Chapter 4 - Chapter 4 Chapter Psychopharmacology Psychopharmacology Psychopharmacology The study of the effects of dugs on the nervous system and

Info iconThis preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: Chapter 4 Chapter Psychopharmacology Psychopharmacology Psychopharmacology The study of the effects of dugs on the nervous system and on The behavior behavior Q: What is a drug? A: “An exogenous chemical not necessary for normal cellular A: functioning that significantly alters the functions of certain cells of the body when taken in relatively low doses” the Drug effect – the changes a drug produces in an animal’s physiological processes and behavior physiological Sites of action – the locations at which molecules of drug interact with molecules located on or in cells of the body, thus affecting some biochemical processes of these cells some Principles of Psychopharmacology Principles Pharmacokinetics – the process by which drugs are absorbed, distributed within the body, metabolized, and excreted within Routes of administration Intravenous (IV) injection – directly into a vein; fastest route Intraperitoneal (IP) injection – into the peritoneal cavity – the space that surrounds the stomach, intestines, liver, and other abdominal organs surrounds Intramuscluar (IM) injection – into a muscle Subcutaneous (SC) injection – into the space beneath the skin Oral administration – admin into the mouth, so that it is swallowed; most common with humans common Sublingual admin – placing substance beneath tongue Intrarectal admin – into the rectum Inhalation – admin of a vaporous substance into lungs Topical admin – directly onto skin or mucous membrane Intracerebroventricular (ICV) admin – into one of the cerebral ventricles; to allow for widespread distribution in the brain allow Principles of Psychopharmacology Principles Distribution of drugs within the body Several factors determine the rate at which a drug in the bloodstream Several reaches sites of action within the brain: reaches Lipid solubility: BBB blocks only water-soluble molecules; thus, lipidsoluble molecules can pass into brain and distribute themselves Depot binding – binding of a drug with various tissues of the body or with proteins in the blood; causes drugs to not reach their site of action proteins e.g. Albumin – a protein found in the blood that transports free fatty acids and e.g. Albumin can bind with some lipid-soluble drugs can Can delay or prolong the effects of a drug Inactivation and Excretion Drugs do not remain in body indefinitely Most deactivated by enzymes Excreted by kidneys Drug effectiveness Drug The best way to measure the The effectiveness of a drug is to plot a dose-response curve dose-response Do this by giving subjects Do various doses of a drug and plotting effects plotting Increasingly stronger doses of Increasingly a drug causes increasingly larger effects, until a maximum effect is reached maximum Drug effectiveness Drug One measure of a drug’s margin of safety is its therapeutic index One therapeutic The ratio b/t the dose that produces the desired effect in 50% of The the animals (ED 50) and the dose that produces toxic effects in 50% of the animals (LD 50) 50% The lower the therapeutic dose is, the more care must be taken The when prescribing the drug Why do drugs vary in effectiveness? Different drugs may have different sites of action Affinity – the readiness with which 2 molecules join together; drugs in CNS produce effects by binding to receptors, transport molecules or enzymes enzymes The higher the affinity, the lower the concentration needed to produce The effects effects Effects of repeated administration Effects In some cases, when a drug is administered repeatedly its effects In will diminish, i.e. develop tolerance tolerance e.g. heroin, once taken regularly enough, individual will suffer e.g. withdrawal symptoms (opposite to those produced by a drug) when withdrawal they stop taking it; caused by same mech as tolerance they Tolerance is the body’s attempt to compensate for the effects of a Tolerance drug drug In other cases, a drug will become more and more effective, In sensitization sensitization Less common than tolerance Some drug effects show tolerance while others may show Some sensitization sensitization e.g. cocaine; repeated admin may causes more movement disorders, e.g. while euphoric effects may show tolerance while Placebo effects Placebo An innocuous substance that has no specific physiological effect Often used for control groups in clinical drug studies Sites of drug action Sites Most drugs affecting behavior Most do so by affecting synaptic transmission: transmission: Antagonist – a drug that opposes or inhibits the effects of a particular NT on the postsynaptic cell the Agonist – a drug that facilitates the effects of a particular NT on the postsynaptic cell postsynaptic Sites of drug action Sites Effects on production of NT precursors can increase rate of NT synthesis and release; agonist precursors (Step 1) (Step NT synthesis is controlled by enzymes; some drugs can inactive NT these enzymes, thus preventing NT production; antagonist (Step 2 in diagram) diagram) Effects of storage and release of NT transporter molecules that fill synaptic vesicles with molecules of NT transporter can be blocked by a drug; thus, preventing NT to fill vesicles; antagonist (Step 3) antagonist Some drugs prevent release of NT from terminal button by Some deactivating proteins that help fuse vesicles to membrane; antagonist (Step 5) (Step some drugs can trigger release of NT; agonist (Step 4) Sites of drug action Sites Effects on receptors Some drugs can bind to postsynaptic receptors like NT Direct agonist – a drug that mimics the effects of a NT by binding with and acting on a receptor (Step 6) acting Receptor blocker – a drug that binds with a receptor but does not activate it; prevents the natural ligand from binding with the receptor (Step 7) prevents Some receptors have multiple binding sites; NT can bind to main sites, while Some other ligands can bind to alternative sites these alternative sites can be blocked by a drug, termed noncompetitive binding these noncompetitive drug attached to alt site could prevent ion channels from opening; indirect antagonist drug indirect drug attaches to alt site and facilitates opening of ion channel; indirect agonist drug indirect some presynaptic membranes have autoreceptors that regulate amount of NT some released; stimulation of autoreceptors causes less NT to be released released; drugs that activate autoreceptors act as antagonists less NT released (Step 8) drugs drugs that block autoreceptors act as agonists more NT released (Step 9) drugs Sites of drug action Sites Effects on reuptake or destruction of NT drugs can attach to transporter molecules responsible for reuptake drugs and block it; thus NT in synapse for longer duration; agonist (Step 10) and drugs can bind with enzyme that destroys NT, preventing enzyme drugs from working; agonist (Step 11) from Neurotransmitters and Neuromodulators Neurotransmitters In the brain, most synaptic communication is accomplished by 2 In NT: NT: One with excitatory effects: glutamate One with inhibitory effects: GABA Most of the activity of local circuits of neurons involves balances Most b/t the excitatory and inhibitory effects of these chemicals b/t Most other NT have modulating effects, i.e. they tend to activate Most or inhibit entire circuits of neurons that are involved in particular brain functions brain Acetylcholine Acetylcholine Primary NT secreted by efferent axons of the CNS All muscular movement is accomplished by the release of ACh, also found in All ganglia of ANS and at target organs of the parasymp branch of the ANS ganglia Involved mostly in 3 systems in brain: Composed of choline and acetate Synthesis: Acetyl-CoA and choline are combined by choline acetyltransferase (ChAT) choline 2 drugs affect the release of ACh: Dorsolateral pons, basal forebrain, & medial septum Botulinum toxin – ACh antagonist; prevents release by terminal buttons; found in improperly canned food improperly Black widow spider venom – stimulates release of ACh Deactivated by acetylcholinesterase (AChE), which is present in the presynaptic Deactivated membrane, and produces choline and acetate membrane, Two types of ACh receptors: Nicotinic – ionotropic ACh receptor that is stimulated by nicotine and blocked by curare Muscarinic – metabotropic ACh receptor that is stimulated by muscarine and blocked by atropine; slower action, longer lasting atropine; Monoamines Monoamines Catecholamines: Dopamine Norepinephrine Epinephrine Indolamines Serotonin Dopamine (DA) Dopamine Produces both excitatory Produces and inhibitory postsynaptic potentials, depending on postsynaptic receptor postsynaptic Implicated in movement, Implicated attention, learning, and reinforcing effects of drugs reinforcing Synthesis of Synthesis catecholamines: catecholamines: 1. 2. 3. Tyrosine (obtained via diet) converted to LLDOPA by tyrosine hydroxylase hydroxylase L-DOPA converted to DA L-DOPA by DOPA decarboxylase by DA converted to DA Norepinephrine (NE) by DA β-hydroxylase Dopaminergic systems Dopaminergic Nigrostriatal system – originates in the substantia nigra and terminates in the neostriatum (caudate and putamen); control of movement movement Mesolimbic system – originates in ventral tegmental area (VTA) and terminates in the nucleus accumbens, amygdala, & hippocampus; reward pathway hippocampus; Mesocortical system – originates in VTA and terminates in prefrontal cortex; formation of STM, planning, strategies prefrontal Dopamine Dopamine Parkinson’s disease – a neurological disease caused by degeneration of DA neurons in nigrostriatal system; movement disorder with symptoms of tremors, rigid limbs, poor balance, difficulty initiating movements; individuals with Parkinson’s are given L-DOPA as Tx given Several types of DA subreceptors: D1 and D2 most common Other drugs effecting DA AMPT Reserpine Apomorphine Monoamine oxidase (MAO) – enzyme that destroys catecholamines catecholamines Norepinephrine (NE) & Epinephrine Norepinephrine Aka Noradrenaline & adrenaline NE found in neurons in ANS Epinephrine produced by adrenal glands NE synthesis is finished in the vesicles of the terminal button DA fills the vesicles, and is then converted to NE via DA β-hydroxylase DA Fusaric acid blocks activity of this enzyme and prevents production of NE without affecting DA without Excess NE is destroyed by MAO, type A Cell bodies of most important NE system are in locus coeruleus Cell locus Most noradrenergic cells release NE via axonal varicosities (beadlike Most axonal swellings of the axonal branches) instead of terminal button swellings Several types of subreceptors: β1 & β2 receptors, and α1 & α2 receptors: sensitive to both NE and epinephrine, all metabotropic with GPCRs all In general, behavioral effects are excitatory Serotonin (5-HT) Serotonin Complex behavioral effects: regulation of mood, control of eating, sleep, and Complex arousal, regulation of pain arousal, Precursor is tryptophan, which is obtained through diet; converted to 5-HTP by the Precursor enzyme tryptophan hydroxylase; which is converted to 5-HT by the enzyme 5-HTP decarboxylase decarboxylase Most 5-HT neurons found in raphe nuclei of the pons, medulla and midbrain and Most project to cerebral cortex; also innervate basal ganglia, dentate gyrus and hippocampal formation hippocampal 5-HT release from varicosities rather than terminal buttons; 2 types D system – originates in dorsal raphe nucleus; thin axonal fibers that do not form synapses with other neurons (i.e. 5-HT serves as modulator here) synapses M system – originates in median raphe nucleus; thick axonal fibers, form conventional synapses synapses 2 systems have different behavioral effects At least 9 different subreceptors Drugs that inhibit reuptake of 5-HT (SSRIs) most widely used clinically for mental Drugs disorders (e.g. fluoxetine, or Prozac) disorders LSD and MDMA affects 5-HT systems Amino Acids Amino At least 8 amino acids have been suggested to serve additionally At as NT as Glutamate GABA Glycine Peptides Glutamate Glutamate Principle excitatory NT in the CNS Produced in abundance, no way to disrupt synthesis without Produced disrupting other cellular activities disrupting 4 types of receptors: NMDA – ionotropic, controls calcium channel that is normally blocked, and allows influx of calcium so it can serve as a 2nd messenger; and involved in forming new memories involved AMPA – ionotropic, controls sodium channel, stimulated by AMPA Kainate – ionotropic, controls sodium channel, stimulated by kainic acid acid Metabotropic glutamate receptor – sensitive to glutamate PCP – a drug that binds with the PCP binding site of the NMDA receptor and serves as an indirect antagonist; hallucinogenic drug receptor GABA GABA Primary inhibitory NT in CNS Produced from glutamic acid by the enzyme glutamic acid Produced decarboxylase (GAD) decarboxylase 2 subreceptors: GABAA – have at least 5 different binding sites: have primary for GABA, of which muscimol acts a agonist and bicuculline acts primary as antagonist 2nd binding site binds with drugs in benzodiazepines (e.g. Valium; anxiolytic – anxiety-reducing) anxiolytic 3rd binding site binds with barbituates GABAB Glycine Glycine Inhibitory NT in SC and lower portions of brain Receptor is ionotropic, controls chloride channel, and thus Receptor produces inhibitory postsynaptic potentials produces Strychnine – glycine antagonist Peptides Peptides Neurons in the CNS release a large variety of peptides from all Neurons parts of the terminal button, not just active zone, allowing molecules to travel to other cells molecules Best known family of peptides is the endogenous opioid family Best endogenous (opioid refers to natural ligands, opiate to drugs) (opioid e.g. enkephalin 3 types of opiate receptors: μ (mu) δ (delta) κ (kappa) Several neural systems activated: analgesic, fleeing and hiding Several behaviors, reinforcement behaviors, Naloxone – opiate receptor antagonist Lipids Lipids various substances derived from lipids can serve as NT Cannabinoids – endogenous ligand for receptors that bind with THC, the active ingredient in marijuana THC, 2 types of cannabinoid receptors: CB1 and CB2, both metabotropic THC produces analgesia, sedation, stimulates appetite, reduces THC nausea (used with cancer treatments), aids in glaucoma; reduces concentration and memory, alters visual and auditory perceptions, etc. etc. Anandamide – natural ligand that binds to cannabinoid receptor Nucleosides Nucleosides compound that consists of a sugar molecule bound with a purine compound or pyrimidine base or Adenosine – serves as neuromodulator in brain, released when cells are short of fuel or oxygen cells Agonists have general inhibitory effects on behavior Caffeine is antagonist, thus producing excitatory effects Soluble gases Soluble Neurons use at least 2 simple, soluble gases, nitric oxide (NO) Neurons and carbon monoxide (CO), to communicate with each other and NO used as a messenger in many parts of the body, e.g. control NO muscle walls of intestines, dilates blood vessels in brain, etc. muscle ...
View Full Document

This note was uploaded on 07/31/2011 for the course PSB 3004 taught by Professor Williams during the Spring '08 term at University of Florida.

Ask a homework question - tutors are online