Too Much… Too little Dopamine

PD & Schizophrenia

Proseminar in Biological

PsychologyLecture 5

First described in 1817By English MD

James Parkinson

Parkinson’s Disease

“…involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported, with a propensity to bend the trunk forwards, and pass from a walking to a running pace, the senses and intellects being uninjured.” J. Parkinson

PD: Motor System Disorder

• Chronic• Progressive• Non Fatal

-1 to 1.5 million cases in the US strikes 1 in every 100 over 50

- Equal opportunity disease… men, women all ethnicities slightly higher rate among whites vs blacks Disease of Aging – onset 55 (idiopathic)

Early Onset: 5-10% diagnosed

400,000 nigral cells in SN

2,400 cells die each year (Apoptosis)…80yrs X 2,400 = 200,000…50% cell death = mild symptomology

PD Pts = less than 100,000 cells

So PD accelerated…why?

• environmental?• genetic?

• Head injury (parkinsonism)

Idiopathic

Monozygotic Dizygotic

Parkinson's Disease •Lewy body in a substantia nigra neuronCaused by alpha synuclein & Parkin: gene responsible for making these proteins suspect early onset

Environmental…

PesticidesHerbicidesInsecticidesWell-Drinking WaterRural Living

Higher incidence inagriculture workers….

Environmental…

Metals:ManganeseCopper Aluminum

Pathology: Basal Ganglia

Striatum

Nigrostriatal Pathway

DopaminergicCell bodies

80% die – degeneration of pathway..bingo NO Dopaminergic transmission

Parkinson’s Disease

Disease of the Basal Ganglia

Globus PallidusSubstantia NigraCaudate & PutamenSub Thalamic Nuclei

Excitesthe pathway

D1Inhibits the pathway D2

Excitatory: green -- Inhibitory: red1. Substantia Nigra axons inhibit the putamen2. Axon loss increases excitation in Globus Pallidus3. Globus Pallidus has increased inhibition to Thalamus4. Then decreased excitation from the Thalamus to Cortex

D2 receptors

neurons from putamen fire excessively…loss of control of motor function

•Muscular stiffness and increased muscle tone•Patients usually unaware of rigidity, troubled with slowness•More apparent to doctor than patient•Cogwheeling – ratchet like movement

1. RigiditySymptoms

2. Hypokinesia & 3. Bradykinesia

•Hypokinesia: inability to initiate a voluntary movement•Bradykinesia: slowness of movement•Decrease in:

EyeblinkFacial expressionEating and chewing

Involuntary movement: head, limbs, body

• Most apparent when limb rested• Increases with stress • Ceases during sleep • Decreases with intentional movements •‘Pill rolling tremor' most prominent in fingers & hand •Most bothersome, yet least disabling of all symptoms

4.Tremor

Treatment...

HEY LETS JUST GIVE DOPAMINE!!!

Dopamine doesn’t cross the blood brain barrier….But levodopa does (l-dopa)!

Phenylalanine

Tyrosine

L- Dopa

Dopamine

Aromatic L amino acid decarboxylase

Problems: 1. doesn’t address the cell death 2. in time l-dopa is not effective (good for early to intermediate stages)

•Sinemet: l-dopa+carbidopa (BBB)l-dopa quickly converted to DAin PNS decarboxylase inhibitor• 75% respond to drug

Selegiline (MAOI)•Delays Parkinsonian disability and the need for levodopa therapy by 9-12 months

•Inhibits dopamine degradation •Allows for 20% smaller doses of levodopa

•Exacerbation of levodopa-associated side effects •Insomnia, postural hypotension

•inhibiting monoamine oxidase-B more pre-synaptic dopamine

Also…inhibits this enzyme …converts MPTP to MPP+ (bad stuff)

“on-off” of PD

“I need to explain the "on-off" phenomenon. This Jekyll and-Hyde melodrama is a constant vexation for the P.D. patient, especially one as determined as I was to remain closeted. "On" refers to the time when the medication is telling my brain everything it wants to hear. I'm relatively loose and fluid, my mind clear and movements under control. Only a trained observer could detect my Parkinson's. During one of my "off" periods, even the most myopic layperson, while perhaps not able to diagnose P.D. specifically, can recognize that I am in serious trouble.” -Michael J. Fox, an excerpt from Lucky Man

http://www.michaeljfox.org/

New Treatment Strategy…..DBS (deep brain stimulation)

- US Food and Drug Administration recently approved (Jan. 15, 2002)- Tiny electrodes on the scalp – connecting wire to implanted pulse generator under the collarbone - 80% reduction of tremor & bradyk.- can modify stimulation based on severity of symptoms

Thalamotomy: remove thalamus (M.J. Fox - 1998)Pallidotomy: remove the globus pallidus Helps the symptoms of tremor, dyskinesia, rigidity & bradykinesia-however, irreversible destruction of brain tissue-Overtime the benefits decline-May compromise other intact brain processes: speech, vision etc.

DBS •Thalamus•Globus pallidus •Sub Thalamic (best)

Thalamus: tremor, safer then lesion •Globus pallidus: dyskinesia safer than lesion•Sub Thalamic: improve all Symptoms improvement of motor scores 40-60% during “off” 10% during “on”

Epidemiology

• Prevalence ~1%; male = female

Right now over 2 million adult Americans have schizophrenia

• Seen in all cultures at similar frequency • Onset usually late adolescence to young adulthood,

earlier in males than females

(reactive: leaving home, loss of parent, 1st sex experience)

• Increased chance of being born in the winter or early spring

Schizophrenics have:

• Increased mortality rate from accidents and natural causes:– life span is shortened by about a decade– some under-diagnosis of medical illness is present

• ~10-15% suicide; ~50% attempt– early in illness and young age– high premorbid function– depression– the latter two often contributing to demoralization

• Illness seems concentrated in urban settings, i.e., it is somewhat correlated with population density in larger cities

• Illness seems concentrated in lower socioeconomic classes (1/3 of homeless)

Subtypes

– Catatonic• Catatonic behavior dominates (catalepsy-muscle

rigidity/agitation)• Less common nowadays

– Disorganized (hebephrenic)• Disorganized speech, behavior, and affect (flat or

inappropriate)

– Paranoid• Delusions and/or auditory hallucinations• Not limited to persecutory themes• Tends to have a later onset and better course

Etiology of Schizophrenia

Genetic Influences

Implies genetic factors not environmental

Adoption Studies - Genetic

Genetics and Family Studies

Etiology of Schizophrenia

Brain Abnormalities

Hippocampus

Due to virus (Flu) 2nd trimester: adhesion molecules causing pathological migration

Frontal Lobe Issues Functional brain imaging (PET, rCBF)

• Failure to increase blood flow to the dorsolateral prefrontal cortex while performing the activation task of the Wisconsin Card Sorting Test

• Reduced blood flow to the left globus pallidus (an even earlier finding in the course of illness) suggests a problem in the system connecting the basal ganglia to the frontal lobes

• Correlation with severity of disease present

Wisconsin Card Sorting Task

• Subjects are asked to sort each upcoming card on to one of the four piles (they are not directed but may use shape, color or number). They are told correct/incorrect. Whichever category they choose is correct for a given number of categories then is met with an “incorrect” response. Subjects must “switch sets” to get a correct response. Failure to switch sets is termed “perseveration”.

• Schizophrenic subjects perseverate relative to normal controls, Green et al, 1992

Ventricles Enlarged

MRI – Discordant

(bigger differences in males - ventricle size)

Post-Mortem NeuroanatomyDisturbed connection between thalamus and PFC

Serendipity Strikes Again!!!!

1960 – discovery that striatums (caudate putamens) depleted of Dopamine

Dopamine Hypotheses of Schizophrenia

• Dopamine– Schizophrenia due to over activity

Dopamine Antagonist

Clorpromazine (Carlsson, 1963) - expected DA levels to decrease-Metabolite increased-D2 receptor blockers work not because to much dopamine but Because to many receptors or tooSensitive…

Dopamine Hypotheses of Schizophrenia (revised)

• Dopamine– Positive symptoms of schizophrenia

attributed to hyperdopaminergic function (more receptors or increased sensitivity, etc, D2)

Evidence in Support and Against…

Evidence in Support

•Dopamine hypothesis - weaknesses:

–Does not account for negative symptoms of schizophrenia

Evidence against DA hypothesis of Schizophrenia – Glutamate???

• Disorganized thought symptoms of schizophrenia attributed to hypofunctional glutamate system

• Glutamate antagonists such as PCP and ketamine mimic disorganized thought, may also cause psychosis and negative symptoms?