THE NEUROBIOLOGY OF ADDICTION AND THE BRAIN’S REWARD SYSTEM

1. THE NEUROBIOLOGY OF ADDICTION AND THE BRAIN’S REWARD SYSTEM A. Horita, PhD University of Washington

2. POINTS TO REMEMBER • What is drug addiction? • What is the brain’s reward system? • Drugs of abuse and the reward system • Conditioning and drug-associated cues as factors in (1) tolerance and withdrawal, and (2) craving, relapse, and extinction • Stress as a factor in the addiction process

3. DRUG ADDICTION is a malfunctioning of the brain’s reward system resulting from the repeated administration of certain psychoactive drugs. Craving,relapse, and extinction are three important properties of the addicitive process. The process is strongly influenced by various psychobiological, social and environmental factors.

4. POINTS TO REMEMBER • What is drug addiction? • What is the brain’s reward system?

5. WHAT IS THE BRAIN’S REWARD SYSTEM? The brain’s reward center(s) are important for the survival of the organism and its species. Functions such as eating, drinking and sexual activity need to be reinforcing in order to ensure that the organism will perform those functions repeatedly. The reward system consists of those brain areas that are involved in the behaviors of “reward”, “pleasure” and/or “reinforcement”

6. Concept of reinforcement was strengthened by experiments that demonstrated that animals would stimulate themselves if electrodes were placed in appropiate parts of the brain.  This is called Intra-cranial Self-Stimulation (ICSS).

8. Stimulation of MFB is reinforcing

10. ICSS site ICSS site Reward Center Reward Pathway

12. Humans also exhibit ICSS when allowed to self-stimulate via elec-trodes placed in appropriate brain areas. It has been reported that when given the opportunity, subjects will press a switch to self-stimulate up to 1100 times/hr.

13. POINTS TO REMEMBER • What is drug addiction? • What is the brain’s reward system? • Drugs of abuse and the reward system

14. CLASSES OF DRUGS OF ABUSE • Stimulants Sedative-Hypnotics • Amphetamine Ethanol • Cocaine Barbiturates • Nicotine Benzodiazepines • MDMA (‘Ecstasy’) • Mood Modifiers • Opioids LSD • Morphine MDMA (‘Ecstasy’) • Heroin Psilocybin • Oxycontin Phencyclidine • Marijuana (THC) • Ethanol

15. PROPERTIES OF MANY DRUGS OF ABUSE • Drugs of abuse are reinforcers that act via the VTA DA system (one of the brain’s reward system) • The user of such drugs find themselves “liking” the effects produced, and they seek to repeat the effects by further drug-taking behavior • After a number of such repetitions, the “liking” transforms into a “wanting” and “needing” of the drug. This transformation is thought to represent the “switch” from drug abuse to drug addiction • The repeated use of such drugs usually lead to tolerance development, and upon stopping the drug, to withdrawal reactions

16. Animals can be trained to self-administer reinforcing drugs

19. NATURAL REWARDS, e.g., food Primary incentive properties Consummatory properties Stimulation of central OPIOID and DOPAMINE reward systems Incentive learning Maintenance Acquisition OF FOOD INTAKE

20. NATURAL REWARDS, e.g., food Primary incentive properties Consummatory properties HeroinEthanol Stimulation of central OPIOID and DOPAMINE reward systems Methamphet- amine Cocaine Incentive learning Maintenance Acquisition OF DRUG INTAKE

21. NEUROTRANSMITTERS INVOLVED INDRUG ADDICTION Dopamine, 1960s- Amino acids • GABA, 1970s- • Glutamate, 1980s, ‘90s- Endocannabinoids, 1990s-

22. THE ADDICTION CYCLE Drug euphoria Positive reinforcement Activated reward pathways Addictive agent Neuroadaptations Tolerance and withdrawal Drug administration Drug-seeking behavior Abstinence, then EXTINCTION Drug CRAVING Negative reinforcement Dysregulated reward pathways Loss of control, RELAPSE Denial/poor decision-making Exposure to low doses of drug, stress, and drug-related cues Limbic activation (modified from Dackis & O’Brien 2005)

23. THE ADDICTION CYCLE (modified from Dackis & O’Brien 2005) Repeated Administration Drug euphoria Positive reinforcement Activated reward pathways Repeated Addictive agent Neuroadaptations Tolerance and withdrawal Drug administration Drug-seeking behavior Abstinence, then EXTINCTION Drug CRAVING Negative reinforcement Dysregulated reward pathways Loss of control, RELAPSE Denial/poor decision-making Exposure to low doses of drug, stress, and drug-related cues Limbic activation Dopamine Glutamate and/orGABA

25. POINTS TO REMEMBER • What is drug addiction? • What is the brain’s reward system? • Drugs of abuse and the reward system • Conditioning and environmental cues as factors in (1) tolerance and withdrawal

26. Pavlovian conditioning • Over 100 years ago, Ivan Pavlov demonstrated that dogs presented with meat powder would salivate. If the presentation was paired with a neutral stimulus, such as a tone, and this was done repeatedly, eventually the presentation of the tone alone caused increased salivation. This is an example of Pavlovian conditioning.

30. Tolerance develops when psychoactive drugs are administered repeatedly over time, and itbecomes necessary to increase their dosage toobtain the original response. Tolerance reflects, in part, the brain’s attempt to oppose the drug-inducedchanges of normal brain activity - therefore a com- pensatory mechanism. Environmental (conditioned) cues play a major role in the development of tolerance.

31. M-HP

32. Strobe light

33. Do environmental cues influ-ence the toxicity and lethality of drugs of abuse?

34. - “In interviews with a number of human ‘overdose’ survivors, the majority of respondents reported that the circumstances of drug administration were atypical on the occasion of the overdose, that is, the usual drug-associated cues were not present when the ‘overdose’ occurred. from Siegel & MacRae, 1984

35. Withdrawal symptoms are generally opposite in character to the drug-induced effects. Withdrawal is not a direct effect of the drug. It is a reflection of the brain’s inability to “turn off” the compensatory response at the same rate as the decline of brain levels of the drug after stopping its administration. Exposure of addicts to drug-associated cues (environ-mental, thoughts, etc.) may trigger withdrawal-like symptoms even in the absence of any drug, accompanied by craving and relapse.

36. CONDITIONED RESPONSE mild version of above symp- toms, which are opposite to drug effects CONDITIONED WITHDRAWAL IN A DEPENDENT SUBJECT WHEN DRUG (e.g. Heroin) IS STOPPED receptors no longer occupied WITHDRAWAL SYMPTOMS rebound activity, e.g. tearing, running nose, tachycardia, diarrhea, etc., which are opposite to drug effects UPON RETURNING TO PLACE OF DRUG USE environmental cues, such as sights, smells, sounds, situations, fantasies of previous drug use

37. AN EXAMPLE OF CUE-INDUCED CRAVING AND RELAPSE IN A FORMER HEROIN ADDICT A 28 yr old patient had a 10 yr history of narcotic addiction. While addicted, he was arrested and incarcerated for 6 months.He experienced severe withdrawal during the first 4-5 days, but later began to feel well. He gained weight, felt like a new man, and decided that he was finished with drugs. Upon being released, he began thinking of drugs and felt nauseated. As the subway approached his stop, he began sweating, tearing from his eyes, and gagging.

38. The subway stop was an area where he had frequently experienced withdrawal symptoms while trying to acquire drugs. As he got off the subway, he vomited on the tracks. He soon bought drugs, and was relieved. The following day he again experienced craving and withdrawal, and again relieved them by injecting heroin. The cycle repeated itself over the next few days and soon he became readdicted. from Siegel, 1988

39. “...the RELAPSE RATE of military personnel addicted to opiates during the Vietnam war and detoxified in Vietnam before return to the United States is much lower than that of civilian opiate addicts treated in a federal treatment program.” From Hinson & Siegel, 1982

40. POINTS TO REMEMBER • What is drug addiction? • What is the brain’s reward system? • Drugs of abuse and the reward system • Conditioning and environmental cues as factors in (1) tolerance and withdrawal and (2) craving, relapse, and extinction

41. CRAVING, RELAPSE, AND EXTINCTION RELAPSE refers to the reinstatement of drug-seeking and drug–taking behavior after a period of abstinence (weeks, months, even years) from the drug. Intense CRAVING generally precedes relapse. EXTINCTION is the apparent diminution or loss of drug-seeking and drug-taking behavior after a period of abstinence (weeks, months, even years) from the drug.

42. FACTORS THAT TRIGGER CRAVING AND RELAPSE IN DRUG ADDICTION • Primer doses of drug • 2. Environmental and drug-associated cues 3. Stress .

43. Drug present Drug absent Drug cue (tone) or Drug inj. or exposure to stress days, weeks tone on tone on tone off STAGES OF DRUG-TAKING BEHAVIOR, EXTINCTION, AND THE EFFECTS OF PRIMING, STRESS AND DRUG-ASSOCIATED CUES ON REINSTATEMENT (RELAPSE) Mainten- ance Extinction Reinstatement tests Initiation Number of responses (lever presses) Session

44. POINTS TO REMEMBER • What is drug addiction? • What is the brain’s reward system? • Drugs of abuse and the reward system • Conditioning and environmental cues as factors in tolerance and withdrawal • Stress as a factor in the addiction process

45. Rats exposed to stress, and especially to repeated stress, tend to exhibit in-creased exploratory behavior and increased amphetamine self-adminis-tration.

47. Offsprings of mothers that had been stressed during the third trimester of pregnancy exhibited greater sensitivity to the actions of amphetamine and self-administered more amphetamine than did offsprings from nonstressed mothers. Remember, neither the mother nor the off-springs had ever been exposed to amphetamine previously.

50. REINSTATEMENT OF WITHDRAWAL SYMPTOMS IN RESPONSE TO “STRESS” (ANGRY MOOD) ‘Angry’ incident 8 7 6 Withdrawal Score 5 4 3 2 16 17 18 19 20 21 22 23 24 25 26 27 28 SESSIONS