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)

Glutamate Synthesis Glutamine Glutaminase Glutamic Acid Glutamate Aspartic Acid Aspartate Psychopharmacology2e-Fig-08-01-0.jpg

Distribution of VGLUTs Psychopharmacology2e-Fig-08-02-0.jpg

Glutamate Synapse Psychopharmacology2e-Fig-08-04-0.jpg

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 Psychopharmacology2e-Fig-05-02-0.jpg AMPA Receptor

All ionotropic glutamate receptor channels conduct Na+ ions into the cell Psychopharmacology2e-Fig-08-05-0.jpg

NMDA receptor properties Psychopharmacology2e-Fig-08-06-0.jpg

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 Psychopharmacology2e-Box-08-01-Fig-A-0.jpg

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 Psychopharmacology2e-Fig-08-13-0.jpg

GABA Synapse Psychopharmacology2e-Fig-08-14-0.jpg

GABA Receptors GABAA receptors GABAB receptors GABAC receptors Iontotropic Metabotropic Psychopharmacology2e-Fig-05-02-0.jpg GABAA Receptor

GABAA receptor properties Psychopharmacology2e-Fig-08-15-0.jpg

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

Three-Component Model of Anxiety General Anxiety Disorder (GAD) Panic Attacks Panic Disorder Phobias Social Anxiety Disorder (SAD) Posttraumatic Stress Disorder (PTSD) Obsessive Compulsive Disorder (OCD) Psychopharmacology2e-Fig-18-01-0.jpg

Neurobiology of Anxiety Psychopharmacology2e-Fig-18-02-0.jpg

Neurobiology of Anxiety Psychopharmacology2e-Fig-18-03-1R.jpg

Neurochemistry of Anxiety Corticotropin-releasing factor (CRF) Norepinephrine (NE) Serotonin (5-HT) Dopamine (DA) GABA 28

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. 29

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. 30

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. 31

Drugs for Treating Anxiety Anxiolytics Sedative–hypnotics Benzodiazepines Barbiturates Antidepressants 32

Benzodiazepines Psychopharmacology2e-Fig-18-19-0.jpg

BDZ binding and antianxiety effect Psychopharmacology2e-Fig-18-16-0.jpg

Barbiturates Psychopharmacology2e-Fig-18-17-0.jpg

Antidepressants Psychopharmacology2e-Table-18-04-0.jpg