parkinsons Flashcards
what are signs and symptoms of parkinson
bradykinesia/akinesia tremor at rest soft monotonic speech swallowing problems dementia
what causes parkinsons
loss of dopaminergic neurones from substantia nigra, dopamine is depleated from nigrostriatal projection zones in striatum
characterised by formation of lewy bodies
70-80% of nigrostrital dopamine neurones have to die before symptoms appear
what may speed up parkinsons
life events such as infection, head trauma and drugs such as MPTP speed up process but only to a small degree
describe the basal ganglia connections
involved in supraspinal motor control:
direct pathway:
striatum receives input from cerebral cortex such are premotor cortex and primary motor cortex
striatum connects to GPi (interior globus pallidus) and pars reticularis of substantia nigra, these inputs are inhibitory via GABA
GPi/pars reticularis then input into the thalamus, this input is also inhibitory via GABA
thalamus then inputs into the cerebral cortex, excitatory input via glutamate
stimulation of direct pathway causes movement (since the striatum inhibits the inhibitory actions of GPi/pars reticularis)
indirect pathway:
striatum inputs into GPe, via negative GABA input
GPe inputs into subthalamic nucleus, again via GABA
subthalamic nucleus inputs into GPi/ pars reticularis via excitatory glutamate
GPi/pars reticularis input into thalamus via inhibitory GABA
thalamus has excitatory input into cerebral cortex via glutamate
(stimulation of indirect pathway via cortex causes less inhibition of subthalamic nucleus, which then causes more excitation of GPi/pars reticularis, inhibiting movement)
how does dopamine relate to indirect/direct pathways of basal ganglia
dopamine is released is via pars compacta of substantia nigra
overall effect is increased movement
impacts both pathways;
excitatory inputs into direct pathway via excitatory D1 receptors in striatum in cells that project to GPi/pars reticularis
inhibitory inputs via D2 receptors in indirect pathway in cells that project to GPe
dopamine input is regulated by GABA input from striatum to pars compacta
dopamine also regulates cholinergic activity in striatum
what is aim of parkinsons treatment
replenishment of dopamine transmitter or mimicking the effects
what is used to control tremor in parkinsons
loss of dopaminergic control on acetylcholine neurones in striatum means muscarinic antagonists can be used to control tremor
they do not however help with the bradykinesia/akinesia
what are dopaminergic pathways in CNS
nigrostriatal pathway: fails in PD and is target of treatment
mesolimbic pathway (A10 to nucleus accumbens), involved in reward pathways, overactivity may lead to psychosis
mesocortical pathway (A10 to frontal cortex) overactivity causes psychosis
median eminence to anterior pituitary: stimulation of anterior pituitary via dopamine causes inhibition of prolactin secretion
chemoreceptor trigger zone/ vomiting centre: dopamine stimulation here induces emesis (vomiting)
describe dopamine synthesis and metabolism
tyrosine is converted to L-DOPA via tyrosin hydroxylase
L-DOPA is converted to dopamine via DOPA decarboxylase
dopamine metabolism:
DA is converted to DOPAC via MAO-B
or to noradrenaline via dopamine-beta hydroxylase
or to 3-methoxytyramine via COMT
is dopamine given to treat parkinsons
dopamine not given since it does not cross blood brain barrier
L-DOPA given instead since it is a precursor and crosses blood brain barrier
describe L-DOPA treatment in parkinsons
since most dopaminergic neurones are dead in PD it is thought that some L-DOPA may be converted to dopamine in other monoamine neurones or in remaining dopaminergic neurones which have some increased compensatory capacity
akinesia and rigidity improve more than tremor with L-DOPA treatment
works best in elderly patients
produces improvement over first 18 months of treatment, this is maintained for 2-3 years before gradual decline, probably due to further degeneration of dopaminergic neurones
large dose of L-DOPA needed (100-500mg/day orally) but due to metabolism only 2% enters brain
what are central side effects of L-DOPA treatment
dyskinesia (uncontrolled movements)
psychotic effects via mesolimbic and mesocortical over stimulation (schizo drugs are dopamine antagonists)
reduction in prolactin release
“on-off” effects; uncontrolled swings from akinesia to dyskinesia, usually occurs after several months of therapy, happens as L-DOPA dosage wears off
what are peripheral side effects of L-DOPA treatment
hypotension due to displacement of noradrenaline; reduction in sympathetic tone
nausea since dopamine stimulates chemoreceptor trigger zone, although it is in medulla it lacks blood brain barrier
what is used alongside L-DOPA treatment to maximise benefits
adjuncts are used to maximise benefits and minimise peripheral formation of dopamine
adjuncts to L-DOPA:
DOPA decarboxylase inhibitors monoamine oxidase inhibitors dopamine receptor agonists muscarinic antagonists COMT antagonists amatadine
how are DOPA decarboxylase inhibitors used in parkinsons
carbidopa and benserazide are DOPA decarboxylase inhibitors
prevent L-DOPA being converted into dopamine
these drugs do not cross blood brain barrier and so reduce dopamine concentrations in periphery
allows reduced L-DOPA dosage since less metabolism in periphery
used in combination with L-DOPA treatment; improvement is faster and smoother