Chapter 4.pptx

Chapter 4 Psychopharmacology and Neurotransmitters  Topics 1. Principles of Psychopharmacology 2. Sites of Drug Actions - Production, storage & release of neurotransmitters - Actions on receptors - Deactivation and re-uptake of neurotransmitters 3. Classes of Ne...

Chapter 4 Psychopharmacology and Neurotransmitters  Topics 1. Principles of Psychopharmacology 2. Sites of Drug Actions - Production, storage & release of neurotransmitters - Actions on receptors - Deactivation and re-uptake of neurotransmitters 3. Classes of Neurotransmitters - Amino Acids (glutamate, GABA) - Acetylcholine - Monoamines - Peptides - Lipids  Topics 1. Principles of Psychopharmacology 2. Sites of Drug Actions - Production, storage & release of neurotransmitters - Actions on receptors - Deactivation and re-uptake of neurotransmitters 3. Classes of Neurotransmitters - Amino Acids (glutamate, GABA) - Acetylcholine - Monoamines - Peptides - Lipids Principles of Psychopharmacology Psychopharmacology The study of the effects of drugs on the nervous system and behavior Drug An exogenous chemical not necessary for normal cellular functioning that significantly alters the functions of certain cells of the body when taken in relatively low doses Psychoactive Drug A drug that has effects on conscious states and/or behavior Includes Drugs of Abuse and Therapeutic Drugs (to treat psychological conditions) Principles of Psychopharmacology Psychopharmacology The bigger picture… Principles of Psychopharmacology Goals of Psychopharmacology 1. To understand behavioral effects of drugs in the nervous system (e.g., site of reward effects, etc.) 2. To develop novel therapeutics (e.g., to treat Alzheimer’s) 3. To understand the nervous system (as a research tool)  Principles of Psychopharmacology Pharmacokinetics How drugs move through the body (kinetics = movement) Considers four basic steps: Route of Administration To Site of Action Blood Brain Barrier Principles of Psychopharmacology Absorption: Routes of Administration – Intravenous injection – Intraperitoneal injection – Intramuscular injection – Subcutaneous injection – Intracerebral administration – Intracerebroventricular (ICV) administration – Oral administration – Sublingual administration – Inhalation – Topical administration Principles of Psychopharmacology Routes of Administration Affects speed of absorption (e.g., fastest is intravenous injection) And blood levels Principles of Psychopharmacology Distribution Most psychoactive drug exert effects on cells of the CNS Therefore, to exert effects, must pass through Blood Brain Barrier Best if drug molecules are: – Lipid soluble – Small – Neutral Principles of Psychopharmacology Metabolism and Excretion Most drugs are metabolized and deactivated by enzymes Brain and liver All drugs are eventually excreted Mostly by kidneys Enzymes sometimes transform molecules into active versions (e.g., benzodiazepines) Principles of Psychopharmacology Describing Drug Effects Keep in mind… – A given drug can have more than one effect (e.g., morphine blocks pain and suppresses respiration) – Drugs can produce same effects through different mechanisms (analgesia from morphine is not same as aspirin) Principles of Psychopharmacology Dose-Response Curves – And, effects vary with dose…. – Hence, drug effects are described for a range of doses  Principles of Psychopharmacology Margin of Safety At high doses, safety becomes a concern – Margin of Safety is difference between therapeutic dose and dose that produces toxicity (like respiratory suppression) Principles of Psychopharmacology Effects of Repeated Administration Tolerance - Decrease in drug effectiveness - Requires higher doses for same effect Sensitization - Drug becomes more effective Withdrawal symptoms occur if individual stops taking the drug - usually opposite to drug effects - indicates physical dependence Principles of Psychopharmacology Effects of Repeated Administration instructor instructor  Topics 1. Principles of Psychopharmacology 2. Sites of Drug Actions - Production, storage & release of neurotransmitters - Actions on receptors - Deactivation and re-uptake of neurotransmitters 3. Classes of Neurotransmitters - Amino Acids (glutamate, GABA) - Acetylcholine - Monoamines - Peptides - Lipids  Sites of Drug Action Pharmacodynamics: Study of how drugs work at their target site. That is, what is the exact mechanism of action? Most psychoactive drugs act by altering the actions of neurotransmitters Agonist: Facilitates the action of a neurotransmitter Antagonist: Blocks or decreases the action of a neurotransmitter  Sites of Drug Action 1. Production, storage and release of neurotransmitters Production: L-DOPA is a precursor for dopamine (agonist) Storage: Reserpine prevents storage of monoamines (antagonist) Release: botulinum toxin blocks release of acetylcholine (antagonist) See Figure 4.7  Sites of Drug Action 2. Action on Receptors Direct effects: Drug binds to the same receptor as the neurotransmitter Direct Agonist: mimics the action of the neurotransmitter when it occupies the receptor of the neurotransmitter (e.g., nicotine and acetylcholine) Competitive Antagonist: Competes for the same binding site as the neurotransmitter but blocks the action of the neurotransmitter (e.g., chlorpromazine blocks dopamine receptors)  Sites of Drug Action 2. Action on Receptors Direct effects Na+ Na + X  Sites of Drug Action 2. Actions on Receptors Indirect effects: Drug binds to a different site than the neurotransmitter but affects the neurotransmitter’s action Indirect Agonist: facilitates the action of the neurotransmitter without binding to the exact receptor – Often seen when drug binds to receptor complex and increases the action of the neurotransmitter (e.g., Valium and GABA) Non-competitive Antagonist: blocks action of a neurotransmitter by binding to a different site (e.g., PCP and ion channel coupled to NMDA receptor).  Sites of Drug Action 2. Actions on Receptors Indirect effects: Na+ Cl - X  Sites of Drug Action 2. Actions on Receptors Also… Effects may be complex, depending on whether the drug binds to a pre-synaptic auto-receptor or a post- synaptic receptor. Example. Apomorphine is an agonist for dopamine receptors. – At low doses it binds to pre-synaptic autoreceptors and decreases dopamine release (antagonist effect). – At higher doses it stimulates post-synaptic receptors (agonist effect)  Sites of Drug Action 3. Deactivation and re-uptake of neurotransmitters Drugs may alter deactivation or re-uptake processes of neurotransmitters: Deactivation example: ACH inhibitors block acetylcholinesterase, leading to increased ACH neurotransmission Re-uptake example: Fluoxetine (Prozac) blocks re- uptake of serotonin, leading to increased serotonin neurotransmission  Sites of Drug Action See Figure 4.7  Topics 1. Principles of Psychopharmacology 2. Sites of Drug Actions - Production, storage & release of neurotransmitters - Actions on receptors - Deactivation and re-uptake of neurotransmitters 3. Classes of Neurotransmitters - Amino Acids (glutamate, GABA) - Acetylcholine - Monoamines - Peptides - Lipids  Neurotransmitters Few Notes Many kinds/classes of neurotransmitters (at least dozen) Most regions of brain involve balance of one of two amino acids: – Glutamate (excitatory) – GABA (inhibitory) Other neurotransmitters found in pathways (from one brain region to another) and modulate brain areas (to which they project)  Neurotransmitters Class Neurotransmitter Functions Glutamate Excitatory, memory  Amino Acids GABA Inhibitory Acetylcholine Learning, memory Dopamine Movement, reinforcement Norepinephrine Attention/vigilance Monoamines Serotonin Mood regulation, sleep Histamine wakefulness Peptides Endogenous Opioids Reinforcement, pain regulation Lipids Endocannabinoids Appetite  Neurotransmitters Amino Acids Amino acid neurotransmitters in the brain: Excitatory Glutamate Inhibitory Gamma-aminobutyric acid, or GABA In the spinal cord and lower brain stem: Inhibitory Glycine  Neurotransmitters Glutamate – Main excitatory neurotransmitter in brain and spinal cord – All sensory neurons release glutamate (except pain) – Stored in vesicles and released from presynaptic neuron following an action potential  Neurotransmitters Glutamate Glutamate Receptors – Three ionotropic (post-synaptic) receptors: NMDA, AMPA, Kainate receptors. Coupled to positively charged ion channels (e.g., Na+ , Ca++) Causes local EPSPs (excitatory post- synaptic potentials) – Also, 1 metabotropic receptor (auto-receptor)  Neurotransmitters NMDA Receptor Complex (chemical and Na+ voltage gated) Involves Ca++ channel but Na+ also enters Multiple binding sites including glutamate and glycine on surface Also, Mg++ binding site deep within ion channel. Mg++ must be dislodged for channel to open (voltage gated) Note: Also PCP binding  Neurotransmitters Glutamate Termination: - transported back into releasing cells (re-uptake) and re- stored - Or, broken down into glutamine by an enzyme (glutamine synthetase) - Astrocytes play important role in regulating glutamate neurotransmission –have glutamate transporters (increases re-uptake of glutamate from synapse). –Too much glutamate is neurotoxic!  Neurotransmitters Glutamate Termination: - Astrocytes are swell… glutamate  Neurotransmitters GABA – Main inhibitory neurotransmitter in brain – inhibitory influence keeps brain stable – Seizures may be result of lacking or poorly functioning GABA-secreting neurons or receptors – Drugs such as barbiturates, alcohol, and benzodiazepines produce their effects by enhancing GABA neurotransmission  Neurotransmitters GABA Two Receptor Types – GABAA and GABAB GABAA – ionotropic, Cl- channel – hyperpolarizations – Multiple binding sites on surface for drugs: benzodiazepines, alcohol, barbiturates GABAB - Metabotropic - Also inhibitory  Neurotransmitters GABA Termination: - GABA transporters - GABA aminotransferase  Neurotransmitters Class Neurotransmitter Functions Glutamate Excitatory, memory  Amino Acids GABA Inhibitory  Acetylcholine Learning, memory Dopamine Movement, reinforcement Norepinephrine Attention/vigilance Monoamines Serotonin Mood regulation, sleep Histamine wakefulness Peptides Endogenous Opioids Reinforcement, pain regulation Lipids Endocannabinoids Appetite  Neurotransmitters Acetylcholine - Earliest known neurotransmitter - Neuromuscular junctions (PNS) - Also in brain (CNS) - Important for learning and memory  Neurotransmitters Acetylcholine - Specific pathways in Brain - Dorsolateral pons (REM sleep) - Basal forebrain or nucleus basalis (facilitate learning) - Medial septum (memory formation)  Neurotransmitters Acetylcholine Two Receptors – Nicotininic: Ionotropic ACh receptor is stimulated by nicotine – Muscarinic: Metabotropic ACh receptor is stimulated by muscarine (found in the mushroom Amanita muscaria)  Neurotransmitters Acetylcholine Reuptake and Deactivation – Deactivated by the enzyme acetylcholinesterase (AChE), present in the postsynaptic membrane AChE inhibitors used to treat myasthenia gravis (neostigmine) memory loss associated with early stages of Alzheimer’s donepezil (Aricept)  Neurotransmitters Class Neurotransmitter Functions Glutamate Excitatory, memory  Amino Acids GABA Inhibitory  Acetylcholine Learning, memory Dopamine Movement, reinforcement Norepinephrine Attention/vigilance  Monoamines Serotonin Mood regulation, sleep Histamine wakefulness Peptides Endogenous Opioids Reinforcement, pain regulation Lipids Endocannabinoids Appetite  Neurotransmitters Monoamines – So named, due to a single amine group (NH2) in chemical structure. – Very important psychological functions (target of many psychoactive drugs) – Include: Dopamine (reinforcement, movement), Norepinephrine (attention, vigilance), Serotonin (mood, sleep), Histamine (wakefulness) – Different classes: Catecholamin Indolamine Ethylamine es Dopamine Serotonin Histamine Norepinephrine  Neurotransmitters Catecholamines Synthesized from tyrosine (Amino Acid) - Series of steps (converting enzymes) - Stored in vesicles - Note: L-DOPA used to treat Parkinson’s Termination - Enzymes: MAO (monoamine oxidase) & COMT - Re-uptake transporters  Neurotransmitters Dopamine Three main pathways Name Origin Location of Behavioral (location terminal effects of cell buttons bodies) Nigrostriat Substanti Neostriatum Control of al a nigra (caudate movement nucleus and putamen) Mesolimbi Ventral Nucleus Reinforcement c tegmental accumbens, (reward) area amygdala, and hippocampus Mesocortic Ventral Prefrontal cortex Short-term al tegmental memories,  Neurotransmitters Dopamine Three main pathways  Neurotransmitters Dopamine – Five metabotropic receptors D1, D2, D3, D4, and D5 D1 and D5 are excitatory (increase cyclic AMP) – Effects depend on location of receptors – For example, D2 receptors are found on pre-synaptic membranes (auto- receptors) but also on post-synaptic membranes – Note: Post-synaptic D2 receptors in mesocortical pathway implicated in schizophrenia (anti-psychotics like  Neurotransmitters Dopamine – Note: Stimulant drugs like cocaine, amphetamines, block dopamine re-uptake transporters – In fact, amphetamine and methamphetamine cause transporter to run in reverse which further increases DA in synapses!  Neurotransmitters Norepinephrine – Found in Brain and PNS (sympathetic NS) – Most (nearly all) brain areas receives NE from pathways originating in pons – Locus coeruleus is the major source – NE leads to increased Note: final step vigilance: attentiveness to occurs In vesicles environmental stimuli  Neurotransmitters Norepinephrine – Pathways Note: NE released from varicosities (swellings) along axons  Neurotransmitters Norepinephrine Receptors: all metabotropic Two families: α and β - α1 (excitatory) - α2 (pre-synaptic auto-receptors) - β1, β2, (excitatory) Termination: - catabolic enzymes (MAO or COMT) - re-uptake  Neurotransmitters Serotonin Synthesis: from tryptophan (AA) Serotonin plays role in regulation of mood; control of eating, sleep, and arousal; and pain regulation Also involved in dreaming Major source is raphe nuclei of the midbrain, pons, and medulla Released from varicosities, like norepinephrine  Neurotransmitters Serotonin Pathways:  Neurotransmitters Serotonin Receptors: At least 7 types: 5-HT1, 5HT2, etc. - But also sub-types: e.g., 5-HT1A - Most are excitatory - Note: 5-HT1A serves as an inhibitory auto- receptor on somas and dendrites (remote from synapse) Termination Monoamine oxidase (MAO) Re-uptake: serotonin transporters on pre- synaptic neurons (SSRI antidepressants like Prozac block reuptake) MDMA (ecstasy) causes transporter to run in reverse (like METH and DA)  Neurotransmitters Histamine – Found in only one place in the brain: the tuberomammillary nucleus, located in the posterior hypothalamus – Histamine plays important role in wakefulness – Drugs that block histamines (antihistamines) cause drowsiness  Neurotransmitters Histamine Production, Storage, and Release - Produced from the amino acid precursor histidine by the action of the enzyme histidine decarboxylase - Stored in vesicles and released following an action potential Receptors - CNS contains H1, H2, H3, and H4 receptors - Antihistamines act as antagonists at histamine receptors  Neurotransmitters Class Neurotransmitter Functions Glutamate Excitatory, memory  Amino Acids GABA Inhibitory  Acetylcholine Learning, memory Dopamine Movement, reinforcement Norepinephrine Attention/vigilance  Monoamines Serotonin Mood regulation, sleep Histamine wakefulness  Peptides Endogenous Opioids Reinforcement, pain regulation Lipids Endocannabinoids Appetite  Neurotransmitters Peptides – Peptides are two or more amino acids linked by peptide bonds – Produced (cleaved) from larger precursor molecules into smaller peptides – Produced in soma, transported to nerve terminals – Often co-released with another neurotransmitter – The best known are endogenous opioids (enkephalins) – High concentrations in periaqueductal gray (midbrain)  Neurotransmitters Peptides Receptors At least 3 opioids receptors (mu, delta, kappa) Produce analgesia (reduce pain) Inhibits defensive behaviors (fight and flight) Rewarding/euphoric effects: Site of action of morphine, heroin, oxycodone, fentanyl, etc. Naloxone is competitive opioid receptor antagonist used to reverse opioid drug overdose  Neurotransmitters Class Neurotransmitter Functions Glutamate Excitatory, memory  Amino Acids GABA Inhibitory  Acetylcholine Learning, memory Dopamine Movement, reinforcement Norepinephrine Attention/vigilance  Monoamines Serotonin Mood regulation, sleep Histamine wakefulness  Peptides Endogenous Opioids Reinforcement, pain regulation  Lipids Endocannabinoids Appetite  Neurotransmitters Lipids Production, Storage, and Release – Lipid neurotransmitters appear to be synthesized on demand, produced or released as needed Not stored in synaptic vesicles – Best known are endocannabinoids (anandamide) – Involved in pain regulation, appetite (munchies) – Act as retrograde signals, released by post- synaptic neurons back onto to pre-synaptic neurons..  Neurotransmitters Lipids Receptors – Two types of cannabinoid receptors, CB1 and CB2 – CB1 receptors located on pre-synaptic nerve terminals and decrease activity of the pre- synaptic neuron Note: THC exerts analgesic effects by stimulating CB1 Acetaminophen also acts on these receptors (in periphery)  Neurotransmitters Class Neurotransmitter Functions Glutamate Excitatory, memory  Amino Acids GABA Inhibitory  Acetylcholine Learning, memory Dopamine Movement, reinforcement Norepinephrine Attention/vigilance  Monoamines Serotonin Mood regulation, sleep Histamine wakefulness  Peptides Endogenous Opioids Reinforcement, pain regulation  Lipids Endocannabinoids Appetite