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
