PD I Flashcards
Voluntary movement originates in the ___ cortex and are mediated abd nodulated by the ______ and _____ systems
Motor (frontal) cortex; pyranidal and extrapyramidal systems
The 2 tracts of the pyramidal system
Corticospinal tract
Corticobulbar tract
Structures of the extrapyramidal system
Basal ganglia (Caudate, putamen, globus pallidus, substantia nigra, subthalamic nucleus)
Thalamus,
Cerebellum
Structures that make up the Basal ganglia
Caudate, putamen, globus pallidus,
substantia nigra, subthalamic nucleus
The _____ is a major target in the pharmacology of movement
disorders
basal ganglia–at the core if movement control
The activity of the motor cortex is increased by ________
excitatory (glutamatergic) thalamo-cortical connections
Excitatory motor control by _____ neurons is regulated by ______
excitatory (glutamatergic) thalamo-cortical connections;
GABAergic inhibitory neurons in the Gpi and SNr
BG Output neurons are…
GABAergic inhibitory neurons in the GPi and SNr
Role of ‘output neurons’
exert a tonic inhibitory effect on the thalamo-cortical neurons
The ‘output” neurons are regulated by
by the coordinated activity of neurons located in the basal ganglia, which form two major pathways (indirect and direct)
2 pathways of BG
Indirect and direct; regulate ‘output’ neuron firing
Both the indirect and direct pathways originate with ____ neurons with ___ receptors
medium spiny GABAergic neuron; dopamine receptors (D1 or D2
Dopamine receptors– __ receptors, __ types
5 receptors, in 2 types
2 DA receptor types
D1-like
D2-like
D1-like receptors
D1 and D5
D2-like receptors
D2, D3, D4
D1R mechanism
activates adenylate cyclase and production of cAMP –> stimulatory
D2R mechanism
inhibits adenylate cyclase and decreases cAMP –> inhibitory
D1Rs are _____ since they ___ neuronal excitability and D2Rs are ____ as they ____ neuronal exciatbility
D1Rs– Activating; Increase
D2Rs–inhibitory; decrease
Other contributions of D1 and D2Rs
D1R and D2R also modulate the activity of various ion channels resulting in opposite effects on neuronal excitability
Thalamocortical connects role
Stimulate motor activity (stim motor cortex)
Striatal medium spiny GABAergic neurons: modulation/role
Role: integrate information from many sources
Receive excitatory synapses from cortical neurons, as well as stimulation from cholinergic striatal interneurons and dopaminergic modulation from the substantia nigra
Activation of the ____ pathway
results in reduced activation of the
motor cortex. Overall ____ effect on movement
Activation of the INDIRECT pathway
results in reduced activation of the
motor cortex.
Overall INHIBITORY effect on movement
Activation of indirect pathway
ACh –> excites GABA neurons –> inhibit GPe
1) –> less inhibition on GPi and SNr
2) –> inhibit STN –> less excitation of GPi and SNr
= can’t disinhibit movement (thalamus inhibited = no movement)
Output neurons w/ activation of indirect pathway
Over-excitation of output neurons –> can’t disinhibit thalamus = no movement
Activation of Direct Pathway
Activate D1 receptor on GABA neurons–> inhibit GPi and SNr –> disinhibition of thalamus –> increase movement
Output neurons w/ activation of direct pathway
Output neurons Inhibited –> thalamus disinhibited –> increased movement
Net effect of activation of Direct pathway
results in increased excitation of the motor cortex (overall stimulatory effect on movement)
Striatal neurons are densely innervated
by _____ afferent fibers from
the _____
Striatal neurons are densely innervated
by DOPAMINERGIC afferent fibers from
the SUBSTANTIA NIGRA PARS COMPACTA
__ released in the striatum activates D1 and D2 receptors
Dopamine
Binding to D1 receptors in the striatum ___ the ___ pathway
Binding to D1 receptors (activating receptors) activates the direct pathway
Binding to D2 receptors in the striatum ___ the ___ pathway
Binding to D2 receptors (inhibitory receptors) inhibits the indirect pathway
Overall effect of DA on movement
dopaminergic transmission in the
striatum overall facilitates movement
BY inhibiting indirect pathway and exciting direct pathway
Damage to the BG causes
altered balance between direct and
indirect pathways leading to motor disorders
2 types of movement disorders
1) hypokinetic
2) Hyperkinetic
In Hypokinetic disorders, the ___ pathway dominates causing ___ output
Indirect pathway dominates causing increased inhibitory output
ex. PD
In Hyperkinetic disorders, the ___ pathway dominates causing ___ output
Direct Pathway dominates causing decreased inhibitory output
ex. HD
Most common neurodegenerative disorder after AD
PD
__% of population over 65 is affected by PD and __% of cases are sporadic
1%; 95%
Characteristic symptoms of PD
- tremor
- bradykinesia
- rigidity
T/F PD also has non-motor symptoms
TRUE
Non-motor features, including cognitive
impairment and psychiatric symptoms,
are also frequently present.
The most affected neurons in PD are
DA neurons in the substantia nigra, which progressively die.
Up to 80% of DA neurons might be lost at the time of diagnosis
Up to __% of DA neurons in the SNr may be lost at time of PD diagnosis
80%
Loss of dopaminergic neurons in PD causes…
… a neurotransmitters imbalance in the striatum, over-activation of the indirect pathway, decreased stimulation of the direct pathway and reduced movement (bradykinesia)
Control of D2 neurons (afferents)
The activity of D2 neurons in the striatum is regulated by the balanced activity of inhibitory dopaminergic and excitatory
cholinergic afferents
T/F There is a cure for PD
There is no cure for PD, nor disease-modifying treatments.
The only approved drugs for PD treat symptoms, not the underlying pathogenic process
Environmental factors affecting PD
Rotenone
Paraquat
MPTP/MPP+
genetic actors affecting PD
Alpha-synuclein Parkin PINK1 DJ1 LRRK2 VPS35 ATP13A2 GBA
Neuronal dysfunction in PD
Neuronal dysfunction may start at synaptic terminal w/ neurons then atrophying
Only ~30% of DA neurons are lost but 50-60% of terminals are lost
Sporadic PD is due to ___, but monogenic PD is also possible (but rarer)
Environmental factors such as Rotenone, Paraquat, MPTP/MPP+
3 cases for PD etiology
Case 1 (complex): distinct genotype and environemental factors (onset ~65)
Case 2: one monogenic event (early onset ~35-40)
Case 3: Enviro event in young age (ex. exposure to toxins MPTP/injury)–onset before 30 yrs
Most PD likely of ___ complex etiology
Complex
mix of genetics and enviro (~95% of cases)
Genetics in PD
genetic risk factors are usually many polymorphisms in many genes –> predispose one to PD as they age
Enviro factors in PD that increase risk
- concussion (head injury)
- pesticides
BUT coffee and tobacco DECREASE risk
MPTP/MPP+
MPTP converted to MPP+ which is a cation that enters Da neurons –> inhibits mitochondrial respiratory complex I
Rotenone, paraquat
Rotenone (pesticide), paraquat (herbicide)
both inhibitors of mitochondrial respiratory complec I
Heavy metals
Probable risk
Mn, Fe
Cause mitochondrial dysfunction, oxidative stress, impaired protein degradation
Commonalities b/t environmental toxin
All toxins affect the mitochondria–may tell ys that it function may play an important role in PD pathogenesis
Drug-induced Parkinson–which drugs
Typical antipsychotic drugs (chlorpromazine etc.) and neuroleptic agents may induce parkinsonism
T/F Drug-induced PD is reversible
TRUE
Cause of drug-induced PD
Caused by D2 receptor antagonism
Those more likely to develop drug-induced PD
Most common among elderly patients, probably due to smaller reserve of dopaminergic neurons
A genetic component predisposes to drug-induced parkinsonism
Drug-induced PD timeline
Symptoms usually appear within days to months after drug use and disappear over weeks or months after cessation of the drug.
Goal in treating PD
to decrease the activity of the indirect
pathway, by increasing dopaminergic
transmission or inhibiting cholinergic activity in the basal ganglia
Strategies in treated PD (pharmacologically)
- Supplementation with L-DOPA (DA does not cross the BBB)
- Inhibition of dopamine catabolism (decreased DA breakdown)
- Use of dopamine receptor (D2R) agonists (inhibit indirect pathway)
- Muscarinic antagonists (balance Ach and DA activity to modulate indirect pathway)
