Exam 2 Lecture 18, Anti- PD I Flashcards
Basal Ganglia
Caudate Nucleus Putamen Globus pallidus Subthalamic nucleus Substantia nigra
Parkinson’s disease
Hypo-Dopaminergic
Due to A9 nigrostriatal dopamine neurons
Motor symptoms ie poverty of movement (bradykinesia)
Parkinson’s Treatment strategies
To replace/preserve dopamine, dopamine agonists, cholinergic blockers, prevent further cell death, surgical treatments
Schizophrenia
Hyper-dopaminergic disorders
Due in part to functional excess of dopamine transmission in limbic cortex and striatum (terminal areas of A10 dopamine neurons)
Psychiatric symptoms: ie disordered thinking, hallucinations
Treatment strategies: Dopamine receptor blocking drugs
What is Tardive dyskinesia, what causes it
Hyper-dopaminergic disorder
due to chronic blockade of D2 dopamine receptors; a man made disease
Motor symptoms: excessive, uncontrollable movements, primarily orofacial movements such as tongue, lip, jaw
Tardive dyskinesia mechanism
Exact mechanism unknown,
known that long term block of dopamine receptors causes up-regulation of striata dopamine receptors; spillover of dopamine onto supersensitive sites = increase dopamine effects on motor circuit = increase movement
in support of super sensitivity hypothesis, raising dose of the antipsychotic drug reduces symptoms of TD but worse at the end
Evidence against supersensitivty Tardive dyskinesia
supersensitivity occurs within weeks, but TD takes months/years
Maybe receptor up regulation is first step in cascade of changes with later downstream changes in GPi/ SNr GABA sensitivty
Treating Tardive Dyskinesia
Hard to treat or reverse, stopping antipsychotic makes symptoms worse initially, increasing reduces symptoms but ethically unacceptable;
Clozapine useful
Best approach is preventative, use lowest effective dose of antipsychotic, overdosing promotes receptor supersensitivtiy and hasten TD
Huntington’s Disease
Hyper-dopaminergic
Autosomal dominant inheritance of mutant gene on chromosome 4, mid-life onset (30-50), fatal ~15 years
Rare in general pop (1 in 10,000), offspring of affected parent at risk have 50/50 of getting
Huntington’s Disease
Motor and psychiatric symptoms:
constant, uncontrollable movements of a writhing or dance-like type (chorea) involving the entire body; gradual loss of intellectual/ genitive function progressing to dementia or psychosis
Huntington’s Disease treatment
dopamine receptor blocking drugs reduce both motor and psychiatric symptoms; drugs do not arrest disease process; there is no cure
Huntington’s Disease Neuropathology
massive loss of striata GABAergic “medium spiny” efferent neurons (striatonigral and striatopallidal cells) with shrinkage of striata volume; D1 and D2 neurons dying
dopamine neurons innervating striatum are NOT affected
Mechanism of gene defect and striata cell loss (HD)
1983, discover gene locus, made presymptomatic test for at risk people
1993, discovery of gene IT15; found to contain polymorphic trinucleotide repeat sequence (CAG) expanded many times beyond normal level. CAG repeat codes for a polyglutamine sequence in the expressed protein, called huntingtin
CAG repeat length positively correlated with onset/severity of disease
IT15 mRNA present in all brain areas, but not in very high levels in striatum or neuron types that die in disease
Function of huntingtin gene
Unkown, but mutation is thought to cause a “gain of function”, with expanded polyglutamine stretch
must be necessary during development because knockout mice cause embryonic death
hard to degrade, accumulates and forms insoluble aggregation
“Knock out” Huntingtin Gene
causes embryonic death so huntingtin protein must be necessary during development
“Knock in” of human HD gene >140 CAG repeats
mouse will have progressive neurological symptoms similar to HD polyglutamine regions of mutant huntingtin aggregate in nuclei and cytoplasm of neurons in HD brain
Mechanism of striata cell death Huntington’s Disease
unknown,
unclear if huntingtin aggregates are cause of pathology or a feature of surviving neurons
mutant huntingtin is known to be susceptible to mis-folding, leading to insoluble aggregates, which escape normal cell degradation and disposal mechanism
Balance between dopamine and acetylcholine in PD
Cell only sense ACh so balancing with DA is important
However in Huntington’s Disease, balance between two doesn’t matter since GABA neurons are dying and those get acted on by those.
Tourettes syndrome
Hyper-dopaminergic disorder
Due to autosomal dominant inheritance of one or more genes, high variable expression
onset in childhood 5-15 often with remission in maturity
Tourette’s Motor symptoms
Motor and vocal tics which intrude in otherwise normal behavior and speech.
ie grunts, barks, yelps, screams, swearing, blowing air in or out
can be difficult to suppress, seen in associating with OCD
Tourettes neuropathology
excess number of dopamine receptors in striatum, especially D2 receptor density in head of caudate
Tourettes treatment strategies
Dopamine receptor blockers (especially haloperidol or pimozide); also used are clonidine or SSRI’s (for OCD case)
What is Restless legs syndrome
Hyper-dopaminergic disorders
causes irresistible urge to move legs, hard to control. Progresses worse over aging
Gets worse at rest, effects sleeping. both patient and partner
thought to affect up to 10% people in US, twice as many cases in women. Genetic links not well known
Iron deficiency is common, thought to down regulate myelin and affect RLS symptoms by altering sensorimotor integration neuronal pathways
Restless legs syndrome (mechanisms?)
Morning increase Dopamine activity (due to circadian activity) can be sufficient to compensate the postsynaptic down regulation caused by hyper-dopaminergic state
Symtoms subside in morning. During daytime and night when dopaminergic activity deficit may arise, can trigger RLS symptoms. Small dose of D2 agonist in evening can correct relative evening decrease in DA.
Restless legs syndrome treatment
RLS induces a hyper-dopaminergic state, but dopamine agonists (D2) show good efficacy.
Calcium channel blockers (gabapentin and pregabalin ) also prescribed and shown effective
Tolerance and augmentation due to receptor overstimulation can happen with DA agonists over time
Progressive Death (Parkinson’s) and Neurochemical findings
Progressive death of A9 nigrostrital DA neurons results in loss of dopaminergic transmission in the striatum
Neurochemical findings: decreased striata DA content with possible changes in DA D2 receptor number or affinity
Parkinson’s Etiology
Most cases idiopathic with onset in middle or late life, prevalent disorder
No obvious genetic component in most cases, there is a rarer inherited form (mutation in a-synuclein gene)
Normal aging process may be responsible, symptoms only occur after > 90% DA cell loss
Environmental factors may accelerate cell loss
PD Cases attributable to infection or drug use
Postencephalitic Parkinsonism of 1919 - 1924 followed epidemic of encephalitis lethargica
Parkinsonism due to antipsychotic drugs DA receptor blockade
1979 - 1981 due to “designer drug” MPTP Bay Area
Neurotoxicity of MPTP
MPTP converted into MPP+ by MAO-B, MPP+ neurotoxic in species
MPP+ taken up by DA neurons, kills them by inhibiting mitochondrial respiration by blocking enzyme NADH dehydrogenase. Cells die due to energy starvation
MPP+ can cross BBB
Idiopathic PD
May be due to inherent, genetically based defect in energy metabolism of DA cells, making them vulnerable to certain environmental toxins which cause oxidative damage and lead to DA cell death.
A-synuclein PD cause
a-synuclein causes misfolded proteins - turn into oligomers then fibrils and form Lewy bodies and neuritis on neuron causing issues
Parkinson’s Symptoms
Termor Bradykinesia and akinesia Rigidity Postural abnormality Mouth slightly open and drooling Micrographia and microphasia - issue writing
Pharmacological basis of PD therapeutics
Try to restore normal functioning of striatum by…
restore DA levels to normal
Correct imbalance between ACh and DA in striatum
Directly stimulate striata D2 DA receptors with agonist drug