end of the night in patients receiving levodopa l 1 patient unchanged with levodopa, discussed possibility of different etiology of PLM syndrome l Authors suggest evaluation of lower extremity blood circulation during sleep

21. Pall 1987 l Disturbances in transition element metabolism, notably iron, in RLS pathogenesis l Background: association of iron deficiency and RLS, treatment response l Radioisotope labeled opiate agonist binding to receptor sites reduced in presence of metal chelating agents but restored by divalent metal ions l Iron is part of dopamine D2 receptor, and metal chelating agents such as desferrioxamine inactivate these receptors, presumably by removing the iron l RLS similar to neuroleptic induced akathisia, dopamine receptor antagonists are metal chelating agents l neuroleptic therapeutic and harmful effects possibly related to their interaction with iron within the D2 receptor l Levodopa ligates with metal ions l Suggest that abnormalities of iron metabolism may be common link between the widely varying clinical associations of RLS and equally varying treatment responses.

22. Walters 1988 l First double blind randomized crossover treatment study l 7.5 bromocriptine l Improvement in restlessness and paresthesias in 5/6, PSG PLM reduction and sleep improvement Walters AS, Hening WA, Kavey N, Chokroverty S, Gidro-Frank BA. Ann Neurol 1988, 24:455-458

23. Walters 1991 l Neuroleptic induced akathisia is a condition similar but not identical to that caused by idiopathic familial RLS l Neuroleptics block dopamine receptor, therefore hypothesis: Idiopathic familial RLS may be caused by a defect that either primarily or secondarily affects dopamine synthesis and / or transmission Walters, Hening, Rubinstein, Chokroverty

24. Backup

26. Missak 1989 l RLS is thought to be due to a caffeine like substance produced by the human body –It is possible that a metabolite of caffeine interacts with dopamine receptors –High concentration of free dopamine in CSF ( Montplaisir 1985) –Beneficial effect of opioids in treatment of RLS –Phenotiazines cause parkinsonism and motor restlessness l Understanding pathogenesis of RLS will help to identify the neurochemical deficiency causing schizophrenia