The Neurobiology of Addiction
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Research review on the neuroscience of addiction. Created in 2005 for an honors course project.
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The Neurobiology of Addiction
- 1. The Neurobiology of Addiction By Colleen M. Farrelly
- 2. Overview of Neurotransmission Key Concepts: Action Potentials Life-cycle of the Neurotransmitter Synapses and Receptor Types G-Proteins and Regulation of Ion Channels
- 3. Electric current through cell membrane resulting in intracellular action at a synapse Absolute threshold All or none behavior Excitatory (EPSPs) increases electrical potential Inhibitory (IPSPs) decreases electrical potential Saltatory conduction, as Schwann cells wrap cell membranes Current hits presynaptic terminal and opens voltage- gated Ca++ channels Leads to neurotransmitter release Action Potentials
- 4. Neurotransmitter Lifecycle Location of synthesis Soma (peptides) Presynaptic terminals (small- molecule transmitters) Storage until release signal (electrical current) Released with Ca++ increase through exocytosis Involves many intracellular proteins Re-uptake after release Degradation after release
- 5. Synapses and Receptor Types Receptor types: Ligand-gated (ionotropic) G-protein-coupled (metabotropic) A subunit activates effector enzyme 2nd messenger effects ion channel Additionally, intracellular receptors Marijuana’s effects on amanamide receptors Can effect gene expression Enzyme coupled (tyrosine hydroxylase)
- 6. Downstream Effects Neurotransmitters interacting with these receptors can: Elicit short- or long-term modulatory processes Impact learning and memory Impact an important process called synaptogenesis Create connections between neurons in memory structures reiterated by the same stimuli Involved in triggers for relapse Ingrained in memory with connections and pathways New pathways that form are difficult to destroy quickly.
- 7. G-Proteins and Secondary Receptors Cascades and amplification of signal G-proteins activated by ligand binding (neurotransmitter) Activates effector protein (such as adenylyl cyclase) Creates many other effectors (such as cAMP) Which then release the catalytic subunit on a kinase (such as PKA) Kinase phosphorylates many second effectors Many targets of which regulate channels Other targets of which impact gene regulation (epigenetic changes)
- 8. The Limbic System Structures Ventral Tegmental Area Nucleus Accumbens Lateral Nuclei of Hypothalamus Reticular Activating System (regulation and affective stimuli), Cingular Gyrus (top of brainstem affecting emotions, too) Main Neurotransmitters Dopamine Associated with pleasure 100,000 molecules per neuron in a dopaminergic system Dopamine in cocaine abuse Main transmitter involved Agonist amantadine decreases craving GABA Inhibition Mediates reinforcement in hippocampus and amygdala when paired with stress Reinforcement Initially build to associate behavior with feeding and sex Controls emotional memory, as well as other behavioral responses Highjacked by drugs of abuse Much like a biological simulation of Pavlov’s conditioning
- 9. Affects of Neurotransmitters Gene Regulation G-proteins effect CREB genes, which modulate cAMP production via adenylyl cyclase cAMP systems implicated in many systemic affects of addiction Additionally, amphetamines and cocaine induce c-fos gene Also acts on CREB gene regulation Creates regulation loop involving CREB, cAMP, and transmitters Channel Regulation Long-term synaptic depression Makes it more difficult to activate the neuron’s electrical potential Long term depression and glutamate Hits NMDA receptor Then acts on PLC, which clips PIP2 to IP3 and DAG DAG, with the addition of Ca++ from intracellular store release and from Ca++ channels opening, acts on PKC IP3 acts on endoplasmic reticulum stores of Ca++, which then binds to calmodulin, which activates CaM-KII PKC and CaM-KII act on channel effectors that produce long-term depression
- 10. Types of Neurotransmitters Acetylcholine Acts on the parasympathetic system Anti-excitatory Substances affecting acetylcholine receptors Nicotine nAChR ionotropic receptors Increases parasympathetic activity Faster response, effect from the neuron Excitatory effect (EPSPs)
- 11. Types of Neurotransmitters Catecholamines Synthesized from amino acid tyrosine Dopamine from dopa conversion via tyrosine hydroxylase Metabolized into norepinephrine and then into epinephrine Pathway modulated by mAChR receptors via PKA interactions with CaM-KII Degraded by COMT and MAO enzymes Functions Reward pathways Mimicked by many drugs of abuse (cocaine, amphetamines)
- 12. Drugs and Catecholamines Norepinephrine Circuits acted upon by amphetamine and cocaine Modulates learning and memory circuits, including emotionally-charged memories Dopamine acts especially in the VTA-NA systems Translates motive states into overt motor responses Powerful reinforcement mechanism Cocaine and amphetamine as main drugs of abuse impacting dopamine
- 13. Specific Drug Mechanisms Dopamine re-uptake transporters inhibited (blocked) by both amphetamines and cocaine Cocaine Works on monamine up-take system (inhibits) Increases mood MAO inhibitors reverse depression similarly, accounting for the high of cocaine Amphetamines Stimulates more release of dopamine NE transporter effected similarly Except that amphetamine works from within the cell on this receptor (“cell-permeant” drug, as opposed to cocaine as “cell-impermeant”) Alcohol Effects specifically: VTA Substantia nigra (“shakes” with withdrawal)
- 14. Types of Neurotransmitters Amino Acids Glutamate Main excitatory neurotransmitter Glutamate synthesized from glial glycine release Converted back to glycine with uptake into glial cells after transmission Also can be turned into GABA (inhibitory analogue) Works through metabotropic receptors Substances effecting glutamate Suspected general role in addiction Possible antagonist of NMDA receptors in hippocampus when reacts with GABA Causes long-term potentiation
- 15. Types of Neurotransmitters Y-aminobutryric Acid (GABA) Structure Ionotropic binding sites Synthesized from recycled glutamate via glutamate decarboxylase Function Main inhibitory transmitter (hyperpolarizing impact through Cl- influx) Effects every brain system (connected with epilepsy) Connection to glutamate (depolarizing effect) Substances effecting GABA regulation Gamma subunit implicated in alcohol’s effects on GABA systems (benzodiazepines and barbiturates, as well) These act on GABA-alpha ionotropic receptors Produces various inhibitory responses in body
- 16. Types of Neurotransmitters Serotonin Structure Indolamine Function Regulate sleep-wake patterns Mood regulation Role in Psychiatric Disorders Imbalances lead to many psychiatric mood disorders. Bipolar I and II Depression Psychodelics and serotonin responsible for psychedelic effects
- 17. Types of Neurotransmitters Neuropeptides Function Endogenous opioid peptides Role in pain regulation Long-term depression in mechanosensory pathways Role in reward systems Substances effecting opioid receptors Mainly opiates Examples include heroin, morphine, oxycodone, and fentanyl Work on mu-1 receptors in the nucleus accumbens, triggering dopamine pathways
- 18. Neuropeptides In-Depth Neuropeptide chains effecting pain regulation, especially (enkephlins and dynorphins) Periaquiductal gray of midbrain Controls pain with dynorphins for long-term depression of pain pathways Also affect reward systems by the pleasure response Works on VTA-NA system, especially with mu receptors Morphine, heroin act as agonists Heroin changed to morphine in brain Heroin has 2 additional acetyl groups on the 3 and 7 carbons, as well as an additional methoxy group) Act on G-protein receptors (mu and delta) Increases PK+ and PCa++ In turn inhibits adenylyl cyclase and cAMP Tolerance develops rapidly Rregular use over a few months, can tolerate 40-50 times dose L50 Mu and delta receptors reduce consumption of alcohol and opioids when blocked (effects of Naltrexone Naloxone is a pure antagonist used in overdoses to block opiate binding
- 19. Neurobiological Mechanisms Agonists Opiates acting directly on opioid receptors Antagonists Block drug from binding (use of naloxone in heroin overdoses) Re-uptake blockers Amphetamines blocking dopamine re-uptake Sensitivization/desensitivization and neuronal adaptation Role in tolerance/reverse tolerance Cells adapt by increasing/decreasing receptor density at synapse Dendrites growing or shrinking in response Remove substance responsible for changes and cells have to re-adjust to less/more neurotransmitters (law of opposites and withdrawal symptoms)
- 20. Neurobiological Model of Addiction Causes Genetic predisposition MZ/DZ twin studies and family studies Trauma plus genetics implicated in veteran studies and survivors of child abuse Genes implicated in addiction Channel abnormalities NMDA glutamate receptor Metabolic abnormalities Alcohol dehydrogenase
- 21. Causes of Addiction in the Neurobiological Model The Substrate Itself Actions on Neurotransmission Channels and Metabolism TIQs Local and Global Effects of Neurotransmission Disturbance Pathways and Neuronal Adaptation Stimulants and Re-uptake
- 22. Diagnosis DSM-IV Criterion Substance abuse vs. substance dependence (withdrawal) Metabolite tests Vital functions Chemical assessment Other medical problems closely associated with addiction Cirrhosis HIV/hepatitis/others related to injecting practices Brain damage and nutritional deficiencies Comorbid psychiatric disorders
- 23. Detoxification as a First Step in Treatment Detoxification Drugs administered Overdose Naloxone and opiate overdoses Rehabilitation detoxification Benzodiazepines and alcohol withdrawal Treatment options after detoxification Psycho-behavioral treatment Cognitive-behavioral therapy 12-step groups Pharmacological treatment
- 24. Maintenance Methadone Programs Long-term treatment Aversion therapy Disulfiram and Alcoholism Treatment of co-morbid disorders Antidepressants Antipsychotics Anti-Craving Drugs Naltrexone Alcoholism, narcotic addiction Bupropion Anti-smoking drug Relapse risk for comorbid cocaine addiction) Pharmacological Treatment of Addiction
- 25. Merits of the Neurobiological Approach Understanding the risks and mechanisms behind behavior Withdrawal avoidance Importance of abstaining from potentially addicting drugs Allows for treatment under Health Care Plans Developing drugs to reverse overdoses Shifts the blame Not completely the addict’s fault Less guilt over the addiction More likely to seek treatment
- 26. Problems of the Neurobiological Approach Not everyone with a biological predisposition becomes addicted to drugs. The phenomena of relapsing Physiology returns to normal at most a 1-2 years after cessation. Emotional memory should also return to normal after cessation. Shifts emphasis from responsibility to determinism Allows for an excuse to relapse or to not seek treatment.
- 27. Sources Crabbe, John C., Jr., Harris, R. Adron, The Genetic Basis of Alcohol and Drug Actions. Plenum Press, New York, New York: 1991 Feldman, Robert S., Meyer, Jerrald S., Quenzer, Linda F. Principles of Neuropsychopharmacology. Sinauer Associates, Inc., Sunderland, MA: 1997 http://www.biopsychiatry.com/in dex.html http://www.psychologytoday.com /articles/pto-19980201- 000010.html http://www.drugdevelopment- technology.com/projects/bifepru nox/bifeprunox3.html Niewink, RJM, Jaspers, RMA, et al. Drugs of Abuse and Addiction: Neurobehavioral Toxicology. CRC Press, Boca Raton, FL: 1999 Perrine, Daniel M. The Chemistry of Mind-Altering Drugs. American Chemical Society, Washington D.C.: 1996 Purves, Dale, Augustine, George J., et al. Neuroscience. Sinauer Associates, Inc., Sunderland, MA: 2004 Thompson, Richard F. The Brain. W. H. Freeman and Company, New York, New York: 1995 Zernig, Gerald, Saria, Alois, et al. Handbook of Alcoholism. CRC Press, Boca Raton, FL: 2000
Notas del editor
- Neuropeptide chains effecting pain regulation, especially (enkephlins and dynorphins) --periaquiductal gray of midbrain controls pain with dynorphins for long-term depression of pain pathways -- also affect reward systems by the pleasure response --works on VTA-NA system, especially with mu receptors Morphine, heroin act as agonists --in fact, heroin changed to morphine in brain --heroin has 2 additional acetyl groups on the 3 and 7 carbons, as well as an additional methoxy group) Act on G-protein receptors (mu and delta) --increases PK+ and PCa++ --in turn inhibits adenylyl cyclase and cAMP Tolerance develops rapidly --regular use over a few months, can tolerate 40-50 times dose L50 Mu and delta receptors reduce consumption of alcohol and opioids when blocked (effects of Naltrexone) Naloxone is a pure antagonist used in OD
- Need to Cross Blood-Brain Barrier --lipid or aqueous soluble properties Agonist/Antagonist display Re-uptake and Cocaine Addiction --dopamine and norepinephrin mechanisms --cocaine blocks re-uptake of these NTs --more NE and DA hit receptors, eliciting a pleasure response (ADAPTS) --dysphoria when cocaine withheld Sensitivization in stimulants --reverse tolerance found in stimulants --augmented response that increases with increased dosage --hence, the mimicking of schizophrenia with extremely high cocaine and amphetamine consumption Desensitivization in Depressants --Tolerance consequence of: --decrease in effective concentration of the agonist --reduction in number of receptors --change in response elicited because of the activation of a homeostatic mechanism --pharmacodynamic tolerance also appears in depressants --which is a general cellular tolerance to the substances Re-uptake and Cocaine Addiction --dopamine and norepinephrin mechanisms --cocaine blocks re-uptake of these NTs --more NE and DA hit receptors, eliciting a pleasure response (ADAPTS) --dysphoria when cocaine withheld Heroin addiction acts on dynorpin/endorphin metabotropic receptors. --activates Gi protein, inhibiting adenylyl cyclase, which decreases cAMP concentration. --decrease of cAMP and downstream effectors counteracted by increasing adenylyl cyclase concentration. --balance regained in time (TOLERANCE) --remove heroin, adenylyl cyclase freed—WITHDRAWAL SYMPTOMS appear --can eventually return to normal Withdrawal effects opposite of drug effects and operates on the same time-frame. --Example: heroin slows stomach contractions, is fast acting. --Withdrawal has stomach contractions, is fast-acting.
- Predisposition --2.5 times higher chance of alcoholism in Children of Alcoholics than other children Channel Abnormalities --second messengers (G-proteins) affected by receptor differences, such as in NMDA receptors and the D4 receptors --can also interfere with IPSP and EPSP interference in membrane potentials as a consequence Metabolic Enzyme Differences -- rate-limiting steps differ --ex. Alcohol Dehydrogenase gene ADH and ALDH (aldehyde hydrogenase) --active ALDH gene increases likelihood of alcoholism --ALDH2-1 as opposed to ALDH2-2 --ADH2 &ADH3 have near loci on chromosomes 11 and 4 --in addition, differences in MAO concentrations in platelet counts --plus differences in B-endorphin response with alcohol consumption
- How Drugs Effect Synapses --increase/decrease synthesis of NTs --increase/decrease transport of NTs --modify storage vesicles --modify release of NTs --increase/decrease rate of degradation of NTs --block re-uptake --mimic NT (agonist) --block receptor (antagonist) --affect up-/down-regulation of receptors TIQs— --dopamine + acetaldehyde (from alcohol breakdown) --possible opioid-like response
- DSM-IV Criteria --tolerance or withdrawal necessary with dependence (physical, rather than only psychological) Physical tests for Alcoholism --malnutrition --red blood cell counts --liver enzyme analysis (glutamate dehydrogenase, AST/ALT levels) --carbohydrate-deficient transferrin (CDT) levels
- OD --naloxone acts as antagonist on opioid receptors, reverses effects of heroin/morphine… AWS Signs --tremor, hyperhidrosis, tachycardia, insomnia, anxiety, clouding of consciousness, seizure (opposite of intoxication) --detoxification with benzodiazepines --usually with diazepam (valium)
- Methadone --less psychological effects than heroin --longer duration to stave withdrawal --lots of controversy Aversion Therapy --Alcohol metabolism -- disulfiram blocks aldehyde dehydrogenase (build of acetaldehyde, which causes unpleasant feelings—flushing, vomiting) --Ro 15-45B blocks behavorial and neurochemical effects of alcohol Co-Morbid disorders can exacerbate substance use (self-medication) Anti-Craving Drugs --Naltrexone in craving prevention in alcoholism (modification of NTs and receptors) --works on opioid system as well, GABAa system, Glutamate system --Amantadine for glutamate and dopamine modification in cocaine addicts --Ibogaine trials in Israel and Netherlands as an anti-craving drug --unfortunately Schedule I substance in USA --danger of Bupropion