Lecture 2 Block 2- Circuits

What is the central reward circuit involved in addiction

The mesolimbic dopamine system — composed of dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), with important inputs from the prefrontal cortex, amygdala, and hippocampus.

What is the function of the ventral tegmental area (VTA)?

contains DA-producing neurons that signal reward prediction and motivational salience, sending projections to limbic and cortical regions.

What is the nucleus accumbens (NAc)?

located in the ventral striatum, integrates dopaminergic input from the VTA and glutamatergic input from the prefrontal cortex, mediating motivation, reward, and reinforcement learning.

How does the prefrontal cortex (PFC) contribute to addiction?

The PFC regulates decision-making, impulse control, and executive functions. Chronic drug use weakens PFC control, leading to compulsive behavior.

What role does the amygdala play in addiction circuits?

It assigns emotional value to drug cues and mediates conditioned responses such as craving when exposed to drug-related stimuli.

What is the hippocampus's role in addiction?

It encodes contextual memories associated with drug use, which can later trigger craving and relapse when the individual is in a similar environment.

What is the medial forebrain bundle (MFB)?

A major white matter tract connecting the VTA to forebrain structures like the NAc and PFC; early electrical stimulation experiments showed it supports self-stimulation and reward behavior.

What neurotransmitters are key in the reward circuitry?

Dopamine (motivation and reinforcement), glutamate (learning and plasticity), and GABA (inhibitory control).

How does glutamate interact with dopamine in addiction circuits?

Glutamatergic projections from the PFC to the NAc and VTA regulate dopaminergic firing and plasticity, contributing to craving and relapse.

What are AMPA and NMDA receptors?

Ionotropic glutamate receptors critical for excitatory synaptic transmission; AMPA mediates fast depolarization, while NMDA receptors trigger calcium influx for long-term plasticity.

How does drug exposure change AMPA/NMDA receptor expression?

Simple summary

• Drugs → more AMPARs → stronger, more excitable synapses.

• Drugs → altered NMDARs → support long-term plasticity and learning related to addiction.

What is synaptic plasticity and how does it relate to addiction?

It's the ability of synapses to strengthen or weaken over time. Drugs hijack this mechanism, producing long-lasting neural changes that encode drug-related learning.

What is the "spiraling circuit" concept in addiction?

It describes the progressive recruitment of dorsal striatal circuits (habit and motor control) from initial ventral striatal involvement (reward and motivation) as addiction develops.

How does the anterior cingulate cortex function in addiction?

It detects conflict and errors, monitors reward expectations, and contributes to craving and relapse when overactivated by cues.

How does chronic drug use affect inhibitory control circuits?

It disrupts PFC-striatal loops, weakening top-down control over impulses and increasing compulsivity.

What role does the extended amygdala (including the bed nucleus of the stria terminalis) play?

It links stress, fear, and reward systems; hyperactivation during withdrawal contributes to negative affect and relapse.

Which circuits underlie the shift from voluntary to compulsive drug use?

The transition from mesolimbic (reward) to dorsal striatal (habit) control systems, reflecting neuroadaptations that make drug seeking automatic.

Binge/Intoxication-

ventral tegmental area (VTA), nucleus accumbens, dorsal striatum.

Withdrawal/Negative Affect -

extended amygdala (amygdala, BNST, nucleus accumbens shell).

Preoccupation/Anticipation -

prefrontal cortex, orbitofrontal cortex, hippocampus, amygdala.

Ventral striatum (nucleus accumbens) -

mediates reward and goal-directed behavior early in addiction.

Dorsal striatum -

mediates habitual and compulsive drug seeking during later stages.

Dopaminergic pathways:

Mesolimbic (VTA → NAc) - reward and motivation.
Nigrostriatal (substantia nigra → dorsal striatum) - habit learning and motor patterns.

How do different drugs affect the mesolimbic pathway? Stimulants:

directly increase dopamine release or block reuptake.

How do different drugs affect the mesolimbic pathway? Opiates

inhibit GABA interneurons in the VTA, disinhibiting dopamine neurons.

How do different drugs affect the mesolimbic pathway? Alcohol

increases dopamine indirectly via GABA and endogenous opioid systems.

How do different drugs affect the mesolimbic pathway? Nicotine

activates α4β2 nAChRs on VTA dopamine neurons.

How do different drugs affect the mesolimbic pathway? Cannabinoids

inhibit GABAergic inputs via CB1 receptors, enhancing dopamine firing.

What are positive and negative reinforcement, and how does this relate to previous models of addiction (e.g., opponent-processing model)?

Positive reinforcement: drug taking increases because it produces pleasure (a-process).
Negative reinforcement: drug taking increases because it alleviates withdrawal (b-process).These mechanisms correspond to stages in the opponent-process model, explaining the shift from pleasure-driven to relief-driven use.

Can you explain between-system and within-system adaptations?

Within-system adaptation: changes occur in the same circuit affected by the drug (e.g., receptor downregulation in the dopamine system).
Between-system adaptation: recruitment of other systems (e.g., stress circuits in the amygdala) that counterbalance drug effects and produce withdrawal and craving.

What are the GO and STOP systems in the preoccupation stage?

GO system: involves the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex, driving craving and drug-seeking motivation.
STOP system: includes the ventromedial prefrontal cortex and orbitofrontal cortex, which inhibit drug-seeking behavior.Chronic drug use weakens STOP circuitry and overactivates GO circuits, leading to loss of control.

How does drug-induced, cue-induced, and stress-induced reinstatement relate to brain circuitry and structures?

Drug-induced: reactivation of dopamine in the VTA-NAc circuit.
Cue-induced: activation of the basolateral amygdala, hippocampus, and prefrontal cortex (context and memory).
Stress-induced: activation of CRF and NE in the extended amygdala and BNST.All three converge on the NAc to reinstate drug-seeking.