The Brain and Addiction Neuroanatomy Neurophysiology Agonist Spectrum
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10/13/2014 ADDICTIONS 101 A Refresher Course The Brain and Addiction Neuroanatomy William J. Lorman, PhD, MSN, PsyNP, CARN-AP Neurophysiology V. P. & Chief Clinical Officer, Livengrin Foundation, Inc. Agonist Spectrum Ass’t Clinical Professor, Graduate Nursing Dept., Drexel University [email protected] mesolimbic pathway Drug Categories Alcohol Canabis Cocaine CNS depressants CNS stimulants Opioids Hallucinogens Inhalants Anabolic-androgenic steroids Synthetic OTC Club drugs Stahl S M, Essential Psychopharmacology (2000) Addicting Molecules Is there a single pathway to addiction? Nicotine Alcohol Drugs of abuse have very different structures and neurotransmitter targets in the brain, but they all exhibit: ◦ acute reward ◦ chronic reward Cocaine Heroin ◦ sensitization ◦ negative withdrawal symptoms ◦ associative cue learning ◦ incentive motivation (relapse) A progression from impulsive to compulsive drug use (which defines the progression from abuse into addiction). 1 10/13/2014 The Body’s Own Psychotropics cannabis GABA amphetamine The brain makes its own morphine (beta alcohol endorphin) and its own marijuana DA (anandamide) opioid The brain may even make its own antidepressants, anxiolytics, and cocaine hallucinogens ACh nicotine PCP Drugs often mimic the brain’s natural alcohol neurotransmitters 5HT Glu Often, drugs are discovered prior to the hallucinogen natural neurotransmitter Stahl S M, Essential Psychopharmacology (2000) Exogenous vs. Endogenous Drugs We knew about : TRANSITION TO Morphine before the discovery of β- ADDICTION endorphin Marijuana before the discovery of cannabinoid receptors and anandamide Valium and Xanax before the discovery of benzodiazepine receptors Taking drugs may begin as a voluntary choice to seek a pleasant stimulus, but for addicts, that Elavil & Prozac before the discovery of choice is no longer volitional, even in the face the serotonin transporter site of terrible personal consequences. During the initial stages of addiction Types of Craving ◦ The pleasure derived from various drugs’ activation of the brain’s natural reward system promotes continued Cue-based craving drug use ◦ Response to environmental cue Repeated exposure to drugs induces the brain ◦ Cue creates internal state which is recognized as mechanism of dependence craving Dependence leads to daily drug use to avert the ◦ Most notable in cocaine & nicotine unpleasant symptoms of drug withdrawal State or stress-based craving Further prolonged use of drugs lead to more ◦ Emotional tone, level of perceived stress, state of long-lasting changes in the brain that may self care set the state underlie the compulsive drug-seeking behavior ◦ Craving appears to emerge out of difficult and related adverse consequences that are the emotional states hallmarks of addiction. ◦ Most notable in alcohol & sedatives 2 10/13/2014 Stressors can trigger drug craving in addicts. THE IMPORTANT Sinha R, Catapano D & O’Malley S. (1999). Stress-induced craving and stress response in cocaine dependent individuals. Psychopharmacology , 142, 343-351. ROLE OF STRESS ◦ One explanation is that abused drugs raise levels of cortisol which plays a primary role in stress responses. ◦ Cortisol raises the level of activity in the mesolimbic reward system. Kreek MJ & Koob GF. (1998). Drug dependence: Stress and dysregulation of brain reward pathways. Drug & Alcohol Dependence , 51(1-2), 23-47. ◦ By these mechanisms, stress may contribute to the abuser’s desire to take drugs in the first place, as well as the subsequent compulsion to keep taking them. The Anatomy of the Nervous System A complex wiring diagram, carrying electrical impulses to wherever the ‘wire’ is plugged in – at the synapse. There are an estimated 100 billion neurons, which make over 100 trillion synapses in the human brain. Stahl, S., Essential Psychopharmacology The Anatomy of the Nervous System Fast-Onset vs. Slow-Onset Signals Neurons send electrical impulses from Some neurotransmitter signals are very one part of the cell to another part of the fast in onset cell. ◦ Rapidly change the flux of ions, thus At the presynaptic terminal, chemicals are altering the excitability of the neuron released to any of a variety of sites on a second postsynaptic neuron or to other ◦ Glutamate: universally stimulates almost sites distant to the synapse by diffusion. any neuron The postsynaptic neuron can also “talk ◦ GABA: universally inhibits almost any back” to the presynaptic neuron with neuron chemical messengers of its own. 3 10/13/2014 Fast-Onset vs. Slow-Onset Signals Neurotransmitters Some neurotransmitter signals take The known or suspected longer to develop neurotransmitters in the brain already ◦ Called neuromodulators number several dozen. ◦ Examples are the monoamines norepi- Based on theoretical considerations of nephrine and serotonin as well as the amount of genetic material in various neuropeptides neurons, there may be several hundred to several thousand unique brain chemicals. Categories of Neurotransmitters Co-Transmitters 1. Cholinergic – Acetylcholine Each neuron was originally thought to use 2. Monoamines one neurotransmitter only and to use it 1. Catecholamines – Norepinephrine, at all of its synapses. Dopamine It is now known that many neurons have 2. Indoleamines - Serotonin more than one neurotransmitter 3. Amino acids – GABA, Glutamate Co-transmission often involves a 4. Neuropeptides – Substance P, Enkephalin monoamine coupled with a neuropeptide 5. Lipids - Anandamide Chemical Neurotransmission: Co-Transmission A Team of Molecular Players Under some conditions, the monoamine is Neurotransmitter released alone; under other conditions, both are Specific ions that interact with ion channels released Various enzymes The rationale behind the use and action of Transport carriers Each molecule is: many drugs arose in the era of thinking about Active transport pumps • a known or potential site one neuron using only one neurotransmitter, so Second messengers of drug interactions that the more selective a drug, the better it Receptors • a theoretical site of mal- could modify neurotransmitters. Transcription factors function that could possibly contribute to a nervous or It is now believed in order to replace or Genes mental disorder influence abnormal neurotransmission, it may be Gene products necessary to use multiple drug actions. 4 10/13/2014 Opening/Closing of Ion Channels Ions: Sodium, Potassium, Chloride, Calcium Regulation of opening/closing: ◦ Electricity Called voltage-gated ◦ Neurotransmitter binding to a receptor Called ligand-gated Transport Carriers Bind to molecules that need to shuttle into cells that otherwise would not be able to get into the cell through the membrane. If a transport carrier is coupled with an energy-providing enzyme such as ATPase , it is called an active transport pump . Example: reuptake of neurotransmitter into its presynaptic neuron Stahl S M, Essential Psychopharmacology (2000) Active Transport Pump Reuptake Inhibition Stahl, S., Essential Psychopharmacology Stahl, S., Essential Psychopharmacology 5 10/13/2014 Regulation of Receptors Regulation of Enzymes Drugs can cause: The enzymes most important in the ◦ A decrease in the rate of receptor synthesis neurotransmission process are those that Down-regulation or desensitization make and destroy the neurotransmitters Takes days to occur Diminishes the sensitivity of neurotransmission There are very few drugs that are enzyme ◦ Immediate desensitization by activating an enzyme inhibitors. (Most drugs target the that makes the receptor immediately insensitive. receptors) ◦ An increase in the rate of receptor synthesis The binding of inhibitors can be either When receptors are blocked by a drug reversible or irreversible Increases sensitivity of neurotransmission May also produce a disease (e.g., Tardive dyskinesia) Special Properties of Receptors Pharmacological Subtyping They are organized into multiple subtypes Each neurotransmitter can act on more Their interactions with drugs define the than one neurotransmitter receptor. type of drug (i.e., agonist, antagonist, There are multiple subtypes of receptors partial agonist, etc.) for every neurotransmitter Allosteric modulation ◦ Serotonin: 1A, 1D, 2C ◦ Norepinephrine: α1, α2 ◦ Dopamine: D2, D4 There is a spectrum of degree to The Agonist Spectrum which a receptor can be stimulated Naturally occurring neurotransmitters stimulate receptors ◦ Agonists Various drugs acting at a receptor exist in a spectrum from full agonist to antagonist to inverse agonist No longer considered Stahl, S., Essential Psychopharmacology 6 10/13/2014 AGONIST ANTAGONIST Stimulates receptors Blocks the actions of everything in the Function Example agonist spectrum ◦ Turns on the synthesis of the second By themselves, antagonists have no messenger to the greatest extent possible intrinsic activity ◦ Opens ion channel column completely Function Example ◦ Neither opens nor closes ion channels INVERSE AGONIST PARTIAL AGONIST Does the opposite of agonists Exerts an effect similar to but weaker than that of the full agonist Function Example Example ◦ Causes ion channel to close completely ◦ Opens the ion channel to a certain extent but only partially as compared with the full agonist Note: An antagonist will also block the ◦ ‘Light & Dark’ as an analogy action of an inverse agonist just as it Can appear as net agonists or as net would an agonist. antagonists depending on the amount of naturally