PS2101%20Neuropharmacology%202022%20BB.txt

PS2101 Topic 1: Neuropharmacology 1 Psychopathology: An integrated approach to disorders of the mind Biological basis of brain function Overview 2 Topics Neuropharmacology – how drugs affect neurotransmission Biological basis of reward and addiction Biological basis of schizophrenia Biological basis...

PS2101 Topic 1: Neuropharmacology 1 Psychopathology: An integrated approach to disorders of the mind Biological basis of brain function Overview 2 Topics Neuropharmacology – how drugs affect neurotransmission Biological basis of reward and addiction Biological basis of schizophrenia Biological basis of depression Overview of clinical relevance Revision and approaches to answering exam questions Builds on material from PS1106 PS1106 Overview – See video 3 Neurone structure Membrane potentials Changes in membrane potential Signal integration The axon hillock The action potential The synapse Neuropharmacology 4 How chemicals affect neuronal function in the nervous system Endogenous - NEUROTRANSMITTERS Exogenous - DRUGS Molecular neuropharmacology Behavioural neuropharmacology (psychopharmacology) Neurotransmitter synthesis, release and clearance 5 See the video on synaptic function The synapse 6 Receptors Neurotransmitter binding to its receptor Neurone in resting state Neurotransmitter binds to receptor Signal transmitted to post-synaptic neurone Receptor activated Excitation or inhibition Synaptic cleft Post-synaptic neurone dendrite How? 7 Ionotropic receptors - regulate ion fluxes Synaptic cleft Post-synaptic neurone dendrite Ions Neurone in resting state Ion channel linked to neurotransmitter binding site Normally closed ⇒ ions do not enter postsynaptic neurone 8 Ionotropic receptors Synaptic cleft Post-synaptic neurone dendrite Ions Ion channel linked to neurotransmitter binding site Normally closed ⇒ ions do not enter postsynaptic neurone Activation by transmitter binding opens the ion channel Allows ions to enter postsynaptic neurone and change the membrane potential Excitation (EPSP) or Inhibition (IPSP) Ions 9 Ionotropic receptors : e.g. Nicotinic acetylcholine receptors Acetylcholine binds to receptor Postsynaptic cell becomes more positive - i.e. depolarisation (EPSP) Na+-channels open Excitation (EPSP) Synaptic cleft Post-synaptic neurone dendrite Na+ Na+ Na+ enters postsynaptic neurone 10 Ionotropic receptors : e.g. GABA-A receptors GABA binds to receptor Postsynaptic cell becomes more negative - i.e. hyperpolarisation (IPSP) Cl–channels open Inhibition (IPSP) Synaptic cleft Post-synaptic neurone dendrite Cl- Cl- Cl- enters postsynaptic neurone 11 Metabotropic receptors - regulate metabolic reactions Synaptic cleft Post-synaptic neurone dendrite Neurone in resting state Receptor linked to chemicals which modulate intracellular reaction cascades Reactions normally inactive ⇒ neurone is at rest 12 Metabotropic receptors Synaptic cleft Post-synaptic neurone dendrite Receptor linked to chemicals which modulate intracellular reaction cascades Reactions normally inactive ⇒ neurone is at rest Activation by transmitter binding to receptor causes intracellular reactions Often involving g-protein mediated second messenger systems Changes in membrane potential, causing excitation or inhibition Normally slower and longer lasting than ionotropic receptors Excitation or Inhibition Chemical Reaction Chemical Reaction Chemical Reaction 13 14 Metabotropic Metabotropic glutamate receptors GABA-B receptors Muscarinic acetylcholine receptors All serotonin receptors except 5HT-3 All the dopamine receptors All noradrenaline receptors Ionotropic Most glutamate receptors GABA-A receptors Nicotinic acetylcholine receptors Serotonin 5HT-3 receptors Summary Receptors are classed as ionotropic or metabotropic, depending on whether they (1) directly ‘gate’ ion channels, or (2) modulate intracellular reactions, respectively Ionotropic and Metabotropic Receptors Therapeutic drugs acting at receptors 15 Agonists Used to treat conditions involving underactivity of neurotransmitters e.g. Dopamine agonists in treatment of Parkinson’s Disease Antagonists Used to treat conditions involving overactivity of neurotransmitters e.g. Dopamine antagonists in treatment of schizophrenia Actions at presynaptic receptors can complicate treatment strategies Drug action at receptors 16 Many venom toxins bungarotoxin (from cobras) : antagonist at acetylcholine receptors curare (from frogs) : antagonist at acetylcholine receptors Antipsychotics (neuroleptics) – antagonists at dopamine receptors Barbiturates and benzodiazapines (anticonvulsants, anxiolylics) increase GABA receptor function (allosteric binding site) Many plant derivatives atropine (belladonna : from deadly nightshade) : antagonist at acetylcholine receptors : first pharmacological treatment for Parkinson’s disease nicotine (from tobacco) : agonist at acetylcholine receptors muscarine (from fungus) : agonist at acetylcholine receptors 17 Modulation of the response to the native transmitter (or an agonist) by a substance binding to a second binding site on the receptor which is separate from the main transmitter binding site Allosteric modulation Neurotransmitter binding to its receptor Neurone in resting state Neurotransmitter binds to receptor Signal transmitted to post-synaptic neurone Receptor activated Excitation or inhibition Synaptic cleft Post-synaptic neurone dendrite 18 Allosteric modulation Neurone in resting state Modulator binds to allosteric binding site No change in postsynaptic potential Receptor ‘potentiated’ Synaptic cleft Post-synaptic neurone dendrite + + + + No Postsynaptic effect Allosteric binding site on receptor Alone, an allosteric modulator has no effect on postsynaptic signal 19 Excitation or inhibition Allosteric modulation Neurone in resting state Modulator binds to allosteric binding site No change in postsynaptic potential Receptor ‘potentiated’ Synaptic cleft Post-synaptic neurone dendrite The allosteric modulator enhances (or attenuates) the effect of the transmitter ENHANCED Excitation or inhibition Action ‘potentiated’ Modulator and transmitter both bound Enhanced postsynaptic response + + + + + + 20 Allosteric modulation Synaptic cleft Post-synaptic neurone dendrite Inhibition GABA GABA-A Receptor Barbiturates or Benzodiazepines + + + + ENHANCED inhibition Barbiturates and benzodiazepines enhance the action of GABA, through allosteric modulation of the GABA-A receptor 21 Summary of allosteric modulation The neurotransmitter produces its action by binding to the receptor Allosteric modulators bind to separate binding sits on the receptor. Alone an allosteric modulator has no effect ….. ….. but it does enhance the effect of the main transmitter There are many examples of allosteric modulation …. ….. but the one you are most likely to come across is the Allosteric modulation of GABA-mediated inhibition by barbiturates and benzodiazepines 22 Therapeutic uses of benzodiazepines and barbiturates 23 Sedative-hypnotics and anxiolytics Barbiturates widely used in the past e.g. Pentobarbital, buspirone BUT can cause fatal respiratory depression high potential to produce dependence Now mainly used only as anticonvulsants and anaesthetics Introduction of benzodiazepines reduced the use of barbiturates e.g. Diazepam Much reduced (although still significant) risk of dependence Widely used in treatment of anxiety disorders, anaesthesia, insomnia Endogenous benzodiazepines 24 Christian, et al. (2013). Endogenous positive allosteric modulation of GABA-A receptors by diazepam binding inhibitor. Neuron 78.6 : 1063-1074. Evidence of endogenous compounds capable of modulation benzodiazepine function Diazepam binding inhibitor (DBI) - brain’s endogenous benzodiazepine Sometimes called “endozepine” Direction of modulation (potentiation or attenuation) of GABA-A varies across different brain areas Little is known about how DBI levels are regulated … ….. nor how its positive and negative effects are mediated Precursor Neurotransmitter Function : The synapse Receptors in postsynaptic membrane Neurotransmitter free in cytoplasm Neurotransmitter packaged in vesicles Presynaptic neurone Postsynaptic neurone - dendrite Synaptic cleft Axon Calcium channel Released neurotransmitter in synaptic cleft These are postsynaptic receptors Primarily responsible for signal transmission Is this always the case? 25 Presynaptic receptors Receptors are also found on neurone terminals …. ….. where they modulate transmitter release These are presynaptic receptors (as opposed to the postsynaptic receptors we have just been looking at) There are two types: Autoreceptors - on the terminals of the same neurone as released the transmitter Heteroreceptors - on terminals of a different neurone 26 Receptors in postsynaptic membrane Presynaptic neurone Postsynaptic neurone Synaptic cleft Calcium channel Released neurotransmitter in synaptic cleft X X X Autoreceptors Autoreceptor activation reduces release, synthesis and/or storage of transmitters from that terminal Inhibitory - negative feedback X 27 Receptors in postsynaptic membrane Presynaptic neurone Postsynaptic neurone Synaptic cleft Calcium channel Released neurotransmitter in synaptic cleft Agonist and antagonist action at autoreceptors Autoreceptor activation reduces release, synthesis and/or storage of transmitters from that terminal Inhibitory - negative feedback Reduced release Transmitter Reduced transmitter release Therefore Reduced postsynaptic effect 28 Receptors in postsynaptic membrane Presynaptic neurone Postsynaptic neurone Synaptic cleft Calcium channel Released neurotransmitter in synaptic cleft Agonist and antagonist action at autoreceptors Autoreceptor activation reduces release, synthesis and/or storage of transmitters from that terminal Inhibitory - negative feedback Reduced release Agonist Reduced transmitter release Therefore Reduced postsynaptic effect Opposite to the effect of binding to postsynaptic receptors 29 Receptors in postsynaptic membrane Presynaptic neurone Postsynaptic neurone Synaptic cleft Calcium channel Released neurotransmitter in synaptic cleft Agonist and antagonist action at autoreceptors Autoreceptor activation reduces release, synthesis and/or storage of transmitters from that terminal Inhibitory - negative feedback Reduced release Therefore Postsynaptic effect intact Opposite to the effect of binding to postsynaptic receptors X Antagonist 30 Autoreceptors - summary Autoreceptors Located on neurone terminals Sensitive to the transmitter released by that neurone Act as a negative feedback mechanism - Reduce (“switch off”) the release of the transmitter from the terminal Several mechanisms have been identified: Inhibition of incoming action potential Decreases calcium channel opening (⇒ reduces calcium influx) Prevents vesicles binding to membrane and releasing transmitter Reduce synthesis by modulating enzyme function Drug effects at autoreceptors are opposite to the effects at postsynaptic receptors 31 Precursor Presynaptic element (“Terminal 1”) Synaptic cleft Axon Calcium channel Neurotransmitter released into synaptic cleft Heteroreceptors Postsynaptic element (“Terminal 2”) +/- Synthesis +/- Packaging +/- Release This is the terminal of another incoming neurone Heteroeceptors activation modulates release of transmitters from the second terminal (also synthesis/storage) Can be excitatory or inhibitory 32 Heteroreceptors - summary Heteroreceptors Located on neurone terminals Sensitive to the transmitter released by a different neurone Modulates release (also synthesis/storage) in that terminal Can be excitatory (enhances release) or inhibitory (reduces release) from the second terminal Several mechanisms have been identified: Increases/decreases calcium channel opening (» calcium influx) Increases/decreases vesicles binding to membrane and releasing transmitter May also affect synthesis by modulating enzyme function 33 Study guide – Presynaptic receptors How much do you need to know about presynaptic receptors? You really only need to be aware that receptors can be either postsynaptic or presynaptic, and the consequences of the actions at receptors in the different locations, as in the summary slide. If you do want to look into this aspect in more depth, there are a number of reviews on presynaptic receptors, but most of them are at a much higher level than you need - they go into details of the subcellular and molecular mechanisms. If you do want to look at the topic in more detail, this is a nice review (it also covers many aspects of fundamental synaptic function as well). However, do not get bogged down in the molecular mechanisms - that level of detail is not relevant for you. Miller RJ (1998). Presynaptic receptors. Annu. Rev. Pharmacol. Toxicol. 38:201–27 http://www3.uah.es/farmamol/Public/AnnReviews/PDF/Pharma_Toxicol/Presynaptic_R.pdf 34 Precursor The synapse Receptors in postsynaptic membrane Neurotransmitter free in cytoplasm Neurotransmitter packaged in vesicles Presynaptic neurone Postsynaptic neurone - dendrite Synaptic cleft Axon Calcium channel Released neurotransmitter in synaptic cleft 35 Receptors in close up Receptors in postsynaptic membrane Synaptic cleft 36 Neurotransmitter binding to its receptor Neurone in resting state Neurotransmitter binds to receptor Signal transmitted to post-synaptic neurone Receptor activated Excitation or inhibition Synaptic cleft Post-synaptic neurone dendrite 37 Drugs acting at receptors : Receptor agonists Neurone in resting state Agonist binds to receptor Causes the same change as the native transmitter in the post-synaptic neurone Receptor activated Excitation or inhibition Synaptic cleft Post-synaptic neurone dendrite Agonists often remain bound to the receptor for much longer than the native transmitter 38 Drugs acting at receptors : Receptor antagonist Neurone in resting state Antagonist binds to receptor No change in post-synaptic neurone Receptor occupied but no action No effect Synaptic cleft Post-synaptic neurone dendrite Prevents transmitter from binding ‘Blocks’ receptor 39 Summary of receptor agonists and antagonists Receptor agonists and antagonists bind to the neurotransmitter receptors Agonists mimic the effect of the native neurotransmitter Antagonists bind to the receptor, but do not change the activity of the postsynaptic neurone However they do prevent the native transmitter, or an agonist from binding - hence they are often called “blockers” The “Glossary of Drugs” contains information on some important receptor agonists and antagonists 40 Drugs affecting clearance Reuptake inhibitors Breakdown enzyme inhibitors 41 Drugs affecting clearance : Reuptake inhibitors Reuptake transporters Transmitter is taken back into presynaptic terminal by active reuptake, leaving synaptic cleft empty and available for next release event 42 Drugs affecting clearance : Reuptake inhibitors Reuptake inhibitor Reuptake transporters Transmitter is taken back into presynaptic terminal by active reuptake, leaving synaptic cleft empty and available for next release event X X X Prevents the re-uptake. Increases the concentration of transmitter in the synaptic cleft More transmitter available to bind to receptors 43 Drugs affecting clearance : Breakdown inhibitors Neurone in resting state Transmitters are normally broken down by enzymes and excreted Breakdown by enzymes Prevent this breakdown, leading to a build up of transmitters in the terminal Enzyme inhibitors 44 Drugs affecting clearance : Breakdown inhibitors Neurone in resting state Enzyme inhibitors Transmitters are normally broken down by enzymes and excreted Breakdown by enzymes … which in turn prevents more being take up. Prevent this breakdown, leading to a build up of transmitters in the terminal 45 Drugs affecting clearance : Breakdown inhibitors Neurone in resting state Prevent this breakdown, leading to a build up of transmitters in the terminal Enzyme inhibitors Transmitters are normally broken down by enzymes and excreted Breakdown by enzymes Increases the concentration of transmitter in the synaptic cleft More transmitter available to bind to receptors … which in turn prevents more being take up. 46 Summary of drugs which prevent clearance Reuptake inhibitors Prevent the active uptake of transmitter from the synaptic cleft into the terminal, by blocking the uptake transporter molecules As a result, the transmitter remains in the synaptic cleft for longer, and is available to bind to receptors for longer Therefore enhances the effect of the transmitter Breakdown enzyme blockers Prevent enzymes from breaking down the neurotransmitter. Leads to the transmitter remains in the synaptic cleft for longer, and is available to bind to receptors for longer Therefore enhances the effect of the transmitter These drugs increase the amount of neurotransmitter in the synaptic cleft, therefore increasing binding of the transmitter to the receptors, and enhancing the signal. Note, however, that the drugs themselves do not bind to the postsynaptic receptors. 47 Drugs which affectsynthesis and storage ofneurotransmitter 48 Precursor Neurone in resting state Enzymatic conversion Precursor Drugs which affect neurotransmitter synthesis Precursor Transmitter synthesis can be increased by giving precursors 49 Precursor Neurone in resting state Enzymatic conversion Precursor Drugs which affect neurotransmitter synthesis X Transmitter synthesis can be decreased by blocking the enzymes which convert precursors to transmitters. Mostly used in research, rather than clinically Enzyme inhibitors 50 Neurone in resting state Neurotransmitter packaged in vesicles, ready for release Drugs which affect packaging of neurotransmitter Some drugs prevent the packaging of transmitter into vesicles, therefore making them unavailable for release One particular drug of this type, which we will come across later, is reserpine X 51 Summary of drugs which affect synthesis and storage Precursors Increasing the amount of precursors enables more transmitter to be synthesised Increases the amount of transmitter available for release Synthesis enzyme inhibitors Blocks the conversion of precursors to transmitters in the terminals Decreases the amount of transmitter available for release Disruption of storage in vesicles Prevents the storage of neurotransmitters in vesicles in the terminal Decreases the amount of transmitter available for release  (since only transmitter packaged in vesicles is available for release) 52 Summary Postsynaptic receptors Located on dendrites on postsynaptic neurone Responsible for transmission of signals to the next cell in the chain Presynaptic receptors Located on presynaptic terminals Modulates the release of transmitter from the terminal Autoreceptors Located on the same terminal that releases the transmitter Inhibitory (negative feedback) - ‘switches off’ signal Heteroreceptors Located on terminals of a different neurone from the one releasing the transmitter ⇒ modulates release in that terminal Can be excitatory (enhances release) or inhibitory (reduces release) from the second terminal 53 Drugs affecting synaptic transmission 54 Drugs affecting synaptic transmission 55 Drugs such which prevent action potentials, normally by blocking voltage-dependant sodium channels (e.g. tetrodotoxin, some local anaesthetics) Drugs affecting synaptic transmission 56 Drugs such which affect synthesis and storage of neurotransmitters (e.g. L-DOPA increases dopamine synthesis; tryptophan; reserpine prevents storage of dopamine, noradrenaline and 5HT.) Drugs affecting synaptic transmission 57 Drugs such which affect release of neurotransmitters (e.g. Botulinum toxin; black widow venom toxin; amantidine) Drugs affecting synaptic transmission 58 Drugs such which affect receptors (e.g. dopamine agonists in the treatment of Parkinson’s disease; dopamine antagonists in treatment of psychosis; benzodiazepines as anxiolytics) Drugs affecting synaptic transmission 59 Drugs such which affect reuptake (e.g. tricyclic antidepressants; SSRI antidepressants ; cocaine; amphetamine) Drugs affecting synaptic transmission 60 Drugs such which affect metabolism (e.g. monoamine oxidase inhibitors (MAOI) in treatment of depression and Parkinson’s disease; GABA transaminase inhibitor anticonvulsants; [amphetamine]) Study guide What do you need to take away from this presentation? You should be aware of the basic mechanisms of synaptic transmission You should know about different classes of receptor, and appreciate the distinction between ionotropic and metabotropic receptors, and between pre- and post-synaptic receptors No detail required! You should know the basic mechanisms of action of the different types of drugs we have covered in this presentation. Future presentations will discuss many examples of drugs acting in these ways The “Glossary of Drugs” summarises the actions of many of the drugs we will come across in the up and coming topics, which will help you put these mechanisms into context. Be clear on what agonists and antagonists are - see “Overview of Drug Nomenclature” 61