Too Much… Too little Dopamine PD & Schizophrenia

1. Proseminar in Biological Psychology Lecture 5 Too Much… Too little Dopamine PD & Schizophrenia

2. Parkinson’s Disease First described in 1817 By English MD James Parkinson “…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

3. 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

4. Idiopathic 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)

5. Monozygotic Dizygotic

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

7. Environmental… Pesticides Herbicides Insecticides Well-Drinking Water Rural Living Higher incidence in agriculture workers…. Environmental… Metals: Manganese Copper Aluminum

8. Pathology: Basal Ganglia Striatum Nigrostriatal Pathway Dopaminergic Cell bodies 80% die – degeneration of pathway..bingo NO Dopaminergic transmission

9. Parkinson’s Disease Globus Pallidus Substantia Nigra Caudate & Putamen Sub Thalamic Nuclei Disease of the Basal Ganglia Excites the pathway D1 Inhibits the pathway D2

11. D2 receptors neurons from putamen fire excessively…loss of control of motor function Excitatory: green -- Inhibitory: red 1. Substantia Nigra axons inhibit the putamen 2. Axon loss increases excitation in Globus Pallidus 3. Globus Pallidus has increased inhibition to Thalamus 4. Then decreased excitation from the Thalamus to Cortex

12. Symptoms 1. Rigidity • Muscular stiffness and increased muscle tone • Patients usually unaware of rigidity, troubled with slowness • More apparent to doctor than patient • Cogwheeling – ratchet like movement 2. Hypokinesia & 3. Bradykinesia • Hypokinesia: inability to initiate a voluntary movement • Bradykinesia: slowness of movement • Decrease in: • Eyeblink • Facial expression • Eating and chewing

13. 4.Tremor • 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

14. Treatment... HEY LETS JUST GIVE DOPAMINE!!!

15. Dopamine doesn’t cross the blood brain barrier…. But levodopa does (l-dopa)! Problems: 1. doesn’t address the cell death 2. in time l-dopa is not effective (good for early to intermediate stages) Phenylalanine Tyrosine L- Dopa Dopamine Aromatic L amino acid decarboxylase • Sinemet: l-dopa+carbidopa (BBB) • l-dopa quickly converted to DA • in PNS  decarboxylase inhibitor • 75% respond to drug

16. 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)

17. “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/

18. 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. 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

19. 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”

24. Epidemiology • Prevalence ~1%; male = female Right now over 2 million adult Americans have schizophrenia • Seen in all cultures at similar frequency • Onsetusually 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

26. 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)

27. 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

28. Etiology of SchizophreniaGenetic Influences

29. Adoption Studies - Genetic Implies genetic factors not environmental

31. Genetics and Family Studies

33. Etiology of SchizophreniaBrain Abnormalities

34. Hippocampus

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

37. Frontal Lobe IssuesFunctional 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

38. 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

40. Ventricles Enlarged

42. MRI – Discordant

43. (bigger differences in males - ventricle size)

44. Post-Mortem NeuroanatomyDisturbed connection between thalamus and PFC

47. Serendipity Strikes Again!!!!

48. 1960 – discovery that striatums (caudate putamens) depleted of Dopamine

49. Dopamine Hypotheses of Schizophrenia • Dopamine • Schizophrenia due to over activity

50. Dopamine Antagonist