Psychopharmacology Chapter 4
Psychopharmacology • Drug – Medication? – Heroin or cocaine? – An exogenous chemical not necessary for normal cellular functioning that significantly alters the function of certain cells of the body when taken in relatively low doses • Drug effect – Changes of physiological process and behavior • Site of action – May only have effect on certain neurons at certain locations
Routes of administration • Intravenous (IV), vein • Intraperitoneal (IP) injection, abdominal wall • Intramuscular (IM) injection • Subcutaneous (SC) injection, beneath the skin • Oral administration • Sublingual administration, beneath the tongue • Intrarectal administration • Inhalation, lung • Topical administration, absorbed by skin • Intracerebral administration • Intracerebroventricular (ICV) administration
• Depot binding – Binding of a drug with various tissues of the body or with protein in the blood • Albumin – A protein found in the blood; serves to transport free fatty acids and can bind with some lipid- soluble drugs • Dose-response curve • Affinity – The readiness with which two molecules join together (compare)
• Tolerance – A decrease in the effectiveness of a drug that is administered repeatedly • Withdrawal symptoms • Sensitization – An increase in the effectiveness of a drug that is administered repeatedly • Placebo effects – An inerr substance that is given to an organism lieu of a physiologically active drug; used experimentally to control for the effects of more administration of a drug
• Antagonists – A drug that opposes or inhibits the effects of a particular neurotransmitter on the postsynaptic cell • Agonists – A drug that facilitates the effects of a particular neurotransmitter on the postsynaptic cell
• Competitive binding: binding of a drug to a site on a receptor interferes with the site for the principal ligand – Direct agonist • A drug that binds with and activates a receptor – Direct antagonist / receptor blocker • A drug binds with a receptor but does not activate it; prevents the natural ligand from binding with the receptor • 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 facilitates the action of the receptor; does not interfere with the binding site for the principal ligand
• Presynaptic heteroreceptor – A receptor located in the membrane of a terminal button that receives input from another reminal button by means of an axoaxonic synapse; binds with the neurotransmitter released by the presynaptic terminal button
Acetylcholine • Choline acetyltransferase (ChAT)
Functions and sites of effects • A. Muscular movements and autonomic nervous system • B. In the brain – 1. Dorsolateral pons—REM sleep – 2. Basal forebrain— activating the cerebral cortex and facilitating perceptual learning – 3. Medial septum— electrical rhythms of the hippocampus and modulate its function
• Acetycholinesterase (AChE)
Two types of ACh receptors • Nicotinic receptor – Ionotropic, fast, muscle fibers • Muscarinic receptor – Metabotropic, slow, dominant in CNS
Related Drugs of ACh Release prevent Botulinum toxin - stimulate Black widow spider venom + Reuptake of block hemicholinium - choline Deconstructi deactivate neostigmine + on enzyme (AChE) Receptor Stimulate nicotinic nicotine + receptors Block nicotinic curare Muscle paralysis - receptors Stimulate Muscarine + muscarinic receptors Block muscarinic atropine - receptors
Monoamine • Classification – Catecholamine • Dopamine, Norepinephrine, Epinephrine • Catecholamine Synthesis – L-DOPA---Dopamine--- Norepinephrine (NE) – Indolamines • Serotonin
Dopamine • Both excitatory and inhibitory – 1. Nigrostriatal system— substantia nigra to caudate nucleus and putamen— control of movement (Parkinson’s disease) – 2. Mesolimbic system— ventral tegmental area to limbic system (amygdala and hippocampus)— reinforcing and rewarding (drug addiction) – 3. Mesocortical system— ventral tegmental area to prefrontal cortex—short- term memory, planning and strategy. • Receptors, D1 and D2
Related Drugs of Dopamine Synthesis facilitate L-DOPA Alleviate Parkinson’s disease + inhibit AMPT - Storage in inhibit reserpine - vesicles Autoreceptor activate Low dose of - apomorphine Post- activate High dose of + synaptic apomorphine receptor inhibit chlorpromazine Alleviate schizophrenia - Reuptake inhibit Amphetamine, Stimulate release + cocaine, methylphenidate Deconstructi destroy deprenyl + on enzyme (MAO)
Norepinephrine (NE) • Autonomic nervous system • Final step of synthesis: Domapine— norepinephrine occurs inside the vesicles • Release through axonal varicosities rather than terminal buttons • Originating site: Locus coeruleus in dorsal pons— increase in vigilance • All adrenergic receptors are metabotropic, α 1, α 2, β 1, β 2 • Both excitatory and inhibitory effects.
Related Drugs of Norepinephrine synthesis inhibit Fusaric acid - Deconstructi block moclobemide + on enzyme (MAO-A) Autoreceptor block idazoxan + Storage in inhibit reserpine Same with Dopamine - vesicles Reuptake inhibit Amphetamine Stimulate release, same as + Dopamine MDMA
Serotonin • Mood, eating, sleep, arousal, pain, dreaming • Originated from Raphe nuclei and projects to basal ganglia and hippocampal formation • Released from varicosities rather than terminal buttons • At least 9 types of receptors
Related Drugs of Serotonin Reuptake inhibit Fluoxetine (Prozac) Treatment of depression, + anxiety disorder and OCD inhibit fenfluramine Treatment of obesity + inhibit MDMA Stimulate releasing + synthesis inhibit PCPA - Receptor stimulate LSD + Storage in inhibit reserpine Same with Dopamine - vesicles
Amino Acids • The most common neurotransmitters in CNS – Glutamate (direct excitatory in brain and spinal cord) – Gamma-aminobutyric acid (GABA) (direct inhibitory in the brain) – Glycine (direct inhibitory in spinal cord) • Direct excitatory/inhibitory role – Independent of receptors, suggesting a general modulating role before the evolution of receptor molecules.
Glutamate • Four major receptors • Ionotropic – NMDA receptor – AMPA receptor – Kainate receptor • Metabotropic receptor – Metabotropic glutamate receptor
NMDA receptor of Glutamate • 6 binding sites, sodium and calcium channels—EPSP and second messenger • Required conditions – Glutamate – Glycine – Removal of magnesium-- depolarization • Modulations – Zinc ion (-) – Polyamine (+) – PCP (-) • Both voltage and neurotransmitter- dependent ion channel
Related Drugs of Glutamate receptor Stimulate AMPA AMPA + receptor Stimulate kainate Kainate acid + receptor Stimulate NMDA NMDA + receptor Blocks NMDA AP5 - receptor
GABA receptor • 5 binding sites • Stimulating: – barbiturate, – Steroid site, – Benzodiazopine • Inhibiting: – Picrotoxin • Ionotropic receptor or metabotropic? • Voltage or neutrotransmittor dependent Chloride channel? • Excitatory or inhibitory?
Related Drugs of GABA synthesis inhibit allylglycine - receptor stimulate muscimol direct + block bicuculline direct - stimulate Benzodiazepine Tranquilizing drugs, reduce + anxiety, sleep medication Diazepam (Valium) Chlordiazepoxide (Librium) stimulate barbiturate calming effect + inhibit Picrotoxin -
Glycine • Inhibitory neurotransmitter in the spinal cord • Ionotropic receptor controlling a chloride channel • Strychnine blocks glycine receptor (-) Receptor block Stychnine -
Neuropeptides and meuromodulators • General characteristics of neuropeptides and neuromodulators • 1. Larger molecular weight • 2. Slower-acting (minutes, hours) • 3. Can act in concert with a neurotransmitter • 4. Like neurotransmitters, there is more than one receptor subtype, and the response is tissue-specific
Peptides • Neurotransmitter: Endogenous opiods • Receptor: Opiate receptor • Effects – Analgesia – Inhibits defensive response such as fleeing and hiding – Reinforcement (addiction) Receptor stimulate Opiates (morphine, + heroin, etc) inhibit Naloxone -
Lipids • Neurotransmitter: anandamide • Metabotropic receptors • Effects – Analgesia and sedation, stimulate appetite, reduce nausea, reduce symptom of motor disorder – Interferes with concentration and memory, alter visual and auditory perception and perception of the passage of time receptor block Rimonabant - stimulate THC + Deconstructi inhibit MAFP + on enzyme (FAAH) reuptake block AM1172 +
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