1. Pre-synaptic Neuron (axon) Post-synaptic neuron (dendrite) 1. produce precursors 2. pack 3. release 4. Bind 5. Post-synaptic changes (e.g., epsp) 6.A Recycle synaptic cleft 6.B Destroy Post-synaptic receptors Pre-synaptic receptors NT ‘x’ AP  Ca ++ inflow - + Neurotransmitters

2. Pharmacology A drug can do only two things, either: –Increase the effect of neurotransmitter X (agonist) –Decrease the effect of neurotransmitter X (antagonist) Thus, in order to understand the action of a ‘drug Y’, we need to understand the neurochemical system it interacts with. In other words, we need to understand how Neurotransmitter X - is produced & released from the pre-synaptic neuron -acts on the receptors of the post-synaptic neuron -is removed from the synaptic cleft

3. Specific Neurotransmitter Systems (& drugs that affect them) Acetylcholine Monoamines –Dopamine –Noradrenaline & Adrenaline –Serotonin Amino Acids –Glutamate –GABA Opioids THC Adenosine (caffeine)

4. Pre-synaptic Neuron (axon) Post-synaptic neuron (dendrite) 1. produce 2. pack 3. release 5. Post-synaptic changes BOTOX 6.B Destroy Ach-E Alzheimer’s treatment Inhibits Ach-E Nicotine: Stimulates Nicotinic receptors Curare: Blocks nicotinic receptors Atropine: Blocks muscarinic receptors Cholinergic neurons (release Acetylcholine) Receptors for Acetylcholine - Muscarinic - Nicotinic 4. Bind

5. curare Belladonna (atropine)

6. Acetylcholine (Ach) Important for: –Muscle Botox prevents release by terminal buttons (Antagonist) –Vigilance Nicotine mimics Ach effect in brain (Agonist) –Memory Anti-cholinesterase drugs for Alzheimer’s disease (Agonist) –Learning Anticholinergic drugs (to prevent vomit) (Antagonist) –Autonomic Nervous System Cholinergic neurons (release Ach) Receptors: –Nicotinic (ionotropic): stimulated by nicotine, blocked by curare –Muscarinic (metabotropic): blocked by atropine (belladona)

7. Pre-synaptic Neuron (axon) Post-synaptic neuron (dendrite) L-Dopa Post-synaptic changes Recycle dopamine Dopaminergic neurons (release dopamine) Receptors for dopamine - D1, D2, D4 Cocaine, amphetamine, Methylphenidate (ritalin) Makes dopamine transporter work in reverse pack release Bind D2D2 D2D2 D1D1 Mono-amino Oxidase (MAO) Inactive substance MAO inhibitor Antipsychotic drugs for schizophrenia Blocks D2 receptors Precursor

8. Dopamine (DA) Important in: –Movement control death of dopaminergic cells in Parkinson’s disease –Drug addiction amphetamine, cocaine (agonist) –Schizophrenia (?) anti-psychotic drugs (antagonists) –ADHD metylphenidate (ritalin) dopaminergic neurons (release DA) –Substantia nigra:movement control –Ventral Tegmental Area (VTA):drug addiction –VTA to frontal cortexschizophrenia (?) Receptors: D1, D2, D4 Group Activity: –Would PD treatment with L-dopa increase or decrease hallucinations? (one of the symptoms of schizophrenia) –Would antipsychotic drugs produce PD like symptoms as a side effect (e.g., motor problems)? Why? Why not? –Schizophrenic patients often fail to take their medication, despite the benefitial effects. Can you provide a physiological explanation? (hint: which systems does the drug block?) Group activity

9. The Reward System: Activities of survival (sex, feed) activate the reward system Drugs of abuse similarly activate the reward system Dopamine Electrical stimulation of the reward system is also addictive

10. Dopamine release in the nucleus accumbens -during ingestion of a preferred food - to a cue associated with food (CS) -during IV cocaine self-administration -to a cue associated with cocaine (CS) - during sexual behavior - in anticipation of sex during Intracranial self stimulation

11. Cocaine and Amphetamine : administration & distribution Administration: intranasal intravenous smoke (‘crack’) Distribution: ‘Crack’: is more liposoluble, thus stronger effect! Cocaine has a very short half life (40 mins)

12. Overview- neurotransmitters Acetylcholine Dopamine Adrenaline Serotonine Glutamate GABA Opioids THC (cannabis)

13. Noradrenaline & Adrenaline Aka: norepinephrine & epinephrine Important for: –Vigilance (adrenaline response) Noradrenaline acts as a neurotransmitter Adrenaline acts also as a hormone Receptors: –Alpha –Beta: beta-blockers are used for hypertension Oh no! my sympathetic nervous system is overactive again!

16. Serotonin (5-HT) Important in: –Depression Receptors: –Way too many! Drugs: –Fluoxetine (prozac): inhibitor of reuptake (recycle) (SSRI) –LSD: agonist of 5-HT 2A –Ectasy: agonist for serotonin and agonist for noradrenaline

17. Glutamate Is the most pervasive excitatory NT in the brain Receptors: –Four types (remember NMDA): Important in: –Learning (NMDA receptor in the hippocampus) Drugs: –Alcohol: NMDA antagonist Sleepy, impaired cognitive performance Alcohol withdrawal  seizures

18. GABA Is the most pervasive inhibitory NT in the brain Receptors: –GABAa: opens Cl - channel –GABAb: opens K + –Question: does it puzzle you that, being GABA an inhibitory NT, GABAa and GABAb receptors open channels of different polarity? Justify Drugs: –Benzodiazepines (valium): GABA Agonist For reducing anxiety, promoting sleep, anti-convulsant, muscle relaxant –Alcohol: GABA agonist Anxiolytic Don’t drink while taking this medication Alcohol withdrawal  seizures

19. Alcohol Alcohol acts on many systems: –Blocks NMDA: that is why memory is impaired, and why alcohol withdrawal can trigger seizures –GABA: That is why at low levels alcohol has an anxiolytic effect, and at higher levels sedative effect –Dopamine (mesolimbic system): increases release of DA in nucleus accumbens, thus the euphoria, addictive power of alcohol

20. Opiates: –Endogenous opiates: secreted in response to survival behaviors analgesia positive reinforcement (encourages the survival behavior) –Exogenous opiates; Morphine (opium) Codeine (opium) Heroin (semisynthetic)

21. 1897 – Mail order advertisement from Sears, Roebuck & Co. for opium-based drink Early 20th century – mothers encouraged to use opium syrup to soothe teething pain Narcotic comes from the Greek word, “narke”, meaning stupor and referred to any drug that induced sleep

22. Opiates: administration & distribution Administration: smoke (Opium, Heroin) intranasal (heroin) intravenous (Heroin) oral, not very good to get high (Codeine, morphine, methadone) Distribution: Heroin is 10 times more liposoluble than morphine, so it reaches brain faster and at larger concentrations, and get transformed into morphine

23. Opioids Drug Effects: –Analgesia (morphine) –Activates Reward system (addictive power) –Inhibits defensive response (e.g., hiding) Antagonist: –Naloxone: Use in the acute treatment of heroin overdose Blocks analgesic effect of placebo morphine Naloxone

24. Opiates: Side effects Most of the risks are secondary to the status as illegal. –Legal: Jail –Health: HIV, hepatitis C, overdose –Financial: loss of employment, cost of drugs –Few direct problems from chronic use (surprisingly) (constipation, bladder cancer, pregnancy)

25. Cannabis: THC is the active ingredient in marijuana. THC receptor: CB1 – large concentration in hippocampus (memory effect) THC stimulates release of dopamine in the nucleus accumbens and the ventral tegmental area –Long-term damage: Cognitive impairments from long-term use appear to be subtle.

26. Cannabinoids (THC) There are endogenous & exogenous cannabinoids (marijuana) They are lipids: –They mix well in butter (cookies) & oil (pesto), but not in alcohol or water. –They depot in fat tissue: thus metabolites can be detected in urine long after the psychoactive effect Drug Effects: –Analgesia –Sedation –Stimulates eating (munchies) –Reduces concentration & memory –Distorts time perception