5.1. Addiction: Neural mechanisms of drug reward

Brainstem

= midbrain, pons, medulla

Major striatum components

Nucleus accumbens

Caudate

• Dorsomedial striatum in

rodents (DMS)

Putamen

• Dorsolateral striatum in

rodents (DLS)

Nucleus accumbens (core and shell)

Pleasure, motivation, reward cues

Dorsomedial striatum (DMS, caudate)

Goal-directed actions

Flexible, rapidly acquired behaviors

Dorsolateral striatum (DLS, putamen)

Habits

Striatum and dopamine

Striatum is a major target of dopamine (DA) axon terminals in the brain

*There are no DA neurons in striatum. The cell bodies for DA neurons are located in the brainstem and they send axon projections to striatum. Therefore, striatum has lots of DA fibers, DA release at synapses, and DA receptors/transporters

Monoamine neurons

(dopamine, norepinephrine, serotonin) are located primarily in brainstem. The cell bodies (somas) are in brainstem, but they send axon projections throughout the brain.

Dopamine neurons (cell bodies)

are in the substantia nigra and ventral tegmental area (VTA) in the midbrain.

Dopamine (DA) pathways: Nigrostriatal pathway

Source: DA neurons in substantia nigra

Target of axons: dorsal striatum

Dopamine (DA) pathways: Mesolimbic pathway

Source: DA neurons in VTA

Target: nucleus accumbens and amygdala

Dopamine (DA) pathways: Mesocortical pathway

Source: DA neurons in VTA

Target: prefrontal cortex

Dopamine influences basal ganglia circuits

Basal ganglia (BG) circuits (loops) are important for:

Voluntary movement

Action selection

Procedural learning

Habits

Globus pallidus internal (GPi), substantia nigra (SNr)

Basal ganglia: Inputs and outputs

Major input structures (cortex) are glutamatergic (excitatory).

Major output structures (GPi, SNr) are GABAergic (inhibitory).

Basal ganglia: Direct and indirect pathways

Striatum projections (also GABAergic) either

go directly to output structures or indirectly

- Direct pathway excites targets of

BG output ("Go"). GABA acting on GABA neurons

- Indirect pathway inhibits targets of

BG output ("No-Go").

Basal ganglia: Feedback

Midbrain dopamine and thalamus provide feedback in the system and complete the loops.

Dopamine influences direct and indirect pathways

- In the striatum, half of GABA neurons express

dopamine D1 receptor (Gs) and half express dopamine D2 receptor (Gi).

- D1 neurons are part of the direct pathway

("go"), which is activated by dopamine.

- D2 neurons are part of the indirect pathway

("no-go") which is inhibited by dopamine.

Neural mechanisms of drug reward

All addictive drugs share the common property of

increasing dopamine (DA), although via different mechanisms.

Reward learning: Liking

"Liking" is the pleasurable aspect of reward.

Liking does not require dopamine!

Reward learning: Wanting

- "Wanting" is the motivational drive to obtain (work for) rewards.

- Wanting involves dopamine.

Reward learning: Reward prediction (1)

- Dopamine neurons increase in firing rate when a

reward is given unexpectedly.

- increased firing when presented with a conditioned stimulus (CS) that predicts reward, and not to the reward itself.

- if reward is omitted, then a decrease in dopamine neuron

firing is observed. reward prediction error.

Reward learning: Reward prediction (2)

- positive prediction error

- zero prediction error

- negative prediction error

Therefore, dopamine serves as a teaching signal for learning

about rewards

Reward learning: Reward prediction and D1/D2

- Positive prediction error activates D1 cells (Gs coupled) and direct pathway

- negative prediction error activates D2 cells (Gi coupled) and indirect pathway

Neural mechanisms of drug reward (2)

1. Properties of the drug

2. Individual differences (genetic and environmental)

3. Drug-induced neuroadaptations