Neuropharmacology NOTES

Transcription

1 Neuropharmacology NOTES Contents Topic Page # Lecture 1- Intro to Neurochemical Transmission & Neuromodulation 2 Lecture 2- Serotonin & Noradrenaline 7 Lecture 3- Acetylcholine & Dopamine 14 Lecture 4- ATP & NO 22 Lecture 5- Amino Acids & Glutamate 34 Lecture 6- Neuropeptides as Transmitters 42 Lecture 7- GABA & Glycine 51 Lecture 8- Neurotrophic Factors 57 Lecture 9- Depression 64 Lecture 10- Neuroleptic Drugs & Schizophrenia 69 Lecture 11- Pain & Analgesia in the CNS 73 Lecture 12- Drug Addiction & Dependence 75 Lecture 13- Sedatives & Anxiolytics 78 Lecture 14- CNS & Control of Breathing 83 Lecture 15- CNS & Control of Feeding 88 Lecture 16 Parkinson s Disease 93 Lecture 17 Stroke & Neuroprotective Drugs 97 Lecture 18 Epilepsy & Anticonvulsants 103 Lecture 19- Neurodegenerative Diseases I (Dementia & Alzheimer s Disease) 109 Lecture 20- General & Local Anaesthetics 115 Lecture 21- Neurodegenerative Diseases II (HD & ALS) 120 Lecture 22- CNS Drugs & the Blood-Brain Barrier 124 1

2 Lecture 1: Intro to Neurochemical Transmission & Neuromodulation In most cases, the precise mechanism of action (MoA) of many therapeutically useful CNS drugs is unknown. Many common drugs can interfere with neurotransmission. Can act via regulating transmitter release, re-uptake, metabolism or can act directly on neurotransmitter receptors (antagonism and antagonism). Each stage of neurotransmission is a potential site of drug action/intervention (generally 10 stages). There are 2 types of signalling (cell-to-cell communication) that can occur in neurotransmission: Electrical synaptic transmission: occurs when a mechanical and electrically conductive link between adjacent neurons is formed at a narrow gap between the pre- and post-synaptic neurons known as a gap junction. Very rapid nerve impulses (signalling) Bidirectional, Graded Chemical synaptic transmission: occurs when a neuron releases neurotransmitter molecules into a small space known as the synaptic cleft via a process of vesicle exocytosis which then chemically signal a mechanism. Slower nerve impulses due to terminal vesicle release Unilateral, Quantal (Steps) Distance between Pre-synaptic and Post-synaptic Membranes ELECTRICAL SYNAPSE ~4nm CHEMICAL SYNAPSE 20-40nm Cytoplasmic Continuity Yes No Ultrastructure Components Gap-Junction Channels Terminals; Pre-synaptic Vesicles & Post-synaptic Receptors Agent of Transmission Ion-current Chemical transmitter Synaptic Delay Virtually Absent >0.3 ms, usually 1-5ms Direction of Transmission Bilateral Graded Unilateral Quantal (Steps) Criteria for transmitter, include: transmitter made/stored in vesicles; transmitter released upon nerve stimulation; action is terminated in some way; exogenous application mimics effects of nerve stimulation. 2

3 Chemical transmission in the CNS can be categorised broadly as having this 3-setp sequece: Critical features release of transmitter Activation of receptor(s) Breakdown (enzymatic) or removal of transmitter from the synapse may involve specific transporters Note: there is much redundancy in transmitter functions many transmitters may serve similar function Anatomic specificity for particular circuits. 3

4 Each transmitter acts on different regions of the brain. Glutamate, the most common excitatory transmitter, acts on multiple regions of the brain; whereas transmitters such as acetylcholine, dopamine, serotonin and noradrenaline have more specialised, local pathways. Receptors are found in many locations in the cell, but mainly on the cell surface (apart from intracellular nucleus-based receptors). There are 4 major types of receptors: Type 1: Ligand-gated ion channels embedded in the membrane (cross the membrane 4-5 times; although not the whole receptor, requires multiple subunits to make up an active ion channel) Type 2: G-protein coupled receptors embedded in the membrane (cross the membrane 7 times) Type 3: Kinase-linked receptors (catalytic linked receptors) embedded in the membrane (cross the membrane once) Type 4: Nuclear receptors floats around in the cytoplasm/nucleus 4

5 In neuropharmacology, the focus is on drug specialisation for the brain and targeting brain cell types. These brain cell types include: Astrocytes ~25-50% of brain volume, have roles in secreting neurotrophic factors, regulating cell death, storage of glycogen, regulate some neurotransmitters (e.g. GABA & glutamate) Oligodendrocytes ensheaths axons with myelination to enhance conduction Microglia defense against infection, clean up after injury Blood vessels supply oxygen, glucose other essential nutrients/amino acids etc to brain Neurotrophins: are proteins made and released in the brain from various types of cell, though not necessarily classed as neurotransmitters. They are important for maintaining neuronal integrity and normal function. Bind to membrane receptor tyrosine kinase. Many examples exist BDNF (brain-derived neurotrophic factor) which appear to mediate important functions and assist during development and/or injury conditions. Not yet usable as a drug (due to size of molecule and limitations in the ability for exogenous BDNF to be made and inserted). For neuropharmacological drug classifications it is useful to: 1. Classify according to transmitter / receptor 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...) 5