neurobiology of addiction

1. NEUROBIOLOGY OF ADDICTION Eugene F. Boss, M.D.

3. Addiction A behavioral and mental disorder characterized by impaired control over drug self-administration, compulsive drug self-administration, continued self-administration despite obvious harm to self and significant others, and drug craving.

4. The 5 C�s Chronic disease Impaired control Compulsive use Continued use despite harm Craving

5. Physical Dependence Normal adaptive process due to continued presence of drug in system Caused by up or down regulation of receptor or enzyme systems Abrupt dose reduction, cessation of drug use, or administration of antagonist causes withdrawal syndrome Symptoms typically opposite of drug�s effect

6. Pseudoaddiction Drug seeking and drug using behavior due to inadequate treatment of the disease for which the drug is given Dose adjustment or drug change eliminates problem behavior

7. Pseudodependence Increase in dosage of drug needed due to disease progression, superimposed new disease, changes in physical activity, or lack of compliance with dosing regimen.

8. Why are some chemicals addicting while others are not?

9. Neurology 101 Neuron: specialized cell in central or peripheral nervous system capable of generating electrical action potential Dendrites: membrane bound protein receptors specific for neurotransmitters; make cell more or less likely to fire Cell body: secondary messengers affect cell functions including up or down regulation of receptors

10. Neurology 101 (continued) Axon: carries action potential to synapse Synapse: release of cell specific neurotransmitters stored in intracellular vesicles, react on receptors of downstream neuron Neurotransmitter has brief existence in synapse due to metabolism, reuptake, or diffusion and excretion

11. Neurology 101 (continued) Agonist: binds to a specific receptor and activates it, causing its downstream effect Antagonist: binds to a specific receptor and inactivates it, blocking its downstream effect Partial agonist: binds to a specific receptor and partially activates it, causing an attenuated downstream effect; blocks binding of natural compound

12. Reward circuits Natural pleasures in life establish habits which dominate our behavior All 5 senses provide input Hunger, thirst, sexual activity: appetites In humans: interpersonal relationships, religion, exercise, art, music, beauty

14. Reward circuits Anterior bed nucleus via myelinated neurons to ventral tegmental area From ventral tegmental area via median forebrain bundle to nucleus accumbens in limbic system; also synapses on amygdala, prefrontal cortex, and olfactory tubercle Nucleus accumbens projects to ventral pallidum Locus ceruleus projects to periaqueductal grey area and lateral reticular nuclei; where dependence and analgesia are produced

16. How do we know this is the reward center? Electrical stimulation of anterior bed nucleus, ventral tegmental area, or nucleus accumbens is rewarding and conditioning Electric self-stimulation is even more rewarding and conditioning Electrical stimulation of no other area in brain is rewarding or conditioning

17. Key neurotransmitter in this circuit is dopamine All addictive drugs cause release of dopamine in this circuit Dopamine antagonists microinjected in this circuit are aversive and block the rewarding effect of electrical stimulation

18. Why is direct stimulation of reward center so rewarding? �Unsensed incentive�: something not detected by 5 senses powerfully stimulates reward center Bypasses �filters� in sensory homeostatic mechanism 3-5 times more rewarding than natural sensations Neutral environmental cues �stamped in� with reward experience No delay in reinforcement

19. Animal models of addiction Lever pushing: initial random behavior very quickly established as compulsive habit Fixed ratio: one lever push results in one stimulation; will perform this compulsively and ignore appetitive stimuli and tolerate aversive stimuli Progressive ratio: each lever push requires progressively more lever pushes before stimulation given (2-4-8�); �breakpoint� where reward no longer worth effort

20. Conditioned reinforcement Stimulus given in presence of environmental stimuli that become associated with subjective sense of reward; �Pavlovian� Conditioned place preference: stimulus available in one environment but not another

21. �Drug seeking� behavior Animal develops conditioned self-stimulatory behavior Reward stopped and behavior extinguishes Given �free� stimulation, quickly and powerfully reinstates self-stimulatory behavior, though never given reward again Mediated by dopamine release in reward system; attenuated by antagonist

22. �Drug craving� behavior: Type one Cue triggered: animal develops conditioned self-stimulation behavior in association with sensory stimuli or preferred place Removed from environment for extended time Reintroduced to sensory stimuli or preferred place, quickly reinstates behavior despite lack of reward Originates in temporal lobe nucleus of hippocampus and amygdala; �emotional memories� Neurotransmitter: glutamate

24. �Drug craving� behavior: Type two Stress triggered: animal develops conditioned self-stimulatory behavior Reward is stopped and behavior extinguishes Relatively minor stress will reinstate behavior and place preference even in the absence of further reward Mediated by corticotropin releasing factor in amygdala, and norepinephrine from brainstem

26. What causes these behaviors? �Drug seeking�: �prime the pump� and trigger all the compulsive behaviors and motor memory in anticipation of further dopamine release �Drug craving�: glutamate system and norepinephrine cause dopamine release in anticipation of remembered conditioned reward; �primes the pump�

27. What about drugs? Addictive drugs mimic all these self-stimulatory behaviors Animals will only self-administer addictive drugs in reward circuits; even in absence of withdrawal; will not self-administer in dependence areas Will self-administer in fixed or progressive ratios Drugs will cause conditioned reinforcement and place preference Can cause drug seeking behavior in animals; any drug of abuse triggers this behavior, independent of original drug which caused habit formation Can demonstrate drug craving behavior in animals

28. How do addictive drugs cause the release of dopamine in the reward center?

29. Alcohol Affects four important aspects of homeostatic inhibitory mechanism on dopamine releasing pathways in reward center Stimulates GABAa receptor: protein complex in cell membrane that allows Cl- into cell and makes it less likely to fire; �inhibits the inhibitor� Blocks the NMDA receptor, where major excitatory neurotransmitter glutamate binds; �inhibits the inhibitor� Causes the release of endorphins that stimulate the mu opiate receptor; �inhibits the inhibitor�; this appears to be a major site of reward from alcohol Causes the release of endocannabinoids which stimulate the CB-1 receptor; �inhibits the inhibitor�

30. Benzodiazepines and Phenobarbital Stimulate GABAa receptor, effect similar to alcohol; �inhibits the inhibitor� and causes their sedative/hypnotic effect

31. Opiates Three endogenous opiate receptors; mu for endorphins, delta for enkephalins, and kappa for dynorphins Stimulation of mu receptor in reward center blocks energy production via adenyl cyclase and cyclic amp; �inhibits the inhibitor� Also stimulate mu receptors in periaqueductal grey area causing analgesia, and adrenergic neurons in locus ceruleus causing autonomic effects Also appears to cause release of endocannabinoids which stimulate the CB-1 receptor; �inhibits the inhibitor�

32. Endocannabinoids 1990 first cannabinoid receptor discovered and cloned CB-1: throughout CNS, especially high concentration in the limbic system, basal ganglia, and hippocampus; also in liver and gut CB-2: localized to cells in the immune system Inhibitory receptors that reduce cyclic-AMP formation, reduce protein kinase activity and gene expression Counteract activation of glutamate/NMDA receptor; �neuroprotective� Seem to play an important role in feeding and �appetite� behaviors

33. Endocannabinoids (cont) Two compounds identified to date, both arachidonic acid derivatives: anandamide and 2 arichidonoyl-glycerol (2-AG) CB-1 antagonists decrease hunger, decrease calorie intake, and inhibit dopamine release in the reward circuit in response to multiple drugs of abuse, including alcohol, opiates, nicotine, and cannabis Close reciprocal relationship between endocannabinoid and endorphin systems; agonists increase reward, antagonists decrease reward and decrease cue related phenomena

34. Cannabis Active ingredient delta-9 tetrahydrocannabinol (THC) Stimulates the CB-1 receptor, �inhibits the inhibitor� Also appears to release endorphins, activate the mu receptor, �inhibits the inhibitor�

35. Stimulants: Cocaine and Amphetamines All enhance monoamine neurotransmitter activity by inhibiting monoamine reuptake transporters in synapse Dopamine release causes reward Norepinephrine release causes physiologic arousal Serotonin release causes mood elevation

36. Nicotine Nicotinic acetylcholine receptors widespread throughout central nervous system Stimulation of receptor causes sodium, potassium, and calcium ions to enter cell and enhances depolarization Results in release of many neurotransmitters, including dopamine in reward center

37. How do these effects cause withdrawal syndromes?

38. Alcohol Chronic stimulation of GABA receptors leads to down regulation of this protein on cell surface; decrease or absence of drug leads to hyperexcitability and lowers seizure threshold Chronic blockade of NMDA receptor leads to up regulation of this protein on cell surface; decrease or absence of drug leads to hyperexcitability and lowers seizure threshold. Autonomic hyperactivity mediated by increased noradrenergic systems in locus ceruleus Benzo�s or phenobarbital administration blunts this effect by stimulating GABA receptors

39. Opiates Chronic stimulation of mu receptor leads to internalization of receptor from surface, and up regulation of adenyl cyclase system in nerve cell Decrease or absence of drug leads to increased firing in autonomic system, hyperesthesia, and dysphoria Administration of opiate agonist mitigates these symptoms Clonidine administration diminishes noradrenergic effects from locus ceruleus

40. Cannabis Chronic stimulation of the CB-1 receptor leads to decreased receptor density and sensitivity Sudden cessation after heavy use or administration of antagonist leads to symptoms of irritability, nervousness, restlessness, loss of appetite, sleep difficulties and dysphoria Slow elimination and accumulation of THC in system may attenuate withdrawal symptoms Similar to, but much less severe than, opiate withdrawal

41. Cocaine and Stimulants No actual withdrawal syndrome All deplete dopamine from reward center; reduction or absence of drug causes severe dysphoria and drug craving Sleep disturbances and fatigue

42. Nicotine Chronic stimulation of nicotinic acetylcholine receptors causes relative desensitization; results in upgrading in receptor number on cell surface Absence or reduction in nicotine leads to fewer receptors in desensitized state and causes hyperexcitability across CNS Increased appetite, irritability, difficulty concentrating, restlessness, intense craving Mitigated by nicotine administration or agonist

43. Why isn�t everyone who tries drugs addicted?

44. Factors affecting addiction potential Agent +/- Host +/- Environment +/-

45. Agent Commercial availability and advertising Route of administration: IV>inhaled>intranasal>oral Rate of elimination; satiety Intrinsic features of drug

46. Host Genetic factors: twin and family studies; chromosomal markers Presence/absence of underlying psychiatric disorder �Hedonic tone�

47. Environment Cultural Religious Socioeconomic

48. Why don�t people just stop using drugs? Powerfully �stamped in� behavior Reward pathways altered in chronic (? permanent) way Humans aren�t lab animals Blurring of cue vs. actual reward Cues difficult to avoid Stresses multifactorial early in recovery

49. Positive and negative reinforcing events Avoiding negative consequences of drug dependence: withdrawal symptoms Drug reward causes more intense and compulsive habit than natural pleasures in life Intense need for and focus on repeating the drug experience Denial, rationalization

50. Protracted abstinence syndrome Chronic dysregulation of the brain�s motivational systems Underactivity of the reward system: low dopamine, low endogenous opioid, high glutamate state Overactivity of the �anti-reward system�: high norepinephrine and CRF state; hyperactivity of the brain stress system

51. Detox is easy; relapse prevention is hard.

52. Cognitive behavioral therapies most effective method Cognitive approach to reframe how the addict relates to and view the world Deconditioning to cues that elicit craving Social rehabilitation Twelve step programs: assistance with guilt, remorse, and repairing relationships

53. Pharmacotherapy: Alcohol Antabuse (disulfiram); available since 1940�s Alcohol metabolized to acetaldehyde, then quickly to acetate by aldehyde dehydrogenase; disulfiram permanently blocks this enzyme for 5-7 days Alcohol use results in build up of acetaldehyde, causing unpleasant nausea, vomiting, flushing and headache Need to be alcohol free for 72 hours 250mg by mouth once daily Compliance a problem Check liver enzymes during therapy

54. Pharmacotherapy: Alcohol Naltrexone: mu receptor antagonist, blocks dopamine release with alcohol use, blocking reward Ameliorates glutamate and noradrenergic mediated release of dopamine with cue or stress Shown to statistically reduce drinking days, volume of drinks, increase time to first drink and abstinent days compared to placebo Compliance a problem; dysphorogenic 50mg once daily by mouth; depot formula available, 380mg IM monthly

55. Pharmacotherapy: Alcohol Campral (acamprosate): indirectly blocks glutamate affect at NMDA receptor, offsetting GABA/glutamate system imbalance Reduces �chronic withdrawal� symptoms, and reduces cue related relapses Good safety profile, well tolerated Can be used in conjunction with naltrexone Two 333mg tablets three times daily by mouth Disappointing results in recent large trials compared to naltrexone alone and placebo

56. Pharmacotherapy: Alcohol Topamax (topiramate): anticonvulsant, stimulates GABA b receptor in reward circuit and reduces dopamine release with alcohol use, limiting reward Also offsets GABA/glutamate system imbalance and reduces �chronic withdrawal� symptoms Reduces drinking days, drinks per day, increases time to first drink and abstinent days 25mg to 300mg daily; need to increase dose slowly to avoid cognitive dysfunction Check liver enzymes during use

57. Pharmacotherapy: Opiates Endogenous opiate pathways chronically (? permanently) altered Dysphoria, �chronic withdrawal� symptoms, craving Chronic use of opiate agonists regulate this dysfunction back to �normal�

58. One year recovery rates after opiate detox �drug free�: 5-30% Naltrexone: 10-20% Opioid agonist therapy: 50-80 %

59. Pharmacotherapy: Opiates Naltrexone: mu receptor antagonist; blocks rewarding effect of opiate use Must be drug free for seven days or precipitate withdrawal Dysphorogenic; early drop out a problem; depot form available Opiate analgesics for pain control inhibited

60. Pharmacotherapy: Opiates Mu receptor agonists: methadone and buprenorphine Significantly reduce rate of mortality, IV drug use, crime, HIV infection, relapse; increase rate of employment, health parameters and social function

61. Pharmacotherapy: Opiates Methadone: long acting, once a day supervised/unsupervised dosing; low abuse potential Dose titrated to reduce or eliminate withdrawal symptoms, craving; restore physiologic functions toward normal Minimal sedation; constipation; decreases libido

62. Pharmacotherapy: Opiates Buprenorphine: approved in 2002; can be administered in office setting by qualified physician; no more than 30 patients Partial mu receptor agonist, will precipitate withdrawal syndrome in heroin or methadone users; drug free 72 hours before starting Combined with naloxone to prevent IV use; bitter taste of naloxone inhibits multiple dosing Equally effective as moderate doses of methadone (60mg/day); not as effective as higher doses of methadone (80-100mg/day)

63. Pharmacotherapy: Nicotine Very difficult addiction to manage: up to 75% of smokers want to quit, 33% try to quit each year, 3-5% succeed One pack per day smoker gets 200 doses of nicotine per day; pairing of drug use to multiple daily life events Unique ability to modulate wide variety of moods Oral gratification Causes weight loss Any type of pharmacotherapy doubles rate of success

64. Pharmacotherapy: Nicotine Nicotine replacement therapy: low tonic dose of nicotine increases number of nicotinic acetylcholine receptors in desensitized state; reduces withdrawal symptoms Number of receptors slowly decreases over weeks

65. Pharmacotherapy: Nicotine Nicotine gum: 2-4mg; chew then �park�; allows self-titration to symptoms; 10-15 pieces per day; mouth irritation Nicotine patch: 7-21mg; change every 24 hours, begin dose taper after four weeks; if sleep disturbance can remove at bedtime; heavy smokers may require more than one patch; adhesive irritation Safe even in patients with coronary artery disease

66. Pharmacotherapy: Nicotine Bupropion: monocyclic antidepressant, inhibits reuptake of dopamine and norepinephrine; does not work by its anti-depressant effect Antagonizes nicotinic acetylcholine receptors and decreases reward of smoking Additive effect with nicotine replacement therapy Minimizes weight gain 150mg by mouth daily for three days, then twice daily Cannot be use in patients with history of seizures

67. Pharmacotherapy: Nicotine Chantix (varenicline): partial agonist at nicotinic acetylcholine receptor; occupies receptor and reduces/eliminates reward of smoking while reducing withdrawal symptoms .5mg daily for three days, then .5mg twice daily for five days, then 1mg twice daily; starter kit available Better than bupropion and/or nicotine replacement therapy Major side effects are nausea, headache and insomnia

68. Pharmacotherapy: Cocaine/Amphetamines Multiple medication trials: ssri�s, tricyclic antidepressants, mao inhibitors, naltrexone, campral, anticonvulsants; none better than placebo Intense psychosocial treatment ? Immunotherapy: vaccinated against drug, prevents it from reaching reward center