Neurobiology of Addiction and Substance Use Disorders

VTA and NAc

They are primarily involved in the initiation of addiction.

Withdrawal/craving brain areas

PFC, DS, and extended amygdala.

GABA's effect on addiction

GABA is inhibitory and generally reduces the rewarding effects of drugs.

Increased GABA levels in VTA

It prevents acquisition and decreases maintenance of heroin self-administration.

Norepinephrine effect on midbrain dopamine neurons

It can drive activity both directly and indirectly.

α1 receptors' effects in addiction

They facilitate dopamine release; blocking them decreases reward.

β1 inhibitors

They reduce cocaine self-administration and stress-induced reinstatement.

MOR

Mu Opioid Receptor involved in reward and analgesia.

KOR

Linked to dysphoria and stress-induced relapse.

Stimulating GABA receptors on drug reinstatement

It diminishes reinstatement.

CB1 receptor knockout effects in mice

Mice fail to self-administer several drugs and fail to show CPP.

Nicotine effect in VTA

It stimulates neurons that excite dopaminergic neurons.

Blocking nicotinic receptors effect

It prevents self-administration of nicotine and other drugs.

Blocked NMDA receptors

It decreases dopamine release and conditioned reward.

Glutamate homeostasis hypothesis

It proposes that basal glutamate levels are lower in addicts, increasing during cravings.

Tonic dopamine release measurement

Microdialysis.

Phasic dopamine release measurement

Fast-scan cyclic voltammetry (FSCV).

Fiber photometry use

To identify active neurons using light-sensitive channels.

Chemogenetics

Designer receptors activated by drugs like CNO.

ΔFosB's role in addiction

Long-term regulation of gene expression, increases self-administration.

PKA's effect on cocaine behavior

Inhibition reduces, stimulation increases cocaine seeking.

PKC inhibition effect

Impairs long-term CPP and reinstatement.

CaMKII effect in addiction

Its inhibition decreases self-administration and relapse.

D1/D2 receptors during addiction

D1 increases initially; D2 decreases, especially with prolonged use.

Fos family genes role

They reflect neuronal activation and are involved in addiction plasticity.

Heritability of SUD

Genetics plays a significant role in SUD development.

Heritability estimate (H2)

H2 = Vg / Vp, ratio of genetic to phenotypic variance.

Receptor types linked to SUD

D2-like more consistently than D1-like.

Telescoping in addiction

Women develop addiction more rapidly despite later onset.

Sex differences in alcohol use

Women get intoxicated with lower doses and progress faster to related diseases.

Women and psychostimulants

They may be more vulnerable to reinforcing effects.

Cannabis gender effects

Women show higher abuse liability and more severe symptoms.

Gender differences in nicotine response

Faster metabolism and stronger reactivity to cues in women.

Hormones in addiction vulnerability

Estradiol increases DA neuron firing and drug seeking.

Socioeconomic factors and SUD

Lower SES is associated with higher substance misuse.

Age influence on SUD

Earlier drug use onset greatly increases addiction risk.

Personality traits in SUD

High neuroticism, extraversion, openness; low agreeableness, conscientiousness.

Stress contribution to SUD

Stress contributes to SUD.

Stress and SUD

It increases vulnerability and risk of relapse.

Chronic stress effects on the brain

Alters reward and control circuits, increasing addiction risk.

Common co-occurring disorders with SUD

Anxiety, PTSD, depression.

Shared risk factor explanation

Trauma/genetics raise risk for both SUD and mental illness.

SUD leading to mental disorders

Drugs can alter brain function and trigger disorders.

Role of pharmacotherapy in SUD

To treat withdrawal, support treatment, prevent relapse.

Drug used to reverse opioid overdose

Naloxone.

Naltrexone function

Blocks opioid effects, reduces cravings.

CBT for addiction

Helps identify and avoid triggers.

Contingency management

Reinforces positive behaviors with rewards.

Motivational enhancement therapy

Builds readiness for change.

Social factors increasing addiction risk

Abuse, neglect, peer pressure, bullying.

Role of epigenetics in addiction

Modifies gene expression without changing DNA.

Gut-brain axis

A bidirectional communication between gut microbiota and the brain.

Cocaine effects on C. rodentium infection

Increases colonization and virulence.

Neurotransmitter elevated by cocaine in the gut

Norepinephrine.

Norepinephrine effect on bacteria

Increases virulence via QseC receptor.

QseC

A bacterial sensor for host catecholamines.

Chemical sympathectomy (6-OHDA)

Blocks NE increase and C. rodentium colonization.

Dopamine influence on C. rodentium

No effect on growth or virulence.

C. rodentium effect on addiction behaviors

It increases addiction-like responses in mice.

Model used to measure addiction in animals

Behavioral sensitization.

Inflammation by DSS effect

Inflammation alone doesn't increase cocaine behavior.

Microbiota composition changes affecting addiction

Increased Proteobacteria enhances addiction.

Amino acid affected in CSF by Proteobacteria

Glycine.

Importance of glycine in the brain

It's a co-agonist for NMDAR and supports glutamatergic transmission.

Glycine in cocaine + Proteobacteria mice

It is reduced in CSF.

Glycine supplementation effect

It prevents increased addiction-like behaviors.

ΔCycA E. coli

A strain lacking glycine transporter; doesn't deplete glycine.

ΔCycA effect on cocaine behaviors

No, it fails to increase addiction behaviors.

Behavior used to test cocaine seeking

Conditioned Place Preference (CPP).

Self-administration tests results

Mice with Proteobacteria take more cocaine.

Final outcome of microbiota manipulation

Proteobacteria reduce glycine and increase addiction behaviors.

Most affected neurotransmitter pathway

Glutamatergic via NMDAR.

Metabolic pathways changing in CSF

Glycine, serine, threonine metabolism.

Link between microbiota and neuropsychiatric disease

Microbiota changes influence behavior and neurotransmission.

FMT

Fecal Microbiota Transplant.

Virulence linked to addiction progression

Bacterial virulence increases gut inflammation and modulates brain chemistry.

Addiction

A chronic and relapsing brain disorder characterized by compulsive drug seeking and use despite harmful consequences.

Substance Use Disorder (SUD)

A pattern of symptoms resulting from the continued use of a substance despite experiencing negative effects.

Difference between physical and psychological dependence

Physical dependence involves tolerance and withdrawal; psychological dependence involves cravings and compulsive behavior.

Physical dependence

Involves tolerance and withdrawal.

Psychological dependence

Involves cravings and compulsive behavior.

Tolerance

Needing increasing amounts of a substance to achieve the desired effect.

Withdrawal symptoms

Unpleasant physical or psychological effects experienced when stopping a substance.

Drug classification by the DEA

From Schedule I (high abuse risk, no medical use) to Schedule V (low abuse risk).

Mesocorticolimbic pathway

The brain's reward pathway involving the VTA, nucleus accumbens, and prefrontal cortex.

Dopamine

The neurotransmitter most involved in the reward pathway.

Prefrontal cortex role in addiction

Controls decision-making, impulse regulation, and inhibitory control.

Nucleus accumbens (NAc)

Processes reward, motivation, and assigns salience to stimuli.

Go system

A system involving the anterior cingulate and dorsolateral PFC that initiates goal-directed behavior.

Stop system

A system involving the ventrolateral and orbitofrontal cortex that suppresses impulsive actions.

Depressants and dopamine

Increase dopamine by disinhibiting dopaminergic neurons, often through GABAergic pathways.

Psychostimulants

Drugs that increase arousal, alertness, and often increase dopamine (e.g., cocaine, amphetamines).

Dopamine depletion hypothesis

The theory that continued drug use aims to restore depleted dopamine levels, driving addiction.

Addiction cycle stages

Binge/Intoxication, Withdrawal/Negative Affect, Preoccupation/Anticipation.

Binge/intoxication stage brain region

The basal ganglia, particularly the nucleus accumbens and dorsal striatum.

Extended amygdala role in addiction

Regulates stress and negative emotions during withdrawal.

Incentive salience

The process of assigning motivational value to a stimulus, like a drug cue.

Craving

An intense desire or urge to use a substance, often triggered by cues.

Compulsive drug-seeking behavior

Continuing to seek drugs despite knowing the negative consequences.

Drug-induced neuroplasticity

Long-lasting changes in synaptic strength and structure due to drug exposure.