Drug Addiction

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
• (µ, 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
  addicts 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 cortexs 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)