Lecture 2 – Acetylcholine

1. Lecture 2 – Acetylcholine

2. Acetylcholine (ACh) • first neurotransmitter identified (Otto Loewi, 1921) • important role in movement: causes muscle contraction • also found in brain: important role in attention, learning & memory

3. Acetylcholine (ACh) synthesis • ACh synthesis is catalyzed by the enzyme choline acetyltransferase (ChAT) • dietary precursors needed to synthesize ACh - • choline - found in egg yolks, liver, fish, grains, nuts, soya • acetyl coenzyme A - from breakdown of glucose • ChAT transfers the acetyl group (CH3CO-) from acetyl-CoA to choline, to form acetylcholine

4. Neural systems where ACh is a major neurotransmitter

5. Acetylcholine (ACh) • basal forebrain nuclei (especially the nucleus of Meynert) are the major source of ACh in brain • cholinergic pathways project from basal nuclei throughout cortex • activation of this neural system is associated with alertness, attention, learning & memory

6. 2 main types of ACh receptor: • named after drugs that bind to (and activate) them • nicotinic receptor – nicotine is an agonist • muscarinic receptor – muscarine (toxin found in mushrooms, e.g. fly agaric - Amanita muscaria) is an agonist • both types of receptor can be activated by ACh (the ‘master key’ for both types of ‘lock’)

7. ACh nicotinic receptor muscarinic receptor muscarine nicotine

9. ACh is broken down in the synaptic cleft by the enzyme acetylcholinesterase (AChE)

10. “Indirect” cholinergic agonists: • acetylcholinesterase inhibitors - inhibit the enzyme acetylcholinesterase (AChE), responsible for breakdown of ACh • this results in increased cholinergic activity (at both nicotinic and muscarinic receptors)

11. Acetylcholinesterase (AChE) inhibitors • AChE inhibitors are found in many plants (e.g. physostigminein the Calabar bean, galantaminein snowdrops), where their toxic effects act as natural pesticides and insecticides • synthetic AChE inhibitors are used in organophosphate pesticides & nerve gas (e.g. Sarin)

12. Acetylcholinesterase inhibitors • increase cholinergic activity • used to improve cognitive function in Alzheimer’s disease • e.g. donepezil (Aricept), tacrine, galantamine

13. Alzheimer’s disease • most common form of dementia • progressive and fatal brain disease • more than 400,000 sufferers in UK • affects about 1 in 14 aged over 65 years, and 1 in 6 aged over 80 • symptoms – memory loss, confusion, mood swings, personality changes, hallucinations • related to loss of cholinergic neurons • no cure, but cholinergic agonists can reduce symptoms and slow down disease progression • Alzheimer’s Society: www.alzheimers.org.uk

14. Damaged ACh pathways in Alzheimer’s disease

15. ACh is broken down in the synaptic cleft by the enzyme acetylcholinesterase (AChE)

16. AChE inhibitors (e.g. donepezil) suppress the action of AChE - so ACh levels increase in the synaptic cleft

17. Alzheimer’s disease • ADAS-cog = cognitive subscale of the Alzheimer’s Disease Assessment Scale • battery of short neuropsychological tests • naming objects, memory for word lists, etc. • scoring range = 0-70 (higher score = more impaired)

18. A 24 week double-blind placebo-controlled trial of donepezil in patients with Alzheimer’s (Rogers et al 1998, Neurology 50, 136-145)

19. Cholinergic antagonists • nicotinic – curare (S. American arrow poison), mecamylamine (used to help stop smoking) • muscarinic – atropine (also called hyoscyamine), scopolamine (also called hyoscine) • atropine & scopolamine are found in a number of toxic plants (deadly nightshade = Atropa belladonna, henbane = Hyoscyamus niger) • these drugs can disrupt normal cognitive performance by blocking the action of ACh at receptors

20. ACh agonists – nicotine & muscarine mimic effect of acetylcholine on receptors • ACh antagonists – scopolamine & atropine block the effect of acetylcholine

21. Belladonna Henbane • high doses of atropine or scopolamine can produce hallucinations, delirium, & death • historical association of belladonna & henbane with witchcraft, sorcery, shamanism (self-administered to induce ‘trance’ states, or used as poisons)

22. Atropine & scopolamine • low doses of atropine or scopolamine produce cognitive impairments similar to those seen in Alzheimer’s disease • effects are greater in older than in younger subjects – suggests ACh depletion may be responsible for normal age-related cognitive decline • scopolamine is used in memory research to induce ‘transient memory impairment’ • cholinergic drugs for treating Alzheimer’s disease (e.g. AChE inhibitors) can be evaluated in normal subjects by testing their ability to reverse scopolamine-induced impairments

23. Effect of scopolamine on free recall task - Grober et al 1989, Journal of Cognitive Neuroscience 1, 327-335

24. ACh & cognitive task performance • manipulation of ACh levels in the brain affects a wide range of cognitive functions including attention, learning & memory • although clinical assessment of Alzheimer’s disease usually focuses on memory performance, attention deficits are often detectable at a much earlier stage of disease (sometimes described as ‘mild cognitive impairment’) – see Storandt (2008) • ‘vigilance’ tasks (which require sustained attention) are particularly sensitive to changes in ACh

25. Measuring vigilance performance • subject must detect occurrence of rare and unpredictable target stimuli • letters or digits are presented on computer screen in quick succession (100-200 per minute) and random order • subject must respond only to specified target (e.g. X) or target sequence (e.g. 3, 5, 7)

26. Measuring vigilance performance • continuous performance task (CPT) • rapid visual information processing (RVIP) • measures - • response time to targets • errors of omission (missed targets) • errors of comission (false alarms)

27. ACh & vigilance task performance • ACh antagonists (e.g. scopolamine) impair vigilance task performance - slower responses and/or more errors • ACh agonists (e.g. nicotine) improve vigilance task performance - faster responses and/or fewer errors

28. Effect of 0.6mg subcutaneous nicotine injection on RVIP task in non-smokers – Foulds et al 1996, Psychopharmacology 127, 31-38

29. Levin et al (1998) – effect of transdermal nicotine patch in non-smokers (all p < .05)

30. nicotine has also been shown to improve cognitive performance in subject groups with - • Alzheimer’s disease • schizophrenia • attention deficit / hyperactivity disorder (ADHD) • see Levin & Rezvani (2000) • nicotine may also be effective in treating ‘normal’ cognitive ageing (or ‘age-related cognitive decline’) - see Murray & Abeles (2002)

31. ACh & inspection time • ‘inspection time’ (IT) is a measure of perceptual information processing speed • simple 2-choice visual discrimination task • measures minimum time stimuli must be viewed in order to categorise them accurately • individual IT scores correlate strongly with IQ

32. IT task stimuli‘same’ ‘different’

33. cholinergic agonists (nicotine, donepezil) reduce (i.e. improve) IT • the cholinergic antagonist mecamylamine increases (i.e. impairs) IT • functional integrity of cholinergic system may be biological basis of information processing efficiency (i.e. intelligence) • see Stough et al (2001)

34. Acetylcholine (ACh) - summary • important role in attention, learning & memory • loss of cholinergic neurons implicated in Alzheimer’s disease • drugs that reduce cholinergic neurotransmission (atropine, scopolamine) impair cognitive performance • drugs that increase cholinergic neurotransmission enhance cognitive performance – especially in tasks requiring sustained attention (i.e. vigilance tasks) • acetylcholinesterase inhibitors – ‘indirect’ ACh agonists that inhibit the enzymatic breakdown of ACh & are used to treat Alzheimer’s disease • nicotine – ‘direct’ ACh agonist that mimics effect of ACh at nicotinic ACh receptors • nicotine improves cognitive performance in neurologically intact non-smokers, and also in a range of neurological disorders – including Alzheimer’s, schizophrenia & ADHD

35. Learning outcomes • Understand the main features of a ‘vigilance’ task and the effects of cholinergic agonists and antagonists on such a task. • Understand what is meant by ‘inspection time’, how it is measured and how it is affected by cholinergic drugs. • Understand the main clinical features of Alzheimer’s disease and the basis for using cholinergic drugs to treat Alzheimer’s patients.

36. Recommended reading • ED Levin et al (1998) Transdermal nicotine effects on attention. Psychopharmacology 140, 135-141 • ED Levin & AH Rezvani (2000) Development of nicotinic drug therapy for cognitive disorders. European Journal of Pharmacology 393, 141-146 • KN Murray & N Abeles (2002) Nicotine’s effect on neural and cognitive functioning in an aging population. Aging & Mental Health 6, 129-138 • M Storandt (2008) Cognitive deficits in the early stages of Alzheimer’s disease. Current Directions in Psychological Science 17, 198-202 • C Stough et al (2001) Examining neurochemical determinants of inspection time. Intelligence 29, 511-522