Lecture 4: Block 2: Dopamine and Dopamine Theory of Addiction

How did the dopamine theory of addiction originate?

From 1950s-70s experiments showing rats would self-stimulate dopaminergic brain areas (Olds & Milner) and that drugs enhancing dopamine increased self-stimulation.

What was the central claim of the dopamine theory of addiction?

That dopamine release in the mesolimbic system mediates the rewarding and reinforcing effects of all addictive drugs.

What evidence supported this theory?

Stimulants like amphetamine and cocaine increased striatal dopamine and produced euphoria; dopamine blockade reduced self-administration in animals.

How did microdialysis research refine this theory?

Di Chiara and Imperato (1988) showed that nearly all addictive drugs increased dopamine release in the nucleus accumbens.

How has PET/SPECT imaging advanced our understanding?

Radiotracers like [11C]-raclopride allowed direct measurement of dopamine receptor availability and release in humans, showing correlations between dopamine increases and drug-induced "highs."

What did imaging reveal about stimulant drugs?

Stimulants (amphetamine, cocaine) robustly increase striatal dopamine, directly correlating with euphoria intensity.

Do all addictive drugs increase dopamine equally?

No. Stimulants produce strong dopamine increases; alcohol and nicotine produce moderate increases; opiates and cannabis show weak or inconsistent effects.

What are the limitations of the dopamine theory?

It fails to explain addiction to drugs with minimal dopamine release (e.g., opiates, cannabis), and dopamine blockade does not eliminate pleasure or addiction behaviors in humans.

What is meant by "blunted dopamine function" in dependence?

Chronic drug users often show reduced striatal D2/D3 receptor availability and lower dopamine release in response to challenges, suggesting downregulation or reduced sensitivity.

How is low D2 receptor availability related to addiction risk?

Individuals with lower D2 receptor levels report greater stimulant-induced euphoria and show higher vulnerability to compulsive drug use.

What paradox does dopamine receptor availability present?

Lower D2 availability predicts higher drug liking — implying that deficiency in dopamine signaling may increase rather than decrease vulnerability.

What did the article conclude about dopamine's universality in addiction?

Dopamine is central to stimulant addiction but not universally responsible for all addictions. Other neurotransmitters (e.g., endogenous opioids, GABA) are crucial in non-stimulant addictions.

What are the implications for treatment development?

Targeting dopamine alone is insufficient. Effective therapies must address multiple neurotransmitter systems and individual neurobiological differences.

How does dopamine contribute beyond reward?

It mediates motivation, attention, habit formation, and learning — signaling "wanting" rather than simple pleasure.

How is dopamine linked to impulsivity and compulsivity?

Low striatal dopamine correlates with higher impulsivity, while altered cortical dopamine function impairs executive control, promoting compulsive use.

What is the relationship between dopamine and pathological gambling?

Pathological gamblers show altered D3 receptor activity and increased dopamine release to reward cues, similar to substance users, despite no external drug input.

What are the main limitations of dopamine imaging research?

PET/SPECT cannot easily distinguish D2 from D3 receptors or pre- from postsynaptic changes, and small dopamine fluctuations may fall below detection thresholds.

What is the future direction suggested by the authors?

To study dopamine alongside other systems (GABA, opioids, serotonin) and in cortical regions responsible for control and compulsion, not just the striatum.

What is the key takeaway from 40 years of dopamine research in addiction?

The dopamine theory was vital for progress but overly simplistic; addiction is a multi-neurotransmitter, multi-circuit disorder with dopamine as one key component — not the whole story.

Do you understand DA synthesis?

Dopamine is synthesized from tyrosine → L-DOPA → dopamine via tyrosine hydroxylase and DOPA decarboxylase. Dopamine is stored in vesicles, released upon stimulation, and degraded by MAO and COMT enzymes.

What are the DA pathways? How do they relate to drug addiction?

Mesolimbic (VTA → NAc, amygdala): reward and motivation; primary addiction pathway.
Mesocortical (VTA → PFC): cognition and control; dysfunction contributes to craving.
Nigrostriatal (substantia nigra → dorsal striatum): habit formation and compulsion.
Tuberoinfundibular (hypothalamus → pituitary): hormone regulation (not directly addiction-related).

What are the two classifications of DA receptors? What G-proteins are they associated with?

D1-like receptors (D1, D5) - coupled to Gs proteins, stimulate adenylate cyclase (excitatory).
D2-like receptors (D2, D3, D4) - coupled to Gi proteins, inhibit adenylate cyclase (inhibitory).Balance between these receptor types regulates motivation and motor activity.

What are clinical aspects of DA? What does electrophysiology tell us? Microdialysis? FSCV? How does this relate to the DA hypothesis?

Electrophysiology: measures firing rates; drugs like cocaine increase phasic VTA neuron firing.
Microdialysis: quantifies extracellular dopamine; shows drugs elevate DA in NAc.
Fast-scan cyclic voltammetry (FSCV): tracks rapid dopamine release and clearance; demonstrates that cues predicting drug availability trigger dopamine bursts.These findings support dopamine's role in reward and prediction error.

What is the Dopamine Hypothesis?

The Dopamine Hypothesis posits that increased dopamine Nac → higher drug abuse potential

Why has this hypothesis emerged as one of the leading theories in drug addiction?

Because nearly all addictive drugs elevate dopamine in the nucleus accumbens, and dopamine activity correlates with the intensity of euphoria. Animal and human imaging studies consistently link dopamine signaling to reinforcement and motivation.

What gaps in the dopamine hypothesis need to be addressed? Provide an example in which dopamine cannot explain the role of addiction.

Some addictive drugs (e.g., opioids, cannabis) do not strongly elevate dopamine, suggesting other neurotransmitters (opioid peptides, GABA, CRF) contribute.
Dopamine blockade does not abolish pleasure or addiction behaviors.
Addiction also involves cortical dysfunction and maladaptive learning, not just reward signaling.Thus, the dopamine hypothesis must be integrated with glutamate and stress-system theories for a full model.