Drug Addiction The Brain

1. Drug Addiction & The Brain According to a 2004 report, the WHO estimates that over 200million people are addicted to drugs. Defining characteristic of drug addiction Continued Compulsive & Out-of-Control drug use despite serious negative consequences.

2. Examples of Addiction Loss of Job & Home Loss of family Cirrhosis Depression Many addicts continue despite such adverse effects.

3. The central question of addiction: What happens in the brain to cause an addicted person to lose control of drug-taking behavior despite such serious consequences? What neurophysiological changes are associated with the addiction cycle?

4. Common Drugs of Abuse Cocaine & Amphetamines Opiates Alcohol Cannabinoids Nicotine Each works by increasing the amount of dopamine in the synapses of the mesocorticolimbic dopamine system.

5. Dopamine is Found in Nigrostriatal Mesolimbic Mesocortical

6. Cocaine Inhibits all 3 monoamine uptake transporters, (dopamine, serotonin, and norepinephrine), thereby increasing the amount of monoamines in the synapse and potentiating monaminergic transmission.

7. Amphetamines Increases release of monoamines. Inhibits all 3 monoamine uptake transporters. Inhibits monoamine oxidase.

8. Dopamine system appears to be the critical substrate for the rewarding effects of cocaine & amphetamines. All 3 dopamine receptor subtypes have been implicated. D1, D2, D3

9. Cocaine & Amphetamines Located in Mesocorticolimbic Dopamine system.

10. Opiates Opioids activate specific receptors (�, d, & ?) that couple with G-proteins

11. Opiates Results in 1) inhibition of adenylyl cyclase, 2) activation of inwardly rectifying Potassium channels, 3)inhibition of Calcium channels. Opiate receptors mediate inhibitory responses, & reduce membrane excitability

12. Opiates Opiate appear to operate on the Ventral Tegmental Area Inhibits GABA & The Nucleus Accumbens Increases dopamine activity

13. Alcohol At low doses of alcohol, dopamine is involved in the rewarding effects of alcohol. Appears to modify the activity of serotonin receptors, nicotinic receptors, & GABBA receptors. Is believed to activate opioid peptide systems. Mice with blocked mu opioid receptors do not drink alcohol.

14. Alcohol The ventral tegmental area The basal forebrain

15. Cannabinoids THC binds to G-protein-coupled cannabinoid-1 receptors. They are densely distributed in the Basal ganglia Cerebral-cortex regions Neural substrates The mesocorticolimbic dopamine system Increases the release of dopamine in the shell of the nucleus accumbens Inhibits excitatory glutamatergic neurotransmission in the substantia nigra.

16. Nicotine Is a direct agonist at nicotinic acetylcholine receptors which are widely dispersed throughout the brain. Nicotinic receptors implicated in reinforcing effects of nicotine are localized in the mesocorticolimbic dopamine system. Increases dopamine neurotransmission & energy metabolism in the nucleus accumbens. Also appears to influence opioid peptide systems.

17. First use is for pleasure, but subsequent usage becomes compulsive. Long term use of drugs causes neurophysiological adaptations and disrupts reward system Tolerance, Sensitization, & Withdrawal

18. Tolerance Leads to modifications of drug use to obtain desired effects, by increasing the dose, or increasing the frequency of use or both. The increased drug use causes deregulations in the reward system as the brain adapts to the over stimulation induced by drug use.

19. Tolerance Some people are able to maintain the same initial dosage by spacing out their usage. However, drug dependence develops when they begin using them more frequently so that tolerance begins to develop. In one experiment ex-addict volunteers were allowed to self-administer heroin or morphine. Eventually, the maximum permissible doses were taken. One guy escalated is dose ten thousand times what was initially effective and he still demanded more.

20. Metabolic Tolerance The body (primarily the liver) adapts by getting better at destroying the drug Each repetition of the initial dose provides less drug for shorter and shorter times at the sites of action in the brain; so progressively higher doses are needed (Goldstein, 2001). Example: Pentobarbital, a short-acting barbiturate used as a sleeping pill. An initial dose is sufficient to cause sleep and remains in the blood for a few hours. But with repeated dosage, the drug is destroyed mor and more reapidly and thus becomes less effective. (Goldstein, 2001).

21. Cellular Tolerance Neurons adapt to the drug becoming less sensitive to it with continued exposure. The underlying neurochemical adaptation is masked by the apparent normality of brain function. But these adaptations become apparent when the drug is withdrawn. (Goldstein, 2001).

22. Tolerance Example: Opiates Opioid tolerance: Prolonged use decreases the number of opioid receptors and desensitizes them, and can lead to their being internalized by the neuron. (Figure from Stahl, 2002)

23. Tolerance

24. Sensitization The opposite of tolerance: brain becomes more sensitive to effects of drug. May act to increase the incentive salience of the drug and thereby contribute to compulsive drug use. Increases craving and vulnerability to relapse even after years of successful detoxification. Usually seen with stimulants, opioids, and nicotine. Brain microdialysis studies have shown an increase in transmitter release to a standard dose of drug. (Nutt, 1997)

25. Sensitization is associated with Alterations in the mesocorticolimbic dopamine system, Particularly in glutamate & dopamine transmission in the nucleus accumbens. Elevated levels of glutamate receptors Long-lasting alterations in patterns of gene expression in the terminal mesolimbic dopamine systems.

26. Sensitization Repeated use of cocaine & amphetamine increases the number of dendritic branch points & spines on neurons in the nucleus accumbens and medial prefrontal cortex.

27. Withdrawal Results from the neurochemical adaptations in the brain associated with tolerance, and is observed when the drug is removed. (Goldstein, 2001) The symptoms of withdrawal are usually opposite of the effects of the drug. (Goldstein, 2001) Compels addicts to resume drug use to prevent or reduce physical symptoms and dysphoria. (Cami & Farre, 2003)

28. Withdrawal: Opiates Chronic activation of opioid receptors produces effects opposite to those of acute activation. It upregulates cyclic adenosine monophosphate (cAMP) signaling pathways. Tolerance to the inhibitory effects of the opioids occurs in the locus ceruleus. The locus ceruleus regulates arousal, stress responses, and the autonomic nervous system. When opiate levels fall, there is an increase in activity in the locus ceruleus. Without the inhibitory effects of opiates, the locus ceruleus becomes over active.

29. Withdrawal The over activity of the locus ceruleus is associated with the severe dysphoria associated with opiate withdrawal. The intense feelings of dysphoria that is associated with withdrawal often serve as motivation to continue drug use. Continuing drug use is negatively reinforcing in that it removes the unpleasant effects of withdrawal.

30. Stress Systems Drug use & withdrawal activate peripheral & central stress systems. Short-term use elevates glucocorticoid levels & CRF levels. (Camil & Farre, 2003)

31. Stress Systems These hormonal elevations have been related to the rewarding properties of drug use. During withdrawal, an increase in CRF in the amygdala has been related to stress & the negative effects of abstinence (Camil & Farre, 2003)

32. Homeostasis Homeostatic adaptations can be understood as compensatory responses of cells or circuits to excessive stimulation due to chronic drug intake. These adaptations tend to dampen drug effects and produce tolerance and withdrawal. Are reversible: with extended abstinence, the homeostatic adaptations dissipate.

33. Homeostasis Homeostatic mechanisms cannot account for addict�s tendency to relapse long after withdrawal symptoms have disappeared. Relapse often occurs upon exposure to situational cues associated with drug use. Thus part of the addiction process involves associative learning.

34. Neuroimaging & The Frontal Cortex Recent neuroimaging studies have implicated the frontal cortex in addiction. Loss in volume of the frontal lobe has been associated with drug addiction. Cocaine abuse results in morphological changes in dendrites & dendritic spines in the prefrontal cortex & the nucleus accumbens.

35. The Frontal Cortex & Intoxication Prefrontal cortex & anterior cingulate gyrus are active during intoxication. Activation in those areas is also associated with the subjective experience of intoxication & its reinforcing effects.

36. The Frontal Cortex & Craving Cocaine abusers exposed to a video depicting drug-related stimuli exhibited greater activation in the pre-frontal and anterior cingulate. (Figure from Goldstein & Volkow, 2002)

37. The Frontal Cortex & Learning in Addiction Alterations in the frontal cortex may be involved in learning new addictive behaviors. One of the functions of the frontal cortex is to regulate goal-oriented behavior. The over activation of dopamine in the frontal cortex areas, as a result of drug abuse, alters the frontal cortex�s ability to regulate goal-oriented behavior.

38. The Frontal Cortex & Learning in Addiction The result is an overvaluing of drug reinforcers & an undervaluing of alternative reinforcers. This shift in value of reinforcers contributes to deficits in inhibitory control & compulsive drug abuse.

39. Expectation & Brain Function in Drug Abuse Reinforcing effects of drugs represent a complex interaction between pharmacological effects and conditioned responses. Expectation enhances the regional brain metabolic & reinforcing effects of stimulants in cocaine abusers. Expectation enhances pharmacological effects of stimulants by amplifying dopamine & norepinephrine signals by blocking their transporters.

40. Expectation & Brain Function in Drug Abuse

41. Vulnerability to Addiction Personality Factors Risk-taking or novelty seeking traits Psychiatric disorders Genetic Factors Children of alcoholic parents were more likely to develop alcoholism even when adopted and raised by non-alcoholic parents.

42. Vulnerability to Addiction Environmental Factors Can alter the reinforcing effects of drugs, particularly cocaine. Drug availability Availability of alternative reinforcers Living in an enriched environment Social status

43. Vulnerability to Addiction Social Dominance in monkeys can influence the Rewarding effects of cocaine. Morgan & colleagues (2002) used PET imaging to study dopanergic activity & measured the amount of cocaine self-administration in monkeys.

44. D2 receptors increase in dominant monkeys. (Morgan et al., 2002)

45. Subordinate monkeys self-administered more cocaine(Morgan et al., 2002) What about drdug taking? The investigators took the same naimals and put hten into a cocaine self-adminstration protocol in which the naimal presssed a levelr to get cocaine. The dominant animals are in green. None of the lever presses among these naimals reached stasticaly significate. This study showed no only the clear assocaition between low levels of dopamine D2 receprr and vulnerabilyt to drug abuse, but he apprent role of hgih level of DA D2 receptors as a protectiona ginast the self-adminstration of high doses of drugs. This brings to light the very interstin gsuggestion that the neivoenrment, in this case a social variable, produces neurobiological hcanges in the brain, which may regulate the adminstraiton of drugs.What about drdug taking? The investigators took the same naimals and put hten into a cocaine self-adminstration protocol in which the naimal presssed a levelr to get cocaine. The dominant animals are in green. None of the lever presses among these naimals reached stasticaly significate. This study showed no only the clear assocaition between low levels of dopamine D2 receprr and vulnerabilyt to drug abuse, but he apprent role of hgih level of DA D2 receptors as a protectiona ginast the self-adminstration of high doses of drugs. This brings to light the very interstin gsuggestion that the neivoenrment, in this case a social variable, produces neurobiological hcanges in the brain, which may regulate the adminstraiton of drugs.