Psychopharmacology (psychoactive drugs) Name ways to get a drug into your system (sources of drug administration) Rank those sources based on how fast they reach blood & thus the brain List the factors that determine the effect of a drug on an individual. (In other words, what makes a psychoactive drug be more effective in one person than another) Psychopharmacology: Examines the relationship between drugs and psychological processes The study of drugs that affect mood, thought or behavior What’s a drug? Salt, vitamins, milk? Well, you say, these are normally found in out bodies (they are endogenous), so a drug is a foreign substance (exogenous). What about L-Dopa?, which is an endogenous brain substance which is turned by the brain into dopamine, a neurotransmitter. L-Dopa is given to Parkinson’s disease patients to treat their symptoms… drug or not? There is evidence that we may have morphine normally present in our bodies (not endorphins, but actual morphine)-- if true, then morphine isn’t a drug anymore? how about olestra, which is a fat substitute that IS fat, but is too big to be digested so goes right through our body (although as far as the taste buds are concerned, it was fat)…drug or not? OK, so maybe a drug is a substance that changes the “normal” body chemistry but so does learning, emotions So, much like any other concept, there is no ‘golden rule’ to discriminate whether something is a drug or not, but there are many properties that a ‘prototypical’ drug has, such as (1) being exogenous, (2) change normal chemistry, etc. Group activity

Outline Pharmacokinetics Pharmacodynamics Dose-response curve Pharmacodynamics Drugs vs. NTs Agonists vs. Antagonists Receptor types Tolerance Specific Neurotransmitter Systems (& drugs that affect them)

Pharmacodynamics Pharmacokinetics Whatever the body does to the drug how drugs are absorbed, distributed within the body, metabolized, and excreted. Whatever the drug does to the body Main effect: increasing or decreasing the effect of neurotransmitter X Side effects (unwanted effects) All drugs have side effects this is because the CNS uses the same chemicals (neurotransmitters) in overlapping circuits (brain structures) to produce complex changes in behavior in other words, no chemical mediates a single behavior Pharmacokinetics: The process by which drugs are absorbed, distributed within the body, metabolized, and excreted.

Pharmacokinetics Sources of administration: oral, intranasal, inhalation, topic, intravenous (i.v), sublingual, intramuscular (i.m.) subcutaneous, intraperitoneal Distribution: Lipids (fats) vs. non-lipids (proteins, ionized molecules) Metabolization: liver Excretion: kidneys Half-life: time it takes to eliminate half the drug from the bloodstream. It is used to determine inter-dose interval Intravenous (IV) injection: Injection of a substance directly into a vein. Intraperitoneal (IP) injection: The Injection of a substance into the peritoneal cavity-the space that surrounds the stomach, intestines, liver, and other abdominal organs. Depot Binding: Binding of a drug with various tissues of the body or with proteins in the blood. Albumin: A protein found in the blood, serves to transport free fatty acids and can bind with some lipid soluble drugs Plasma half-life .

Ways to administer a drug (& time to reach blood)

therefore, how much “door opening” you get is a function of: number of keys (ligand concentration) number of locks (protein concentration) fit (affinity) ability to open lock (intrinsic activity) all other things being equal, the higher the dose of drug you give, the higher the ligand concentration is going to be at the relevant binding sites, the more proteins are going to be activated, and the bigger biological effect you’re going to have you can present the relationship between dose and biological effect (or response) graphically; a dose-effect or dose-response curve (or function) to make one, you simply give subjects a range of doses, and measure and plot their responses (make a D-R curve on the blackboard) dose is virtually always presented in mg/kg of drug, on the x-axis (sometimes a log scale will be used) response is presented in whatever objective or subjective scale is relevant, and on the y-axis; usually, up means a bigger effect Dose-response curve: Effect of a drug as a function of the amount of the drug administered.

Therapeutic index: The ratio between the dose that produces the desired effect in 50% of the animals and the dose that produces toxic effects in 50% of the animals.

Pharmacodynamics 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 X’, 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

Pre-synaptic receptors Post-synaptic receptors 2. pack 3. release - - precursors 2. pack 3. release NT ‘x’ 4. Bind 1. produce 5. Post-synaptic changes (e.g., epsp) + + AP  Ca++ inflow 6.A Recycle 6.B Destroy Each of these steps has a technical term and is a potential mechanism of action for drugs Produce = Synthesis Recycle = reuptake Destroy = enzimatic degradation Metabolite (the ‘destroyed’ substance) Drugs can also act by mimicking neurotransmitter by binding and activating (or not): Presynaptic receptors Postsynaptic receptors Pre-synaptic Neuron (axon) synaptic cleft Post-synaptic neuron (dendrite)

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Metabotropic Receptors Receptors are specific for individual neurotransmitters More than one receptor for each neurotransmitter. e.g., Acetylcholine (muscarinic & nicotinic receptors) Ionotropic Receptors (e.g., nicotinic) Metabotropic Receptors (e.g., muscarinic) Metabotropic Receptors: - Open Ion Channels - Alter intracellular environment - Affect gene transcription: affect structure/function of cell a ligand (any relatively small molecule) diffuses around, and binds to a receptor, ( usually a protein ) ligands can be hormones, neurotransmitters, or drugs; > 300 receptors, probably more like a thousand; 16 for serotonin proteins embedded in the cell membrane, are perfect for getting information (like the presence of drugs) from the outside of a cell to the inside!

Agonists and Antagonists Agonist (Greek: Agon, meaning contest) Substance that facilitates post-synaptic effects Antagonist Substance that inhibits or blocks the post-synaptic effects

Exogenous vs. Endogenous (drugs vs. neurotransmitters) Partial Agonist- binds to a receptor, and has less intrinsic activity than the endogenous ligand Inverse Agonist- binds to a receptor and produces an effect that is opposite to that of the endogenous ligand Agonist – mimics the natural (endogenous) ligand (Neurotransmitter) Direct agonist – binds to post-synaptic receptor and exerts same effects Indirect agonist – block re-uptake, inhibit degrading enzyme, increase release. Antagonist Blocks the post-synaptic receptor, in a direct (binds to receptor but doesn’t activate it) or indirect fashion (increased enzymatic degradation, decreased release via autoreceptor stimulation) Noncompetitive binding: Binding of a drug to a site on a receptor; does not interfere with the binding site for the principal ligand. Indirect antagonist: A drug that attaches to a binding site on a receptor and interferes with the action of the receptor; does not interfere with the binding of the principal ligand. Indirect agonist: A drug that attaches to a binding site on a receptor and facilitates the action of the receptor; does not interfere with the binding site of the principal ligand. Affinity – how well the drug or neurotransmitter binds to the receptor – how long it stays bound. Efficacy – the effect of the drug (stimulate the receptor or block the receptor). Exogenous vs. Endogenous (drugs vs. neurotransmitters) Agonist vs. Antagonist: Both bind to a receptor. The agonist activates it, the antagonist does not (antagonists block the receptor) Competitive vs. non-competitive: whether the drug works at the same receptor as the NT or at a different receptor as the NT, but one that modifies the NT’s action

Will an antagonist produce a rightward shift or a leftward shift in the dose-response curve? (graph) How would a competitive antagonist modify the curve? (draw with a solid line) How would a non-competitive antagonist modify the curve (draw with a dotted line) Group activity

Tolerance a decreased response due to frequent use. Metabolic tolerance: faster metabolism of the drug.This is a pharmacokinetic mechanism (e.g., alcohol metabolization by hepatic enzimes) Cellular-adaptive tolerance: down-regulation of receptors (a pharmacodynamic mechanism) Example of metabolic tolerance: alcohol and hepatic function Before drug After Drug

Factors that determine the effect of a drug on an individual Age Weight Setting in which the drug is used History of use (tolerance) Level of proteins in blood Time of day drug is consumed These effects are underlined by both pharmacokinetic and pharmacodynamic modulations set: what the user brings to the drug 6 pack after a promotion after getting fired expectations setting: social and physical environment in which the drug is taken culture (Irish vs. Japanese)