Elaboration of case 3: addiction is a brain disease

Addiction
Case 3
Addiction is a brain disease
Problem statement: “?”
Learning goals:
I. How does the reward system work normally and within addiction?
II. What is the dopaminergic pathway of addiction?
III. What is the difference between a healthy and a drug addicted brain?
IV. What determines the maintenance of the addiction?
V. What neurobiological treatments are there for addiction?

BDMA: Brain Disease Model of Addiction " addictive behaviors change the brain in various ways,
which makes repeated relapse more likely, including changes in reward sensitivity, stress reactivity
and negative affect, and reduced cognitive control and self-regulation.
 Addiction is a chronic disease.

How does the reward system work normally and within addiction? i
Chemicals in drugs boost the activity of the brain’s reward system ultimately.
 A complex circuit of neurons which gives pleasure and encourages to repeat the activity.
o The reward by drug-stimulation is greater than any neutral reward.
 The pathway extends from the dopamine-producing nerve cells (neurons) of the ventral
tegmental area (VTA) to dopamine-sensitive cells in the nucleus accumbens.
= The mesocorticolimbic dopamine system
o Stimulation of this pathway by cues reinforces drug-behaviors, leading to relapse.
 Involved brain regions:
o Ventral tegmental area (VTA):
 “Tells” other brain centers how rewarding an activity is.
 VTA-neurons communicate by dispatching dopamine from the axon-
terminals to receptor-neurons on nucleus accumbens.
o Drugs cause a higher sensitivity to dopamine in the nucleus
accumbens.
o Animals with lesions in VTA or nucleus accumbens show no interest
in drugs.
 All the regions talk to the reward pathway by releasing glutamate.
o Changes in the sensitivity to glutamate in the reward
pathway enhance both the release of dopamine from the
VTA and responsiveness to dopamine in the nucleus
accumbens " promoting CREB- and delta FosB-activity, and
the unpleasant effects of these molecules.
o The glutamate-sensitivity also strengthens the neuronal
pathways that link memories of drug-taking experiences
with high reward " desire to drug-seeking.
o Striatum:
 Forming habits; routines of behavior we do without thinking.
 Processing reward.
o Amygdala:
 Helps to determine whether an experience is pleasurable or aversive
 Determines whether the behavior should be repeated

,  Creates connections between an experience and other cues
 Emotion regulation
o Hippocampus:
 Forming memories and learn of an experience (incl. where, when, with who)
o Frontal cortex:
 Coordinate and process all this information and determine the ultimate
behavior.
Chronic/repeated drug-use causes changes in the structure and function of the reward system,
causing lower pleasurable effects, increased cravings, tolerance, and dependence.
 Tolerance and dependence occur because frequent drug use can suppress parts of the
brain’s reward circuit.
o CREB (cAMP response element-binding protein) is a transcription factor; regulates
the expression/activity of genes, and thus neuron-behavior
 cAMP gets active because of the dopamine in the nucleus accumbens, which in
turn activates CREB. After CREB is turned-on it binds to a specific set of genes,
triggering production of the proteins the genes encode.
 Chronic drug use causes sustained activation of CREB, which enhances
expression of its target genes, some of which code for proteins that inhibit
the reward circuitry " causing tolerance by making the same-old dose of
drugs less rewarding.
 CREB is switched off in days after drug-use stops, and thus can’t account for
long-lasting drug abuse.
 Relapse is driven by sensitization = reinforcement of the drug-effect.
o Sensitization is caused by delta FosB (transcription factor).
 Delta FosB concentrations rise gradually and
progressively in the nucleus accumbens.
 It remains active in these neurons for weeks to
months after drug-administration, causing
hypersensitivity to drugs.
o Sensitization is also caused by sprouting of dendritic spines;
they support the cells’ connections to other neurons.
 Delta FosB is responsible for the added spines
months after drug-use.
 By the sprouting, there is heightened signaling "
overreaction to drug-related cues.
All drugs of abuse cause the nucleus accumbens to receive a flood of dopamine  this explains why
all drugs can be addictive.