DRUG ADDICTION AND REWARD

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DRUG ADDICTION AND REWARD

• 60 MILLION PEOPLE ADDICTED TO NICOTINE, ALCOHOL
  OR BOTH.
• 5.5 MILLION PEOPLE ARE ADDICTED TO ILLEGAL DRUGS.
• 4 MILLION ARE ADDICTED TO PRESCRIPTION DRUGS.

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FIVE COMMONLY ABUSED DRUGS

• TOBACCO
• NEXT TO CAFFEINE, TOBACCO IS THE MOST WIDELY
  ABUSED DRUG IN OUR SOCIETY.
• NICOTINE IS THE MAJOR PSYCHOACTIVE INGREDIENT OF
  TOBACCO.

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TOBACCO

• CONSIDERABLE TOLERANCE DEVELOPS TO SOME OF THE
  IMMEDIATE ADVERSE EFFECTS OF TOBACCO.
• -NON-SMOKER.
• -SMOKER.

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TOBACCO

• HEAVY SMOKERS WHO STOP SMOKING CAN EXPERIENCE
• DEPRESSION, ANXIETY, RESTLESSNESS, IRRITABILITY,
  CONSTIPATION, DIFFICULTIES IN SLEEPING AND
  CONCENTRATION.

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LONG-TERM TOBACCO USE

• SMOKERS SYNDROME--CHEST PAIN, LABORED BREATHING,
  WHEEZING, COUGHING, INCREASED SUSCEPTIBILITY TO
  INFECTIONS OF THE RESPIRATORY TRACT.
• LETHAL LUNG DISORDERS--PNEUMONIA, BRONCHITIS,
  EMPHYSEMA, LUNG CANCER.

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LONG-TERM TOBACCO USE

• OTHER CANCERS--MOUTH, THROAT, KIDNEYS, PANCREAS,
  BLADDER AND STOMACH.
• CARDIOVASCULAR DISEASE--CULMINATING IN HEART
  ATTACK OR STROKE.

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ALCOHOL

• APROXIMATELY 2/3 OF THE POPULATION CONSUME
  ALCOHOLIC BEVERAGES.
• OF THESE, 15 MILLION ARE ADDICTED.

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ALCOHOL

• MODERATE DOSES--COGNITIVE, PERCEPTUAL, VERBAL AND
  MOTOR IMPAIRMENT.
• CAN ALSO LEAD TO INTERESTING BEHAVIORS IN SOCIAL
  SITUATIONS.

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ALCOHOL

• HIGH DOSES--UNCONCIOUSNESS AND RISK OF DEATH FROM
  RESPIRATORY DEPRESSION.

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ALCOHOL WITHDRAWAL

• 5 OR 6 HOURS AFTER CESSATION OF A LONG BOUT OF
  DRINKING.
• -SEVERE TREMORS, AGITATION, HEADACHE, NAUSEA,
  VOMITING, ABDOMINAL CRAMPS, PROFUSE SWEATING AND
  HALLUCINATIONS.

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ALCOHOL WITHDRAWAL

• 15-30 HOURS.
• -CONVULSIVE ACTIVITY.

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ALCOHOL WITHDRAWAL

• 2-3 DAYS.
• DELERIUM TREMENS (DTs).
• DISTURBING HALLUCINATIONS, DELUSIONS, AGITATION,
  CONFUSION, HYPERTHERMIA AND RAPID HEARTBEAT.

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CHRONIC ALCOHOL CONSUMPTION

• EXTENSIVE BRAIN DAMAGE.
• CIRRHOSIS OF THE LIVER.
• HEART DAMAGE.
• GI TRACT DAMAGE.
• TRAFFIC FATALITIES.

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ALCOHOL AND DEVELOPMENT

• LIKE NICOTINE, ALCOHOL READILY PENETRATES THE
  PLACENTAL MEMBRANE AND AFFECTS THE FETUS.
• FETAL ALCOHOL SYNDROME (FAS).

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ALCOHOL HAS MULTIPLE SITES OF ACTION

• CALCIUM CHANNELS.
• GABA RECEPTORS.
• GLUTAMATE RECEPTORS.
• 2ND MESSENGER SYSTEMS.

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MARIJUANA

• THE PSYCHOACTIVE EFFECTS OF MARIJUANA ARE LARGELY
  ATTRIBUTABLE TO A CONSTITUENT CALLED THC
  (DELTA-9-TETRAHYDROCANNABINOL).

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HAZARDS

• LUNG DAMAGE.
• MORE LIKELY TO DEVELOP CHRONIC BRONCHITIS AND
  ASTHMA.

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MECHANISM OF ACTION

• THC BINDS TO RECEPTORS THAT ARE DENSE IN THE
  BASAL GANGLIA, HIPPOCAMPUS, CEREBELLUM AND
  NEOCORTEX.

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POT AND THE BRAIN
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ENDOGENOUS LIGAND?

• RECENTLY, THE GENE FOR THE THC RECEPTOR HAS BEEN
  CLONED.
• TRIGGERED RESEARCH FOR AN ENDOGENOUS THC-LIKE
  CHEMICAL.
• ANANDAMIDE.

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COCAINE

• COCAINE HYDROCHLORIDE.
• USERS REPORT BEING SWEPT AWAY BY A WAVE OF
  WELL-BEING.
• CONFIDENT, ALERT, ENERGETIC, FRIENDLY, OUTGOING,
  FIDGETY, TALKATIVE.

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HAZARDS

• RISK OF SEIZURES, LOSS OF CONCIOUSNESS, DEATH
  FROM RESPIRATORY ARREST OR STROKE.
• INSOMNIA, TREMORS, NAUSEA AND PSYCHOTIC BEHAVIOR.

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MECHANISM OF ACTION

• EXERTS BEHAVIORAL EFFECT BY FACILITATING
  CATECHOLAMINERGIC TRANSMISSION.
• HOW?

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OPIATES

• EXTRACTED FROM SAP OF SEEDS FROM THE OPIUM POPPY.
• MORPHINE AND CODEINE.

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OPIATES

• HEROIN IS A SYNTHESIZED OPIATE.
• ADDITION OF 2 ACETYL GROUPS TO THE MORPHINE
  MOLECULE.

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OPIATES

• THE EFFECT OF OPIATES MOST VALUED BY OPIATE
  ADDICTS IS THE RUSH THAT FOLLOWS IV INJECTION.
• OPIATES ARE HIGHLY ADDICTIVE.

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COLD TURKEY?

• SYMPTOMS OF OPIATE WITHDRAWAL HAVE BEEN GREATLY
  EXAGGERATED.
• MAIN RISKS OF OPIATE ADDICTION ARE INDIRECT.

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MECHANISM OF ACTION

• BIND TO OPIATE RECEPTORS.
• ENDOGENOUS LIGAND?
• ENDORPHINS.

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BIOPSYCHOLOGICAL THEORIES OF ADDICTION

• PHYSICAL-DEPENDENCE THEORY
• POSITIVE-INCENTIVE THEORY
• -PRIMARY REASON MOST ADDICTS TAKE DRUGS IS TO
  OBTAIN THE PLEASURABLE EFFECTS OF THE DRUG.

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ROBINSON AND BERRIDGE(1993)

• ARGUE THAT IT ISNT THE PLEASURE OF DRUG TAKING
  PER SE THAT IS THE BASIS OF ADDICTION IT IS THE
  ANTICIPATED PLEASURE OF DRUG TAKING.

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REWARD CIRCUITS IN THE BRAIN

• OLDS AND MILNER (1954)
• INTRACRANIAL SELF-STIMULATION.

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ICSS

• ANIMALS WILL PERFORM A RESPONSE, SUCH AS PRESSING
  A LEVER, IN ORDER TO ADMINISTER BRIEF BURSTS OF
  ELECTRICAL STIMULATION TO SPECIFIC SITES IN THEIR
  OWN BRAIN.

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ICSS
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OLDS AND MILNER (1954)

• ARGUED THAT THE SPECIFIC BRAIN SITES THAT MEDIATE
  SELF-STIMULATION ARE THOSE THE NORMALLY MEDIATE
  THE PLEASURABLE EFFECTS OF NATURAL REWARDS (FOOD,
  SEX, WATER).

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REWARD CIRCUIT VIEW OF ICSS

• 1) BRAIN STIMULATION THROUGH ELECTRODES THAT
  MEDIATE SELF-STIMULATION OFTEN ELICITS NATURALLY
  MOTIVATED BEHAVIORS.
• 2) INCREASES IN NATURAL MOTIVATION INCREASES
  SELF-STIMULATION RATES.

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REWARD CIRCUIT VIEW OF ICSS

• 3) LEVER PRESSING FOR STIMULATION AT SOME BRAIN
  SITES IS OFTEN QUITE SIMILAR TO LEVER PRESSING
  FOR NATURAL REWARDS.

• Acquisition is slow.
• Response rates are low.
• Extinction is slow.
• Priming not necessary.

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THE DOPAMINE SYSTEM

• THIS ASCENDING NEUROTRANSMITTER SYSTEM PLAYS A
  PARTICULARLY IMPORTANT ROLE IN ICSS.
• NEURONS OF THIS SYSTEM HAVE THEIR CELL BODIES IN
  2 MIDBRAIN NUCLEI.
• SUBSTANTIA NIGRA AND THE VENTRAL TEGMENTAL AREA.

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NEUROANATOMICAL NOTE

• SUBSTANTIA NIGRA--gtSTRIATUM (NIGROSTRIATAL
  SYSTEM).
• VTA--gtLIMBIC AND CORTICAL STRUCTURES
  (MESOCORTICAL SYSTEM).
• VTA--gtNUCLEUS ACCUMBENS.

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EVIDENCE

• MAPPING STUDIES MANY OF THE BRAIN SITES AT WHICH
  ICSS OCCURS ARE PART OF THE DOPAMINE SYSTEM.
• CEREBRAL DIALYSIS STUDIES MICRODIALYSIS.

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EVIDENCE

• 3) DOPAMINE AGONIST AND ANTAGONIST STUDIES
• 4) LESION STUDIES

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NEURAL MECHANISMS OF ADDICTION

• TWO BEHAVIORAL PARADIGMS HAVE BEEN USED
  EXTENSIVELY IN THE STUDY OF THE NEURAL MECHANISMS
  OF ADDICTION

• Drug self-administration paradigm.
• Conditioned-place preference (CPP).

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SELF-ADMINISTRATION
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CPP
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DOPAMINE AND ADDICTION

• LAB ANIMALS SELF-ADMINISTER MICROINJECTIONS OF
  ADDICTIVE DRUGS DIRECTLY INTO BRAIN AREAS
  INNERVATED BY THE DOPAMINE SYSTEM BUT NOT OTHER
  BRAIN AREAS.

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DOPAMINE AND ADDICTION

• INTRACRANIAL INJECTIONS INTO SIMILAR BRAIN AREAS
  PRODUCE CPPS.
• ADDICTIVE DRUGS INCREASE REWARDING EFFECTS OF
  ELECTRICAL STIMULATION.

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DOPAMINE AND ADDICTION

• DISRUPTION OF DOPAMINE SYSTEM WITH SELECTIVE
  LESIONS OR ANTAGONISTS REDUCE THE REWARDING
  EFFECTS OF ADDICTIVE DRUGS.

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DOPAMINE AND ADDICTION

• IN-VIVO VOLTAMMETRY AND MICRODIALYSIS RECORDINGS
  FROM THE NUCLEUS ACCUMBENS HAVE SHOWN THAT
  SELF-ADMINISTRATION OF MOST ADDICTIVE DRUGS IS
  ASSOCIATED WITH INCREASED DOPAMINE RELEASE.

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MULTIPLE MEMORY SYSTEMS AND DRUG ADDICTION

• This theoretical view focuses on various learning
  and memory systems in which the normal functions
  of these complex neural circuits become subverted
  leading to compulsive drug seeking behaviours.
• White, 1996 Everitt et al., 2001.

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MULTIPLE MEMORY SYSTEMS AND DRUG ADDICTION

• Amygdala?acquires information that promotes
  approach and interaction with drug associated
  stimuli.
• Dorsal striatum?promotes the acquisition of
  stimulus-response (S-R) habits.
• Hippocampus?acquire information about the context
  in which drug stimuli are obtained.

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MULTIPLE MEMORY SYSTEMS AND DRUG ADDICTION

• Powerful plasticity processes and associated
  memories are formed during drug experiences that
  come to dominate behavioural control.

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GDE FACTORS

• These factors could produce an organizational
  change in the relationship of these
  memory/behavioural systems to one another, and
  with other brain systems that could make an
  individual more susceptible to drug addiction.

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SCENARIO 1

• Enhanced behavioural control exhibited by one
  memory/behavioural system.
• Ease of access to common output sites.
• Enhanced plasticity processes.

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Striatum
Hippocampus
Memory Systems Interaction
Amygdala
Addictive
Habit dominance
GDE factors
Behaviour
Nucleus Accumbens
Prefrontal Cortex
Brainstem nuclei
Other Neural Systems
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SCENARIO 2

• Bigger reward signal occurring when drugs of
  abuse are administered.
• Result in an acceleration of specific types of
  learning and memory processes associated with
  compulsive drug seeking.

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SCENARIO 3

• Reduction of inhibitory control.
• Could result in alterations in behavioural
  control because of a loss of a contribution from
  executive systems necessary for appropriate
  choice behaviours.

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Striatum
Amygdala
Hippocampus
Memory Systems Interaction
Addictive
Decreased Inhibitory Control
GDE factors
Prefrontal Cortex
Brainstem nuclei
Nucleus Accumbens
Behaviour
Other Neural Systems
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FUTURE WORK

• Need to emphasize the dynamic and interactive
  nature of these systems.
• Particularly when trying to develop treatment
  regimes.

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FUTURE WORK

• The logic behind this claim is that it appears
  that certain drugs of addiction modulate
  plasticity processes in specific learning and
  memory systems but not in others.
• While another drug of abuse might have a
  different pattern of influences.

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FUTURE WORK

• Certain addictions might be based on certain
  neural circuits while addictions to another drug
  could be mediated by a different set of neural
  circuits.
• Examples.