Exam 2 Lecture 18, Anti- PD I

Caudate Nucleus Putamen Globus pallidus Subthalamic nucleus Substantia nigra

Hypo-Dopaminergic Due to A9 nigrostriatal dopamine neurons Motor symptoms ie poverty of movement (bradykinesia)

To replace/preserve dopamine, dopamine agonists, cholinergic blockers, prevent further cell death, surgical treatments

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

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

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

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

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

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

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

dopamine receptor blocking drugs reduce both motor and psychiatric symptoms; drugs do not arrest disease process; there is no cure

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

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

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

causes embryonic death so huntingtin protein must be necessary during development

mouse will have progressive neurological symptoms similar to HD polyglutamine regions of mutant huntingtin aggregate in nuclei and cytoplasm of neurons in HD brain

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

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.

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

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

excess number of dopamine receptors in striatum, especially D2 receptor density in head of caudate

Dopamine receptor blockers (especially haloperidol or pimozide); also used are clonidine or SSRI’s (for OCD case)

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

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.