Download Restless legs syndrome (RLS): Diagnosis

Dopaminergic pathophysiology:
hypothesis on RLS mechanisms
Walter Paulus
Göttingen
Germany
Why does l-dopa work at all if the firing
rate of dopaminergic neurons is not
altered?
Increase of vesicular size by 350 %
More dopamine release per spike
Iron deficiency: different implications in untreated
and overtreated patients
Overtreatment:
iron deficiency
deteriorates
function of the
dopamine transporter
leading to even
higher dopamine levels
untreated RLS:
impairment of tyrosine
hydroxylase?
Iron deficiency reduces
D2 receptors Erikson et al J Nutr 2000.
How much L-DOPA do we need in RLS?
What happens with 100 mg L-Dopa?
• 10 mg L-Dopa are supposed to finally enter the brain
• 1 mg is available for dopamine synthesis
•
which amounts to 3 x 1018 molecules of dopamine
being synthesised
• „empty vesicles“ can be refilled completely within
10 – 15 min after absorption (cf Segawa disease)
Σ 1 tablet L-Dopa can „double“ the
dopamine content of the dopaminergic
system
de la Fuente-Fernandez, 2004
100 mg L-DOPA very likely to be (very or too?) efficient in RLS
With increasing L-Dopa dosage symptoms reoccur:
U shaped dose response curve
Why too much dopamine with 200 to 300
mg/day in RLS and not in Parkinson‘s disease?
In contrast to Parkinson‘s disease in RLS there is probably no
degeneration of dopaminergic neurones (exception A11
degeneration?), hence small doses of L-DOPA may cause an
overflow of dopamine.
Why too much dopamine with 200 to 300
mg/day in RLS and not in Parkinson‘s disease?
.
“suggesting absence of short and long loop regulation of this
system within the spinal cord”
“undoubtedly affects their response to DA agonist treatment”
Spinal cord under dopaminergic overdosage and iron deficiency:
particular high potential for too much dopamine in the synaptic cleft
How much L-Dopa is too much and causes augmentation ?
Second key question:
How can the same drug l-DOPA be beneficial in RLS in low
concentrations and worsening in high concentrations?
• D2 / D3 / D4 antinociceptiv
• D1 / D5 pronociceptiv
Augmentation: The D1 hypothesis
Paulus and Trenkwalder, 2006
A relative overstimulation of the dopamine D1 receptors
compared to D2 receptors (in the spinal cord) may lead to
D1-related pain and generate periodic limb movements
– More D1 receptors are located outsite the synaptic cleft
– Increased dopmine in the synaptic cleft:
(too much) dopamine leaves the synaptic cleft
– private synapses convert to social synapses
Hyperdopaminergic state:
D2 receptors reduced in number, unlike D1 receptors that
are recycled to the plasma membrane (Bartlett, 2005)
How does a higher dopamine
concentration induce
a shift towards D1 stimulation?
Further support for a „D1 Hypothesis“
Dopaminergic excitation of spinal locomotor circuits
appears to be facilitated mainly by D1 receptors in
mice by
– decreasing IA current
– SKCa (small-conductance calcium-activated K channel) currents
– increasing glutamatergic synaptic transmission
A11 lesion reduces D1,
D2, D3 receptors
Iron deficiendy shifts
D1 : D2/D3 balance
Combination induces
largest shift in balance
Relative shift from D2/D3 to D1 receptors in
a) RLS (in iron deficiency)
b) Augmentation
So far D1 and D2/D3 separated in space!
• Augmentation develops over time
• We need to take care for a separation in time as well!
Augmentation is comparable to medication
overuse headache, short term improvement with
drug therapy and long term worsening
amelioration
pain
increase
Increase in receptor internalization may occur rapidly
within 1 min in response to increased synaptic DA concentrations;
Kim et al. (2004)
Relatively long time-course of amphetamine-induced reduction in D2
tracer binding as measured by PET as compared with the shorter
timescale of increased DA concentrations as assessed by microdialysis .
Sensitivity of dopaminergic receptors was augmented
by L-DOPA, and a drug-free period was required to
develop the receptor super-sensitivity. For L-DOPA
induced hyperalgesia a 1 h drug-free period to
produce hyperalgesia was required.
Repeated intermittent L-DOPA treatment is usually
required to produce sensitization
Sulpiride induces hyperalgesia in L-DOPA-naive
mice.
It however failed to enhance L-DOPA-induced
hyperalgesia, suggesting that the endogenous
dopaminergic inhibitory system of pain sensation
was impaired.
Further statements from Shimizu et al, 2007
immediately related to augmentation
The D1 antagonist SCH23390 significantly depressed the enhancement of pain
perception.
D1 receptors modify the pain conduction only in L-DOPA-primed animals, not
in the L-DOPA-naive animals.
In the physiological condition, D1 receptors may slightly facilitate the
conduction of pain sensation and this effect can be suppressed by an activation
of D2 receptors
After a withdrawal of LDOPA, effect of D1 receptors to facilitate pain
conduction could become apparent. This suggests that D1 receptors only work
in pathological conditions.
The dopaminergic inhibitory system for pain conduction, in which D2 receptors
are mainly involved, is impaired after L-DOPA priming, and D1
receptors take part in the pain conduction system in this pathological condition.
4 pieces of evidence of long term plastic
alterations by L- DOPA or dopamine
agonists
L-Dopa treatment:
Acute: alleviation of RLS sympt,
not of mechanical hyperalgesia,
Chronic: alleviation of both
CW = cotton whisp
QT = Q-tip
BR = brush
Induction of
augmentation by
„inhibitory“ D2
receptor agonism
over time
Kuo et al, 2008
Dopamine dramatically
Prolongs tDCS (transcranial direct
current Stimulation) and PAS
(paired associated
Stimulation) aftereffects
Some open questions
• Dopamine (production) deficit versus increased dopamine
turnover?
• RLS untreated: shifted balance between dopamine D1 / D2
receptor stimulation versus D2 / D3 / D4
• D1 / D2 receptor balance depending on absolute dopamine
concentration?
• Augmentation: long term shift towards D1 / D5?
• If so, why can D2 agonists cause augmentation at all?
• short versus long term time course of D1 versus D2 receptor trafficking
•Do plastic changes like those in the ELL-DOPA study play a role in RLS?
• Role of Priming by L-DOPA