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Neurotransmitters •Neuropeptides •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) •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) Glutamate Synthesis • Glutamine • Glutaminase • Glutamic Acid • Glutamate • Aspartic Acid • Aspartate Distribution of VGLUTs Glutamate Synapse Glutamate Receptors • AMPA receptors • • Kainate receptors • • GluK1-5 NMDA receptors • • • • GluA1-4 GluN1 GluN2A-C GluN3A-B Metabotropic receptors • mGluR1-8 Iontotropic Metabotropic AMPA Receptor All ionotropic glutamate receptor channels conduct Na+ ions into the cell NMDA receptor properties Types of Memory (iconic memory) (7 bits for 30seconds) Cellular Mechanism for Learning Hebbian Synapse: Frequent stimulation can change the efficacy of a synapse Enrichment Protocol Impoverished Enriched Quantifying Dendritic Arborization Hippocampal Brain Slicing Hippocampal Pathways 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 Learning Requires Protein Synthesis! Anisomycin: (protein synthesis inhibitor) blocks long term memory 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 Anxiety Disorders • • • • • • • • • feelings of concern or worry increased muscle tension restlessness impaired concentration sleep disturbances irritability increased heart rate Increased sweating other signs of “fight-or-flight” response ThreeComponent Model of Anxiety • General Anxiety Disorder (GAD) • Panic Attacks • Panic Disorder • Phobias • Social Anxiety Disorder (SAD) • Posttraumatic Stress Disorder (PTSD) • Obsessive Compulsive Disorder (OCD) Neurobiology of Anxiety Neurobiology of Anxiety Neurochemistry of Anxiety • Corticotropin-releasing factor (CRF) • Norepinephrine (NE) • Serotonin (5-HT) • Dopamine (DA) • GABA GABA and Anxiety • 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. GABA and Anxiety • Inverse agonists bind to BDZ sites and produce actions opposite of BDZ drugs— increased anxiety, arousal, and seizures. • The β-carboline family produces extreme anxiety and panic. They are presumed to uncouple the GABA receptors from the Cl– channels so that GABA is less effective. GABA and Anxiety • Animal studies have found that natural differences in anxiety levels are correlated with the number of BDZ binding sites in several brain areas. • PET scans of patients with panic disorder show less benzodiazepine binding in the CNS, particularly in the frontal lobe. Drugs for Treating Anxiety • • • • • Anxiolytics Sedative–hypnotics Benzodiazepines Barbiturates Antidepressants Benzodiazepines BDZ binding and antianxiety effect Barbiturates Antidepressants
