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Biological Aspects of Addiction


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Final presentation for the Scaife Advanced Student Medical Seminar by Kyle Patrick Smith

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Biological Aspects of Addiction

  1. 1. Biological aspects of addiction Kyle Smith Scaife Fellow Presentations 27 July 2012
  2. 2. OverviewDopamine Glutamate CorticosteroidsPleasure + Plasticity + Stress Motivation Potentiation
  3. 3. Dopamine + Euphoria• Conventional wisdom says drugs give hedonic pleasure, promoting further use – Mediated by dopamine in striatal regions• Food, sex, and music produce a like effect – But drugs promote a faster, stronger, longer dopamine release
  4. 4. D2 Receptors + Anhedonia• Versus controls, addicted subjects were found to have lower D2 receptor (D2R) expression and lower baseline dopamine release – These changes cause a blunted response to natural rewards such as food and sex – Drug-induced dopamine overcomes baseline deficienciesRed=high D2R expression
  5. 5. Beyond Hedonic Pleasure• Decreased striatal D2R has been associated with decreased activity in inhibitory centers of the brain (ACC, OFC, dorsolateral PFC) – Associated with compulsive behaviors and impulsivity• Overexpression of D2R has been found to be protective against drug addiction – Non-addicts with a family history of addiction have shown increased D2R in the striatum
  6. 6. Orbitofrontal Cortex + Motivation• OFC participates in decision-making – Studies show decreased glucose metabolism in OFC of addicted subjects – Also associated with D2 receptor availability
  7. 7. Dopamine + OFC metabolism
  8. 8. OFC + Motivation, cont.• Dopamine increases motivation, energizes goal-seeking, and informs cost-benefit choices in OFC• Drug paraphernalia and related stimuli has been shown to activate the OFC in addicts – “Beware people, places, and things” D2R activation indicated by decrease in availability
  9. 9. Incentive-Salience Model• Hypermetabolism of OFC enhances saliency of drug-induced cues• Drugs are consumed not because they bring pleasure, but because they are wanted – Wanting does not equal enjoying
  10. 10. More on the OFC• Changes to OFC impact the assessment of the value of delayed gratification – Causes preferential selection of immediate, small rewards versus larger, delayed rewards• Damage to OFC interferes with the elimination of learned cravings for rewards that are no longer pleasurable – Even when drugs do not give reward, it is hard to unlearn the desire for them
  11. 11. Glutamate + Learning• Glutamate is an excitatory neurotransmitter – Affects synaptic plasticity and long-term potentiation (LTP) in dopaminergic cells• Studies show that antagonism of glutamate receptors AMPAR and NMDAR impair various drug responses in mice – Reduces lever pressing, place preference, stress- induced relapse, and cue-induced relapse
  12. 12. Long-Term Potentiation• In dopaminergic cells in the ventral tegmental area (VTA), there is an upregulation of AMPAR during drug-induced LTP – Even a single exposure sensitizes the VTA to drug- induced challenge
  13. 13. Long-Term Potentiation, cont.• Two hypotheses: – Increased AMPAR responses induce burst firing of dopamine, as opposed to low-level tonic firing – Excessive AMPAR activation causes a depolarization block, reducing action potential response to ordinary stimuli
  14. 14. Stress + Addiction• The limbic system, which mediates addiction, is also involved in the stress response• In rats, stresses such as tail pinch, social defeat, neonatal isolation, electric footshocks, novelty stress, and immobilization have been shown to increase drug acquisition• Rats and humans exposed to stress have been shown to be more sensitive to drug effects
  15. 15. Stress + Dopamine• Evidence shows that in early drug use, glucocorticoids sensitize the reward pathways• Rats without adrenal glands do not self- administer cocaine – When injected with corticosteroids, they self- administered cocaine in a dose-dependent fashion
  16. 16. Hedonic Allostasis Model• During addiction, elevated glucocorticoids create an internal form of stress that resembles anxiety• In hedonic allostasis model, downregulation of reward pathways and upregulation of stress factors creates negative affect in the patient – Withdrawal symptoms, dysphoria, anxiety• Relief from symptoms becomes primary factor in drug use – Users take drugs to “feel normal”
  17. 17. Genetics + the HPA axis• Hypothalamic-pituitary-adrenal axis responses to ethanol challenge have been shown to predict future alcoholism• Family history positive individuals have a higher response to the Trier Social Stress Test
  18. 18. Stress Tests in Family-History Positive vs. Negative Individuals
  19. 19. Genetic Variation in Stress Responses
  20. 20. Genetic Variation in Stress Responses
  21. 21. Early-Life Stress + HPA Axis• Evidence suggests some genetic variations increase development of addiction only in individuals who have experienced significant early-life stress – Physical, emotional, or sexual abuse or neglect
  22. 22. Early-Life Stress + HPA Axis• These genetic variations can affect the HPA axis, the dopamine reward pathway, and brain morphometry – PER1 circadian rhythm gene, KCNJ6 dopamine- inhibiting potassium channel, SLC6A4 serotonin transporter, BDNF affects brain shrinkage in response to stress – In rats, early-life stress has been shown to alter opiate and GABA receptors
  23. 23. Conclusions• Dopamine affects addiction through mediation of reward, but also motivation and salience – Genetic differences in dopamine networks can be predisposing or protective• Glutamate affects synaptic plasticity and long- term potentiation in addiction• Stress responses differ in addicted and non- addicted individuals – Early-life stress can also trigger addiction