Chemical Messengers Autocrine Paracrine Endocrine Pheromone Allomone self signal Paracrine neighbor signal Endocrine distant signal Pheromone airborne signal same species Allomone different species

Endocrine Glands

Homeostasis Mechanism Receptors input signals skin responds to cold temperature sends signal to brain Control Center integrating center brain interprets temp signal makes you shiver Effectors output mechanism muscles shiver creating heat

Neurotransmitters Neuropeptides Amines Amino acids Opioid peptides Enkephalins (ENK) Endorphins (END) Peptide Hormones Oxytocin (Oxy) Substance P Cholecystokinin (CCK) Vasopressin (ADH) Neuropeptide Y (NPY) Brain-derived Neurotrophic factor Hypothalamic Releasing Hormones GnRH TRH CRH Lipids Anandamide Gases Nitric Oxide (NO) Amines Quaternary amines Acetylcholine (ACh) Monoamines Catecholamines Epinephrine (EPI) Norepinephrine (NE) Dopamine (DA) Indoleamines Serotonin (5-HT) Melatonin Amino acids Gamma-aminobutyric acid (GABA) Glutamate (GLU) Glycine Histamine (HIST)

Acetylcholine Synthesis Breakdown

Cholinergic Synapse Choline Acetyl CoA Cholinesterase (ChAT) Acetylcholinesterase (AChE) Choline transporter Vesicular ACh transporter (VAChT)

Cholinergic (Ach) System

Cholinergic Receptors Nicotinic receptors Muscle Type Neuromuscular junction Autonomic ganglia CNS Type Muscarinic receptors M1 CNS M2 Heart M3 Blood vessels Lungs Exocrine Glands M4 M5 Cholinergic Receptors Iontotropic metabotropic Nicotinic ACh Receptor

Catecholamine Synthesis

Noradrenergic (NE) System

Noradrenergic Receptors Alpha 1 receptors Smooth muscle Skin GI tract Kidney brain Alpha 2 receptors Beta 1 receptors Heart kidneys Beta 2 receptors Lungs Liver uterus Vascular smooth muscle Skeletal muscle Beta 3 receptors Fat cells Noradrenergic Receptors All metabotropic

Dopaminergic Synapse Tyrosine Tyrosine Hydroxylase DOPA Aromatic Amino Acid Decarboxylase Dopamine Transporter Vesicular Monoamine Transporter D2 Autoreceptor

Dopaminergic (DA) System 1 Mesolimbic * Ventral Tegmental Area (VTA)

Dopaminergic (DA) System 2 Mesostriatal * Basal Ganglia

Dopaminergic Receptors D1 receptors D2 receptors D3 receptors D4 receptors D5 receptors

Serotonin (5-Hydroxytryptamine) (5-HT)

Serotonergic Synapse Tryptophan Tryptophan hydroxylase 5-HTP Aromatic l-amino acid decarboxylase (AADC) 5-HT 5-HT transporter 5-HT autoreceptor

Serotoninergic (5-HT) System

Serotonergic Receptors 5-HT1A-F receptors CNS Blood Vessels 5-HT2A-C receptors PNS GI Tract 5-HT3 receptors 5-HT4 receptors 5-HT5A-B receptors 5-HT6 receptors 5-HT7 receptors Serotonergic Receptors Iontotropic Metabotropic 5-HT1B receptor

Glutamate Synthesis Glutamine Glutaminase Glutamic Acid Glutamate Aspartic Acid Aspartate

Glutamate Synapse

Glutamate Receptors AMPA receptors Kainate receptors NMDA receptors GluA1-4 Kainate receptors GluK1-5 NMDA receptors GluN1 GluN2A-C GluN3A-B Metabotropic receptors mGluR1-8 Glutamate Receptors Iontotropic Metabotropic AMPA Receptor

Long-Term Potentiation (LTP) each triangle represents a single action potential Slope of the EPSP (one characteristic measure of an action potential) baseline response potentiated response Hippocampus has a three synaptic pathway Stimulate one area (mossy fibers) and record the action potentials in another (CA1) Stimulate multiple times to get a baseline response Once a stable baseline is established give a brief high frequency stimulating pulse Use the same stimulating pulse as in baseline but now see a potentiated response This potentiated response can last hours, days, or even weeks (LTP)

Normal Synaptic Transmission Glutamate Channels: NMDA Mg2+ block no ion flow AMPA Na+ flows in depolarizes cell

LTP Induction With repeated activation the depolarization drives the Mg2+ plug out of the NMDA channels Ca2+ then rushes in through the NMDA channels Ca2+ stimulates a retrograde messenger to maintain LTP Ca2+ also stimulates CREB to activate plasticity genes

LTP-induced Neural Changes

Neurobiological Changes via Learning Dendritic changes: Increased dendritic arborization Increased dendritic bulbs Synaptic changes: More neurotransmitter release More sensitive postsynaptic area Larger presynaptic areas Larger postsynaptic areas Increased interneuron modulation More synapses formed Increased shifts in synaptic input Physiological changes: Long-Term Potentiation Long-Term Depression

GABA Synthesis Glutamate Glutamic Acid Decarboxylase (GAD) GABA

GABA Synapse

GABA Receptors GABAA receptors GABAB receptors GABAC receptors Iontotropic Metabotropic GABAA Receptor

GABAA receptor properties

Benzodiazepines (BDZ) and barbiturates cause sedation and reduced anxiety by binding to modulatory sites on the GABA receptor complex BDZ binding sites are widely distributed in the brain. They are in high concentration in the amygdala and frontal lobe. Natural differences in anxiety levels are correlated with the number of BDZ binding sites. PET scans of patients with panic disorder show less benzodiazepine binding in the CNS, particularly in the frontal lobe. GABA and Anxiety 32

The Science of Drug Action Pharmacology: study of the actions of drugs and their effects on living organisms. Neuropharmacology: study of drug-induced changes in nervous system cell functioning. Psychopharmacology: emphasizes drug-induced changes in mood, thinking, and behavior. Neuropsychopharmacology: identifies chemical substances that act on the nervous system to alter behavior. . 33

The Science of Drug Action Drug action: molecular changes produced by a drug when it binds to a target site or receptor. Drug effects: The molecular changes that alter physiological or psychological functions. Therapeutic effects: the drug–receptor interaction produces desired physical or behavioral changes. Side effects: all other non-therapeutic effects. Specific drug effects: are based on physical and biochemical interactions of a drug with a target site in living tissue. Nonspecific drug effects: are based on certain unique characteristics of the individual, (e.g., mood, expectations, perceptions, attitudes, placebo effects). 34

Therapeutic Index Effective dose Lethal dose dose of a drug that produces a meaningful effect in some percentage of test subjects ED50 = effective dose for half the animals in a drug test Lethal dose dose of a drug that has a lethal effect in some percentage of test subjects LD50 = lethal dose for half the animals in a drug test Therapeutic index = LD50/ED50 Always greater than one Most drugs have an LD1 well above the ED95 35

Pharmacokinetic Factors

1. Drug Route of Administration

2. Absorption and Distribution Lipid Solubility Ionization pH Stomach Content Gender Other BBB Placenta

3. Drug Binding Drugs bind to proteins in blood, or temporarily stored in bones or fat cells (inactivating drug) Reduces the concentration of drug at site of action Competition of binding can alter the concentration of free active drug potentially leading to overdose Drug is not altered by liver enzymes Can terminate action of drugs

4. Inactivation (Biotransformation)

5. Excretion Organs: Products: Intestines Kidneys Lungs Sweat glands Feces Urine Water Vapor Sweat Saliva

Mechanism of Drug Action Effects on specific neurotransmitter systems: Drugs may alter the availability of a neurotransmitter by changing the rate of: Synthesis Metabolism Release Reuptake Drugs may activate or prevent the activation of a receptor

Drugs can acts as Agonists Agonist binds and has same effect as endogenous neurotransmitter, channel opens Normal receptor at rest, channel is closed Neurotransmitter binds receptor and opens channel

Drugs can act as Antagonists Typical antagonist binds in place of endogenous neurotransmitter, prevents neurotransmitter action Non-competitive binding antagonist doesn’t interfere with neurotransmitter binding but still prevents neurotransmitter action

Presynaptic Drug Actions 8. Blockade of NT degradation MAO inhibitors Prozac Chemical Weapons

Postsynaptic Drug Actions