1. BASAL GANGLIA PHARMACOLOGY Sammy Case & Matt Vreugde s.case@warwick.ac.uk m.vreugde@warwick.ac.uk

2. What are the Basal Ganglia ■Collection of nuclei in the base of the forebrain ■Predominantly modulate descending motor signals from cortex to cerebellum ■Many nuclei but you don’t need to know it all (yay!)

3. Basal Ganglia anatomy (Quick ‘n Dirty) 1.Striatum (+nucleus accumbens) 2.Globus pallidus 3.Subthalamic Nuclei 4.Substantia Nigra

4. Direct and Indirect Pathways MOTOR CORTEX STRIATUM THALAMUS GLOBUS PALLIDUS (INTERNAL) Substantia Nigra Pars Reticulata SUBTHALAMIC NUCLEI SUBSTANTIA NIGRA PARS COMPACTA GLOBUS PALLIDUS (EXTERNAL) D I

5. PARKINSON’S HUNTINGTON’S BALISMUS/HEMIBALISMUS ATHETOSIS WILSON’S DISEASE Where can it go wrong?

6. Parkinson’s Disease What causes the symptoms? Loss of 80-90% of dopamine neurons in the substantia nigra What are the 4 cardinal symptoms? (and any extras for brownie points?!) TRAP! Tremor (resting) Rigidity (cog-wheel) Akinesia (bradykinesia) Postural instability Mask-like face, micrographia, sleep disturbances

7. Parkinson’s Pharmacology Need to replace dopamine lost and any side effects of this loss! Dopamine Agonists How do they work? Replace dopamine loss by acting on D2 receptors Who are they used for? Younger patients and as an initial treatment option Name some examples Pramipex ole Ropinir ole.

8. Parkinson’s Pharmacology Dopamine Replacement How do they work? Dopamine can't cross the blood-brain barrier o Use a pre-cursor Pre-cursors are metabolized quickly o Use an inhibitor of metabolism alongside it Name the pre-cursor used Levodopa Name some relevant catabolic inhibitors Dopa-decarboxyl ase inhibitors, catechol-o-methyltransfer ase inhibitors, monoamine oxid ase inhibitors What are some side effects? On-Off effects, psychosis, hypomania, hypotension

9. Parkinson’s Pharmacology Anticholinergics Why are these needed? Decrease in dopamine leads to an increase in acetylcholine concentration. To redress the balance anticholinergics may be used Name some examples Orphenadr ine, Procyclid ine

10. Huntington’s Disease What is the genetic basis of Huntington’s? Autosomal dominant trinucleotide repeat disorder (CAG) on chromosome 4. What happens in the brain as a consequence of this? Degeneration of cholinergic cells in the striatum, particularly in the caudate nucleus. What is the basis of the treatment? Too little cholinergic cells means dopamine levels will be too high leading to involuntary movements. Dopamine depleting drugs needed! Name a dopamine depleting drug and any other drugs used to treat the symptoms Tetrabenazine Antipsychotics to help control violent outbursts Benzodiazepines and SSRIs to treat depressive moods

11. Wilson’s Disease What is it? An autosomal recessive disorder in which copper accumulates in tissues. What main organs does it affect? Brain! Liver Kidneys Cornea What is the basis of treatment? Too much copper so we need to get rid! Copper chelators Zinc – blocks copper absorption in the gut

12. A Brief Aside! - Chorea What is it? Involuntary, irregular, dance-like movements. What can cause it? Inherited e.g. primary feature of Huntington’s Secondary e.g. side effect of rheumatic fever, caused by drugs such as levodopa and anti-psychotics What are the 4 classes of drug used to treat? Dopaminergic antagonists Dopamine depleting drugs GABAergic drugs Steroids

13. Ballismus/Hemiballismus What is it? Large, violent proximal flinging movements of the limbs What is it caused by? Neurodegeneration of the subthalamic nuclei What is the treatment? Treat as for chorea PLUS IV diazepam and oral haloperidol

14. Athetosis What is it? Slow writhing movements, especially of the fingers What is the treatment? Treat as for chorea!

15. Whistle stop tour of Schizophrenia and Antipsychotics (What you need to know for the summer exam!) Schizophrenia is defined by both positive symptoms and negative symptoms PositiveNegative (4 A’s) Thought echo, withdrawal, broadcasting and insertion Apathy (indifference) DelusionsAlogia (poverty of speech) Hallucinations (both auditory and visual) Anhedonia (lack of pleasure in activities) Affective blunting (failure to express emotions) Schizophrenia (and many other mental health disorders) is treated using antipsychotics Classical antipsychotics are antagonists at the D2 receptors – Haloperidol Atypical antipsychotics primarily antagonise the 5HT and dopamine receptors, however many interact with histaminergic, muscarinic and adrenergic receptors too – Olanzapine, Risperidone Main side effects: Extrapyramidal symptoms e.g. dystonias, parkinsonism. Tardive dyskinesia! (tongue protruding, choreiform movements, grimacing and twisting of the face)

16. MCQ Practice! A 68 year old woman is brought to the emergency department by her godson. He explains that she unexpectedly began to have sudden movements of her left arm. The examination reveals periodic, uncontrollable flailing movements of her left upper extremity suggestive of hemiballismus. Assuming this resulted from a vascular occlusion, MRI would most likely show an infarction in which of the following structures? A. Left substantia nigra B. Left subthalamic nucleus C. Right motor cortex D. Right substantia nigra E. Right subthalamic nucleus A 64 year old man is brought to a rural health clinic by a neighbour. The history reveals that the man is a recluse, lives by himself, and does not regularly visit a physician. The examination reveals that the man has difficulty walking, chorea and dystonia, and is suffering from dementia. The neighbour believes that the man's father died from a similar disease. What tentative diagnosis can be made? Huntington’s Disease What drug treatment would you choose? A. Pramipexole B. Orphenadrine C. Tetrabenazine D. Haloperidol E. Diazepam