Biological Bases of Behaviour. Lecture 5: Pharmacology of Synapses.

1. Biological Bases of Behaviour.Lecture 5: Pharmacology of Synapses. Normal monkey Monkey exposed to ecstasy Kalat (2001) p 73

2. Learning Outcomes. • By the end of this lecture you should be able to: • 1. Describe the formation and the functions of the key neurotransmitters. • 2. Explain (using examples) how drugs affect synapses. • 3. Describe how drugs of abuse affect synaptic events.

3. Transmitter Substances. • Recall that neurotransmitters can have two types of effect: • 1. Depolarization (EPSP) • 2. Hyperpolarization (IPSP) • One would perhaps expect that two types of neurotransmitter would exist - excitatory and inhibitory. • However, while some neurotransmitters are exclusively excitatory or inhibitory, others can produce either effect depending upon the nature of the postsynaptic receptors. • The commonest neurotransmitters are as follows:

4. 1. Acetylcholine (ACh). • ACh consists of choline and acetate. • Normally these two substances cannot join together as the acetate is connected to molecules of Acetyl coenzyme A (Acetyl CoA). • However in the presence of the enzyme choline acetyltransferase (CAT), the acetate ion is transferred to the choline molecule producing a molecule of ACh and a molecule of CoA. Carlson, (1994), p 61

5. Acetylcholine (continued). • Acetylcholine is released at acetylcholinergic synapses on skeletal muscles where it is excitatory. • In the CNS it plays a role in learning, memory, and in sleep regulation. • In the PNS acetylcholinergic synapses are inhibitory. • There are two kinds of ACh receptors: • 1. Nicotinic: Ionotropic, and stimulated by the poison nicotine. They produce very rapid but short-lived potentials and are found principally in muscle fibres and in the CNS. • 2. Muscarinic: Metabotropic, and stimulated by the poison muscarine (in mushrooms), they produce slower but longer-lived potentials and are found principally in the CNS.

6. Reuptake of Acetylcholine. Recycled choline • ACh is split into its consituent parts by the enzyme acetylcholinesterase (AChE). • The choline returns to the presynaptic terminal by means of reuptake. Choline transporter Presynaptic membrane Acetate ion ACh molecule choline Actions of AChE breaks down ACh molecule AChE Carlson, (1994), p 62

7. 2. The Monoamines. • There are four neurotransmitters in this class all distributed widely throughout the brain: • Dopamine • Epinephrine • Norepinephrine • Serotonin • They act as modulators - decreasing or increasing various brain activities. • As they are all chemically very similar many drugs can affect their activity. • There are two subclasses of monoamines: catecholamines and indoleamines.

8. The Catecholamines. • Dopamine (DA): Dopaminergic neurons produces both EPSP's and IPSP's depending on the nature of the postsynaptic receptor. • Dopamine can only be obtained from phenylalanine derived from a protein-rich diet. • This is then converted into the amino acid tyrosine which then creates L-Dopa by the actions of Tyrosine hydroxylase. • The actions of the enzyme DOPA decarboxylase finally converts L-Dopa into Dopamine. • At least 5 types of dopamine receptors have been identified so far referred to as D1 - D5each with differing properties.

9. Dopamine (continued). • Dopamine has been implicated in several important functions including movement, attention and learning. • Degeneration of dopaminergic neurons in the substantia nigra (part of the basal ganglia) causes Parkinson's disease, some symptoms of which can be alleviated by the drug L-Dopa. • Dopamine may also play a role in schizophrenia as drugs that block the activity of dopamine alleviate the more serious symptoms of this disorder and drugs which increase dopamine production increase such symptoms.

10. Norepinephrine (NA). • This is also called noradrenalin and is created within dopamine-containing synaptic vesicles by dopamine -hydroxylase. • In the brain, noradrenergic synapses are involved in the control of alertness and wakefulness and produce IPSP's. • In the target organs of the sympathetic nervous system noradrenergic synapses have excitatory effects. • There are several types of noradrenergic receptors which are usually referred to as adrenergic because they are also sensitive to epinephrine (adrenalin). • In the CNS there are 1, 2, 1 and 2-adrenergic receptors. These are coupled to G-proteins that generate the secondary messenger cyclic AMP and are metabotropic. • Catecholamine synthesis is regulated by the enzyme monoamine oxidase (MAO).

11. The Indoleamines. • Serotonin (5-Hydroxytryptamine or 5-HT): The precursor of serotonin is the amino acid tryptophan. • The enzyme tryptophan hydroxylase converts tryptophan into 5-hydroxytryptophan (5-HTP). • Another enzyme 5-HTP decarboxylase then produces 5-HT (serotonin). • At most serotonergic synapses this transmitter produces IPSP’s and its behavioural effects are also inhibitory. It plays a key role in mood; eating; pain; sleep and dreaming; and arousal. • There are at least 7 different types of serotonergic receptors 5-HT1A-1D and 5-HT2-4 all being metabotropic except for the 5-HT3 receptor.

12. Other Transmitters. • Some neurons use amino acids as transmitter substances, the most important being: • 1. Glutamate: Also known as glutamic acid and is found throughout the brain. It produces EPSP's in the postsynaptic membrane but also directly affects axons by lowering their threshold of excitation, thus increasing the rate at which action potentials occur. • Some Oriental foods contain high levels of monosodium glutamate and this can cause mild neurological symptoms. • There are several ionotropic and metabotropic glutamate receptors. • The ionotropic NMDA receptor seems to involved in the synaptic changes underlying learning and memory.

13. Other Transmitters (continued) • 2. GABA (gamma-aminobutyric acid): Produced from glutamic acid by the actions of an enzyme called glutamic acid decarboxylase (GAD). • It is inhibitory and is widely distributed throughout the brain and spine and some investigators believe that it is the widespread presence of GABA that prevents epilepsy. • Two GABA receptors have been identified - the ionotropic GABAA and the metabotropic GABAB. • The GABAA receptors contain bindings sites for at least 3 different substances, one being for GABA, the second being for benzodiazepines and third being for alcohol and barbiturates each of which have inhibitory effects.

14. Other Transmitters (continued) • 3. Peptides: Neurons in the CNS also release peptides. • One of the most important are the endogenous opiates discovered by Pert et al., (1975). • They discovered that that the reason that drugs such as morphine and heroin are so addictive is that they act on the naturally-occurring opioid synapses that are normally stimulated by the brain’s own substances. • These natural opiates are called enkephalins and appear to be important for pain relief and pleasure.

15. Pharmacology of Synapses. • Many natural substances affect the functioning of the synapses. • Key drugs of abuse are derived from plants or grains (e.g. alcohol, nicotine, opium, caffeine, cocaine). • Effective drugs either increase or decrease the effects of a neurotransmitter. • A drug that blocks the effects of a neurotransmitter is an antagonist, while a drug that mimics or increases its effects is an agonist. • Whether a drug is an agonist or an antagonist is determined by its affinity (the strength of its binding to the receptor) and its efficacy (how well it activates the receptor).

16. Individual Differences. • Everyone’s brain uses the same neurotransmitters which gives the impression that drugs will have the same effects on everyone. • Clearly this is not so. There are large individual differences in drug responsiveness, and these are determined by the fact that different receptors are found in different numbers and sensitivities, determined by genetic and environmental factors. • E.g someone may have a large number of dopamine D4 receptors and few D1 or D2 receptors, but someone else may have more of the latter and fewer of the former (Kalat, 2001). • Synaptic function can be affected by different drugs in several ways:

17. 1. Production of the Transmitter. • A transmitter substance must first be synthesised from a precursor and this process is controlled by enzymes. • Drugs that affect these enzymes can thus influence the production of the transmitter substance. E.g: • L-Dopa is a dopamine agonist as it increases the rate at which dopamine is synthesised. • The drug PCPA prevents the enzyme tryptophan from making serotonin (it is thus an antagonist) and is often used to halt the progress of certain tumours that derive from serotonergic neurons.

18. 2. Storage and Release. • Reserpine (snakebite cure) makes the synaptic vesicles that contain monoamines leak and the molecules of neurotransmitter are mopped up by MAO before being released. Reserpine is thus an antagonist. • Other substances do not affect the storage of the transmitters but prevent their release. • E.g Botulinum toxin causes paralysis by preventing the release of ACh. • Other drugs, such as the venom of the black widow spider cause the release of too much ACh which can be fatal in the very young and old.

19. 3. Effects on Receptors. • Once a neurotransmitter is released, it must stimulate the postsynaptic receptors. • Nicotine mimics the effects of ACh at the nicotinic receptors and is thus an agonist. • Atropine (Belladonna) blocks the acetylcholinergicmuscarinic receptors and causes paralysis in the autonomic nervous system, it is an antagonist. • The plant toxin curare blocks the nicotinic receptors found in the muscles and causes paralysis, it was originally used as a hunting weapon but is now used during surgery to prevent muscle contraction.

20. 4. Reuptake and Destruction. • Cocaine prevents the reuptake of NA and DA and is thus an agonist. • Physostigmine prevents the enzymes that destroy ACh from working and is also agonistic. • Iproniazid inactivates MAO allowing more monoamines to be released when the axon fires. It is a potent antidepressant as it acts as a serotonergic agonist. Carlson, (1994), p 73

21. Drugs of Abuse. • Highly addictive drugs produce their pleasurable effects because they increase activity in dopamine receptors in the nucleus accumbens. Axons from nucleus accumbens Nucleus accumbens Kalat (2001) p 70

22. Drugs of Abuse. • i) Amphetamine: Stimulates dopaminergic synapses by increasing the release of dopamine at the presynaptic terminal. Effects are short-lived and are usually followed by depression as dopamine is then released at a much lower rate than normal. • ii) Cocaine: Blocks reuptake of dopamine, norepinephrine and serotonin. Again, the effects are short-lived and are followed by reduced neurotransmitter release. • Cocaine users rapidly develop a tolerance to the drug and have to take more and more to achieve the same effects. • Permanent alterations are also caused to the dopamine system which alters brain metabolism and blood flow increasing the risks of stroke and epilepsy.

23. Drugs of Abuse (continued) • iii) MDMA (methylenedioxymethamphetamine or Ecstasy): Stimulates dopamine release at low doses (mimicking cocaine or amphetamine). At higher doses it stimulates serotonergic synapses producing sensory hallucinations and mood changes. • The highly stimulating nature of the drug also destroys the same synapses over time. • iv) Nicotine: Stimulates acetylcholinergic nicotine receptors in the nucleus accumbens. It is rapid-acting, highly addictive, and also produces pronounced withdrawal effects.

24. Drugs of Abuse (continued) • v) Marijuana: The leaves of the cannabis plant contain cannabinoids such as D9-tetrahydrocannabinol. • These are rapidly absorbed but leave the body slowly which is why the drug has weak withdrawal effects. • Cannabinoid receptors are found in the hippocampus and basal ganglia (which is why memory and movement are affected) and in the pain centres. • vi) LSD (lysergic acid diethylamide): This hallucinogenic drugs mimics the effects of serotonin though exactly how its causes distortions in perception and mood are not yet understood.

25. Drugs of Abuse (continued) • vii) Caffeine: This interferes with the effects of the inhibitory substance adenosine which acts upon presynaptic terminals to prevent the release of dopamine and acetylcholine. • By blocking the inhibitory effects of adenosine more dopamine and acetylcholine are released. • viii) Alcohol: This has many effects on the nervous system but it principally: • Inhibits the flow of sodium across the neuronal membrane. • Decreases serotonin activity. • Facilitates the response of the GABAA receptor. • Increases dopamine activity. • Blocks the actions of glutamate.

26. Reference and Bibliography. • Carlson, N.R. (1996). Physiology of Behaviour. • Kalat, J.W. (2001). Biological Psychology. • Pert, C.B., Snowman, A.M., & Snyder, S.H. (1974). Localization of opiate receptor binding in presynaptic membranes of rat brain. Brain Research, 70: 184-188.