Lec.9_drugs_Student V2.pptx Manchester Metropolitan

Drugs

1. Biopsychology: Lecture 9 Actions of Drugs on the Nervous System Dr Paula Trotter: Office hours Mon 12:30-15:30, Room BR3.53

2. Recap

3. Releasing Neurotransmitters Synaptic vesicles ‘dock’ against the pre-synaptic membrane Action potential Ca+ Ca+ Ca+ Voltage-dependent calcium channels open Calcium ions (Ca 2 +) enter the cell At rest

4. Releasing Neurotransmitters Calcium ions cause vesicles to fuse with pre-synaptic membrane . Ω Vesicles release neurotransmitters The entire process is called exocytosis

5. Postsynaptic Receptors Neurotransmitters bind to specific receptor sites in post-synaptic membrane. - ‘Lock and key’ mechanism They affect the post-synaptic membrane potential by opening ion channels . There are two main classes of receptor… Receptor site membrane neurotransmitter This neuro -transmitter does not ‘fit’ this receptor

6. **1. Ionotropic Receptors Neurotransmitter receptor site on ion channel. Neurotransmitter causes ion channel to open or close. Membrane potential of postsynaptic cell altered due to change in ion distribution. Effects are direct and rapid (<1 ms ) and short-lasting (effects of decay with a half-life ~ 5 ms ) Receptor site Neurotransmitter Ions Ion channel Most ionotropic effects rely on glutamate or GABA (most of the sensory/motor information) Transmitter-gated or ligand-gated channels

7. 2. Metabotropic Receptors Neurotransmitter receptor site on signal protein that is linked to a G-protein. Portion of G-protein breaks away, and activates ‘ second messenger ’ chemicals. G-proteins or second messengers bind to ion channels Effects are indirect, slower (~30 ms ), and longer-lasting (~several seconds). Ion channel Second messenger G-protein neurotransmitter Signal protein Metabotropic synapses use many NT such as DA, NE, 5-HT, and sometimes Glu and GABA (taste, smell, pain, cognitive functions) Guanosine triphosphate GTP

8. Postsynaptic Effects Depolarisation (Excitatory) Hyperpolarisation (Inhibitory) e.g. sodium channels open, and Na+ enters the cell. e.g. potassium channels open, and K+ leaves the cell Inside of postsynaptic cell becomes more positive Inside of postsynaptic cell becomes more negative Postsynaptic c ell more likely to fire Postsynaptic c ell less likely to fire. Threshold for activation: -65mv Depend on which ion channels are opened EPSP: excitatory postsynaptic potential IPSP: inhibitory postsynaptic potential

9. Ending the signal Reuptake Neurotransmitters transported back into the cytoplasm of the neuron (requires energy). Degradation Enzymes break down and deactivate neurotransmitter molecules.

10. Autoreceptors Some receptors are found on the presynaptic membrane . They detect and regulate levels of neurotransmitter in the synapse. They affect the amounts of neurotransmitter that are released. Action potential Post synaptic receptors Autoreceptor

11. The big picture 100 billion (or more!) neurons in the nervous system. Each neuron can communicate with thousands of other neurons: an estimated 200 trillion synapses. There are over a hundred different types of neurotransmitter. Neurotransmitters can have different effects depending on the receptor type .

12. Actions of drugs on the nervous syste m

13. Learning objectives Define what is meant by agonistic and antagonistic drugs. Describe some of the mechanisms by which agonistic and antagonistic drugs can affect the production, release, reception, reuptake and degradation of neurotransmitters. Understand the importance of drug research in the field of biopsychology.

14. Drug Agonist Antagonist Precursor Transporter Key Vocabulary

15. What is a drug? An exogenous chemical that: - is not necessary for normal functioning and - significantly alters the functions of certain cells in the body when taken in low doses. Includes therapeutic and ‘recreational’ drugs. Biopsychologists are interested in drugs that affect the nervous system.

16. Synthesis of neurotransmitters Storage in vesicles ‘Exocytosis’ Regulation by autoreceptors Binding to postsynaptic receptors Reuptake or degradation of neurotransmitters * * * * * enzymes The behavioural effects of many drugs are due to their influence on synaptic communication. May influence: - Production, storage or release of neurotransmitters. Pre or Postsynaptic receptors Reuptake or degradation of neurotransmitter. The sites of drug actions

17. Facilitate the effect of a particular neurotransmitter. e.g. increase the amount of dopamine released. Counter the effects of a particular neurotransmitter. e.g. decrease the amount of dopamine released. Agonists Antagonists IMPORTANT: This distinction is NOT the same as excitation vs. inhibition…

18. Agonists If the neurotransmitter has an excitatory effect … … an agonistic drug will increase this excitatory effect If the neurotransmitter has an inhibitory effect… … an agonistic drug would increase the inhibition -70 -65 -70 -65 -70 -65 -70 -65 Depolarise Hyperpolarise

19. Antagonists If the neurotransmitter has an excitatory effect… … an antagonistic drug will decrease this excitatory effect If the neurotransmitter has an inhibitory effect… … an antagonistic drug would decrease the inhibition -70 -65 -70 -65 -70 -65 -70 -65

20. Agonistic Effects Neurotransmitters bind to specific receptor sites on the postsynaptic membrane. Some agonist drugs bind to the same receptor sites as the neurotransmitter and open ion channels. Greater postsynaptic effect e.g. “ Valium ” binds to receptors for the neurotransmitter GABA Postsynaptic neuron Agonist drug neurotransmitter Chloride ions

21. Agonistic Effects Neurotransmitter molecules are made from precursors . Some agonist drugs may : Increase the amount of precursor . Activate enzymes that speed up synthesis. More neurotransmitter is made. * * * * * precursors enzymes e.g. “L-DOPA” is the precursor to dopamine https:// www.youtube.com/watch?v=sf1N0Zf5IqA

22. Agonistic Effects Neurotransmitter molecules are made from precursors . Some agonist drugs may : Increase the amount of precursor . Activate enzymes that speed up synthesis. More neurotransmitter is made. * * * * * precursors enzymes e.g. “L-DOPA” is the precursor to dopamine https:// www.youtube.com/watch?v=sf1N0Zf5IqA

23. Agonistic Effects enzymes transporter Neurotransmitters in the cleft can be transported back into the presynaptic neuron (‘reuptake) or broken down by enzymes. Some agonist drugs block transporters or stop the enzymes from working . Neurotransmitters stay in cleft for longer. e.g. drugs that stop acetylcholinesterase will facilitate acetylcholine activity

24. Antagonistic Effects Neurotransmitters bind to postsynaptic receptor sites. Antagonist drugs may block these receptor sites Fewer postsynaptic receptors are activated. e.g. “chlorpromazine” blocks dopamine receptors Postsynaptic neuron Antagonist drug neurotransmitter

25. Antagonistic Effects Neurotransmitter molecules are released from the synaptic vesicles. Drugs that block the release of neurotransmitters are antagonists. Less neurotransmitter is released. e.g. “ Botox ” blocks acetylcholine at neuromuscular junction

26. Antagonistic Effects Autoreceptors detect and regulate the level of neurotransmitter – provides a negative feedback loop. Some antagonist drugs stimulate these autoreceptors . The presynaptic neuron reduces the amount of neurotransmitter that is released . e.g. “clonidine” binds to presynaptic α2 receptors, inhibiting further release of adrenaline and noradrenaline.

27. Agonist or Antagonist? Drug Action Agonist or antagonist? Black widow spider venom Stimulates the release of neurotransmitters from vesicles. PCPA Para- chloro -phenyl-alanine Inactivates the enzyme needed to make the neurotransmitter (5-HT). Cocaine Inactivates presynaptic transporters responsible for reuptake of neurotransmitter. Idazoxan Blocks (NA) autoreceptors on presynaptic membrane. Agonist Antagonist Agonist Agonist

28. Black widow spider venom Venom is " Latrotoxin " Stimulates the release of neurotransmitters from vesicles. Latrotoxin is a neurotoxin ; it stimulates nerve cells to release large amounts of neurotransmitters, ( Glutamate, GABA, norepinephrine, & acetylcholine .) affects motor nerve endings and endocrine cells https:// www.youtube.com/watch?v=UG4VNMA8TG8

29. Cocaine Inactivates presynaptic transporters responsible for reuptake of neurotransmitters. Amphetamines and cocaine bind to — thus blocking — transporters used for the reuptake of dopamine (and noradrenaline and serotonin) into presynaptic neurons. This causes the level of dopamine to rise in the synapses. The resulting chemical build-up between nerves causes euphoria or feeling " high“ (30 min / 2 h) an increasing sense of energy and alertness an extremely elevated mood a feeling of supremacy Excited, full of energy irritability paranoia restlessness anxiety National Institute on Drug Abuse (NIDA ) (2016) Cocaine https :// www.drugabuse.gov /publications/research-reports/cocaine/how-does-cocaine-produce-its-effects

30. Cocaine is responsible for more U.S. emergency room visits than any other illegal drug. Gastrointestinal tract: Ulcers Perforations Kidneys: Kidney failure Sexual dysfunction

31. Why do we care… Understand the neurochemical basis of: psychological functions and behaviours. psychological disorders. Develop treatments for psychological disorders. Acetylcholine agonists improve memory Acetylcholine antagonists make memory worse Acetylcholine is involved in memory Memory loss can be due to reduced Acetylcholine activity Acetylcholine agonists to treat memory loss! (e.g. Donezepil )

32. A Survey of Abused Drugs

33. The mouse house party http://learn.genetics.utah.edu/content/addiction/mouse/ See how these drugs influence synaptic communication!

34. Some other physical effects of drugs http://tobaccobody.fi / http:// www.dailymail.co.uk/news/article-2589612/Shocking-images-devastating-physical-toll-drugs-take.html http:// www.bbc.co.uk/news/av/uk-scotland-21843181/app-showing-ageing-effects-of-alcohol-goes-global

35. Reading Kalat , Module 3.3 Pinel : sections 4.7 Or relevant sections in another biopsychology textbook Any questions?