This is a mechanism module, not a disease. Do not create a generic "Substance Use Disorder" or "Addiction" Disease entry from it. The agent-specific use disorders (alcohol, opioid, nicotine, cocaine, methamphetamine, cannabis) and gambling disorder are the disease entries, and they declare conforms_to on their own nodes.
The trigger node is named for dopamine reinforcement rather than for a drug so that a behavioural addiction can conform. In gambling disorder the reinforcer is non-drug reward, modulated by endogenous opioid signalling in the striatum.
The module deliberately carries no pathway that belongs to only one drug class: the monoamine-transporter pharmacology of stimulants, CB1 receptor downregulation, nicotinic receptor upregulation, and the locus coeruleus cAMP superactivation of opioid withdrawal all live on the disorder entries. The dynorphin/kappa-opioid arm of the central node is bound to the generic GO opioid-receptor signalling process; GO has no kappa-specific signalling term.
Worked conformers: Alcohol_Use_Disorder, Opioid_Use_Disorder, Gambling_Disorder.
Acute Mesolimbic Dopamine Reinforcement
trigger
Addictive drugs, and in behavioural addictions the reward itself, produce large, fast increases in extracellular dopamine released from ventral tegmental area neurons into the nucleus accumbens. The increase exceeds that produced by natural rewards and is the proximate reinforcing signal. Drug classes reach this step by different routes (transporter blockade or reversal, disinhibition of dopamine neurons, nicotinic excitation), which conforming entries record upstream of this node.
Downstream
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Incentive Salience and Habit Formation
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Reward Deficit and Stress-System Recruitment
Show evidence (2 references)
"Drugs abused by humans (e.g., opiates, ethanol, nicotine, amphetamine, and cocaine) increased extracellular dopamine concentrations in both areas, but especially in the accumbens"
Rat microdialysis shows that pharmacologically unrelated drugs of abuse converge on increased accumbens dopamine, which is what makes this node shared across drug classes.
"In humans the reinforcing effects of drugs are associated with large and fast increases in extracellular dopamine, which mimic those induced by physiological dopamine cell firing but are more intense and protracted."
Summarizes human PET studies linking drug reinforcement to supraphysiological dopamine increases.
Reward Deficit and Stress-System Recruitment
central effector
Repeated exposure provokes opponent-process adaptations. Within the reward system, dopamine release and D2 receptor availability fall, so natural and drug rewards produce less effect. Between systems, corticotropin-releasing factor and dynorphin signalling are recruited in the extended amygdala, and dynorphin acting at kappa-opioid receptors further suppresses accumbens dopamine. The result is hyperkatifeia, an intensified negative emotional state during withdrawal that persists into protracted abstinence. Relief of that state drives seeking through negative reinforcement. This is the key conformance target: the adaptation that turns repeated reward into a chronic, relapsing disorder.
Downstream
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Compulsive Seeking and Loss of Control
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Prefrontal Executive Control Deficit
Show evidence (4 references)
"The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor..."
States both arms of this node, the within-system dopamine deficit and the between-system recruitment of CRF and dynorphin in the extended amygdala.
"Indeed, imaging studies show that drug abusers have marked decreases in dopamine D2 receptors and in dopamine release."
Human PET evidence for the within-system reward deficit in addicted individuals.
"drugs with aversive properties (e.g., agonists of kappa opioid receptors, U-50,488, tifluadom, and bremazocine) reduced dopamine release in the accumbens"
Kappa-opioid agonism lowers accumbens dopamine and is aversive in rats. This supports the dynorphin arm of the node as a cause of the dopamine deficit. It is indirect because exogenous agonists stand in for endogenous dynorphin.
+ 1 more reference
Prefrontal Executive Control Deficit
effector
Prefrontal and insular control over the basal ganglia and extended amygdala is dysregulated, including their glutamatergic projections. Response inhibition fails, salience is attributed excessively to the reward, and craving dominates the preoccupation/anticipation stage. Reduced striatal dopamine function is associated with lower activity in orbitofrontal, cingulate and dorsolateral prefrontal cortex.
Downstream
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Compulsive Seeking and Loss of Control
Show evidence (3 references)
"The craving and deficits in executive function in the so-called preoccupation/anticipation stage involve the dysregulation of key afferent projections from the prefrontal cortex and insula, including glutamate, to the basal ganglia and extended amygdala."
Defines this node: dysregulated prefrontal and insular glutamatergic output underlying craving and executive dysfunction.
"Disruption of the PFC in addiction underlies not only compulsive drug taking but also accounts for the disadvantageous behaviours that are associated with addiction and the erosion of free will."
A review of human functional neuroimaging that places prefrontal disruption upstream of compulsive drug taking.
"This decrease in dopamine function is associated with reduced regional activity in orbitofrontal cortex (involved in salience attribution; its disruption results in compulsive behaviors), cingulate gyrus (involved in inhibitory control; its disruption results in impulsivity) and dorsolateral..."
Supports the edge from the reward deficit to prefrontal dysfunction: in human imaging, reduced dopamine function goes with lower orbitofrontal, cingulate and dorsolateral prefrontal activity. The association is correlational.
Compulsive Seeking and Loss of Control
consequence
The clinical endpoint shared by addictive disorders: compulsive seeking and taking, loss of control over intake, persistence despite harm, and a negative emotional state when the reward is unavailable. The course is chronic and relapsing. Conformers substitute the substance or behaviour and wire this node to their clinical phenotypes.
Show evidence (1 reference)
"Drug addiction can be defined as a chronically relapsing disorder, characterised by compulsion to seek and take the drug, loss of control in limiting intake, and emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) when access to the drug is prevented."
The standard definition of the addicted state that this node represents.