Neuropharmacology PHAR3202 Lecture Notes PDF

Neuropharmacology PHAR3202 A brief introduction to neurochemical transmission & neuromodulation Dr Natasha Kumar [email protected]  Objectives The lecture will explore: Cellular and molecular sites of drug action in CN...

Neuropharmacology PHAR3202 A brief introduction to neurochemical transmission & neuromodulation Dr Natasha Kumar [email protected]  Objectives The lecture will explore: Cellular and molecular sites of drug action in CNS The diversity of transmitters, and implications for drug action The process of neurotransmission Challenges of drug development for CNS diseases  Sites of drug action in the central nervous system (CNS) Examples of CNS Acting Drugs: Receptors - Dopamine agonists – Parkinson’s Disease - Dopamine antagonists – Schizophrenia Ion channels - Sodium channel blockers – epilepsy Enzymes - Acetylcholinesterase Inhibitor – Alzheimer’s Disease Transporter - Selective serotonin reuptake inhibitor – depression / anxiety Figure 3.1 - Rang and Dale’s Pharmacology, 9th Edition  Types of receptors in CNS Figure 3.2- Rang and Dale’s Pharmacology, 9th Edition  Neuropharmacology – general principles Drugs can act via regulating transmitter release, reuptake, metabolism or can act directly on neurotransmitter receptors Many commonly used CNS drugs can interfere with neurotransmission In many cases, the precise mechanism of action of many therapeutically useful CNS drugs is unknown Each stage of neurotransmission is a potential site of drug action 1. Action potential in presynaptic nerve 2. Synthesis of transmitter (increase, decrease or enhance) 3. Storage 4. Metabolism 5. Release 6. Reuptake (nerve or glia) 7. Degradation 8. Receptor binding (activation, enhance or inhibit activation) 9. Receptor-induced increase or decrease in ionic conductance 10. Retrograde signalling Chemical transmission occurs at CNS synapses Criteria for transmitter: Transmitter made/stored in vesicles Transmitter released upon nerve stimulation Action is terminated in some way Exogenous application mimics effects of nerve stimulation  CNS Neurotransmitters - a diverse range of chemicals Biogenic Amines - serotonin, dopamine, noradrenaline & adrenaline - acetylcholine Serotonin Dopamine Amino acids - GABA, glutamate GABA Peptides Acetylcholine - opioids (endorphin), tachykinins (substance P), Adrenaline Noradrenaline neuropeptide Y (NPY) Glutamate Purines - ATP, adenosine ATP Diffusible mediators Endorphins Substance P Nitric Oxide - nitric oxide, carbon monoxide An example of the complexity of a neuronal terminal  Chemical transmission in the CNS Critical features – release of transmitter Activation of receptor (s) Breakdown (enzyme) or removal of transmitter from the synapse – may involve specific transporters Note – there is much redundancy in transmitter functions – many neurotransmitters may serve similar function…….. Anatomic specificity – particular circuits have specific neurotransmitters GLUTAMATE  Some key markers of neurotransmission TRANSMITTER PROTEIN MARKERS Amino acids γ-Aminobutyric acid (GABA) Glutamic acid decarboxylase Glutamate Enzymes operating general metabolism Monoamines Dopamine Tyrosine hydroxylase Noradrenaline Tyrosine hydroxylase & dopamine β-hydroxylase Adrenaline Tyrosine hydroxylase, dopamine β-hydroxylase, PNMT Serotonin Tryptophan hydroxylase Acetylcholine Choline acetyltransferase Nitric Oxide Neuronal nitric oxide synthase Neuropeptides Respective peptide Choline acetyltransferase galanin AMPA Receptor Tyrosine hydroxylase Brain cell types  Neuropharmacology – drug classification 1. Classify according to transmitter system that the drug acts upon (e.g. Dopamine or Acetylcholine etc...) 2. Drugs acting in the CNS are also classified according to application or indication (e.g. Antidepressant drugs are used to treat depression, antipsychotics are used to treat schizophrenia, anxiolytics are used to treat anxiety etc...)  Centrally acting drugs….…. Can produce dependence with prolonged use Used for social purposes as well as a range of therapeutic uses In order to exert an effect, the drug must access the brain (needs to cross the BBB) Major implications for drug development  Summary Neurochemical transmission Molecular and cellular targets of transmitters Transmitter localisation and function Receptor localisation and function Drug treatment strategies for CNS conditions Neuronal survival / death Implications for drug development see you at the Q&A   Exam-style revision question A) What are the THREE major mechanisms for termination of neurotransmitter action (3 marks), and how do they differ in their efficiency and speed (3 marks)? B) Provide ONE example of a neurotransmitter that is terminated by each mechanism (3 marks). To be discussed during the Q&A 