Lecture 13: Additiction and Substance Abuse Disorder

What is Addiction

• A treatable brain disorder or disease

• Characterised by compulsive substance use or compulsive behaviours despite harmful consequences

• Addiction risk and treatability vary by substance and individual

• No longer a matter of choice, with substance use driven by brain changes and adaptations

• Not everyone who uses drugs becomes addicted → some drugs are more addictive than others

• Influenced by genetic, neural, developmental, environmental, and social factors

  • Complex interplay between factors - difficult to define what makes an individual addicted

Why do Individuals Take Substances

• To feel good

• To feel new things

• To get new experiences – group share effect in a social setting

• To have fun and relax

• A for of self medication

• The reasoning behind addiction depnends on how driven we are to continue using a substance or how likely an individual is likely to continue to use a substance

Why is Substance Abuse Described as a Form of Self Medications

• Individuals take medications to:

  • Feel better

  • Lessen isolation

  • Lessen depression

  • Lessen fears

  • Lessen worries

  • Lessen anxiety

What Are The Biggest Research Questions in Addiction?

• Addiction is complex → research looking beyond processes within the brain

• Research examines:

  • Vulnerability vs. resilience to developing SUDs

    • Possible genetic component (linked to dopamine, DA receptors/processing)

    • Genetics increases risk but does not predict certainty → not absolute

    • How these issues can be addressed

  • Comorbidity with mental health conditions

    • Reason unclear

    • May involve self-medication (through substance use)

  • Psychological adaptations

  • Neuronal adaptation

What are the key features of Substance Use Disorder (SUD) according to DSM-5?

• DSM-5 breaks down SUD using 11 criteria to assess severity.

• Severity levels determined by the number of symptoms that fit these criteria:

  • Mild: 2-3 criteria

  • Moderate: 4-6 criteria

  • Severe: >6 criteria

• ICD-11: Used in the UK, similar to DSM-5 criteria.

• Severity of SUD is determined by the number of criteria that fit the symptoms experienced determines the treatment pathway used

• The number of criteria fit can vary depending on the substance.

  • Each substance has a breakdown on how likely an individuals it to fit the criteria

What Can Individuals Get Addicted To?

• Smartphones

• Gambling

• Fast food

• Sugar

• Shopping

• Exercise

• Sex

• Social media

• Prescription drugs

• Drugs

• Tanning

• Plastic surgery

• Gaming

What Are The Most Addictive Substances?

• UK spends £10bn on addiction treatment annually.

  1. Heroin (Opioid)

     • 80% of users who inject or smoke become addicted.

     • Opioids are highly addictive.

     • Prescription medication → use can lead to addiction.

  2. Alcohol

     • Legal and widely available, causing significant harm.

     • High potential for addiction.

  3. Cocaine

  4. Barbiturates

  5. Nicotine

     • Legal, readily available, and causes high addiction potential.

• Tobacco, cannabis, amphetamines, opioids, and benzodiazepines rank in the top 10

  • These substances activate the dopamine reward pathway

• Harm generated by these substances can refer to harm to self or society.

Which Substances Cause the Most Harm to Society?

• Alcohol and nicotine cause the greatest harm to society.

• Alcohol has a large impact, affecting not only the individual but also family life and employment.

  • Contributes to social, economic, and health problems.

• Key reason for harm:

  • Legal status and widespread availability.

  • Constant exposure makes avoidance difficult.

• This ongoing exposure in society makes long-term recovery and treatment hard

Describe the Dopamine Pathway

• A pathway runs from the Ventral Tegmental Area (VTA) to the Nucleus Accumbens (NAc).

• Dopaminergic neuron cell bodies in the VTA project to the NAc and act on D1 and D2 receptors.

• The NAc is a GABAergic nucleus of cell bodies that projects to:

  • Prefrontal cortex (PFC)

  • Orbitofrontal cortex

  • Amygdala

  • Hippocampus

  • Ventral pallidum

• The ventral pallidum projects back to the VTA and to the thalamus.

• Addiction and SUD involve multiple brain regions, not just the VTA → NAc pathway.

What is the Addiction Cycle

• Addiction is not a one of occurrence → occurs as a cycle with repeated exposure to the substance and the decision to take the drug

• Initial Use causes a high (reward) due to dopamine (DA) release in the Nucleus Accumbens (NAc) → pleasurable reward feeling

  • The size of the DA release determines the intensity of the high and the likelihood of repeated use.

• Impulsivity in taking the drug continuously leads to Habitual Compulsivity of taking the drug, which leads to brain adaptations over time, making the cycle more entrenched.

• After use, DA withdrawal from the NAc leads to a “come down effect.”

  • After initial use, withdrawal is small → overcome quickly

  • With repeated use, withdrawal becomes more severe, and tolerance develops (requiring more of the substance to achieve the same effect → less of a high is achieved).

• Dependence grows as withdrawal symptoms worsen and cravings increase.

  • This leads to habitual compulsive drug use to maintain DA levels and reward.

• The addiction cycle is driven by the brain's need to maintain DA levels and reward, leading to compulsive behaviour

What happens during the initial stage of the addiction cycle?

• Initial Exposure: Begins with the first use of a substance or behaviour that is addicitve.

• Immediate Effect: Surge in dopamine in the nucleus accumbens, causing a pleasurable high.

• Reinforcement: The pleasurable feeling reinforces the desire to repeat the behaviour.

• For substances like heroin, crack cocaine, and amphetamines, just 1–2 exposures can drive the cycle forward.

What occurs with repeated exposure in the addiction cycle?

• Neuroadaptations → changes in receptor sensitivity, neurotransmitter release, and neural circuitry.

• Tolerance → Brain becomes less responsive, requiring more of the substance to produce the same effect (i.e., higher doses for the same high).

• Dependence → Withdrawal symptoms occur if the substance isn't used, leading to the need for more to avoid withdrawal.

How does the addiction cycle evolve with repeated drug use?

• Dysregulation of the Dopamine System → Repeat drug exposure leads to increased reliance on the substance for pleasure.

• The need for the substance grows, increasing cravings and causing negative emotional effects.

• Relapse is triggered by exposure to the substance or cues/contexts associated with the substance, reactivating neural pathways involved in addiction.

• Even if neurocircuitry returns to normal, re-adaptation back to the dysregulated dopamine system occurs

What is incentive Salience

• Stimuli are paired with drug use, which are associated with motivation and leading to repeated drug-taking behaviour.

• The body begins to recognise cues (like sights, smells) related to drug use, which activates the amygdala and hippocampus, areas involved in emotional memory and learning, forming cues and memories, particularly emotional memories when taking the drug.

How do the amygdala and hippocampus contribute to addiction?

• Amygdala: Involved in emotional memory and withdrawal symptoms.

  • It has projections to the hypothalamus, which activates the HPA axis (fight or flight response), stimulating norepinephrine (NA) release, causing stress and withdrawal symptoms similar to a fight-or-flight state.

• Hippocampus: Forms associations and memories related to drug use.

• Together, they increase the likelihood of drug-seeking behaviour triggered by memories or cues.

What role do the prefrontal cortex and orbitofrontal cortex play in the addiction cycle?

• The prefrontal cortex and orbitofrontal cortex are involved in decision-making and self-control.

• In addition, these areas become dysregulated, leading to impaired judgment and decisions that would be associated with not taking the drug are removed.

• This explains why decisions not to take the drug are overridden, contributing to the expansion of the reward pathway and continued drug use.

What is the role of long-term potentiation and incentive salience in the neurobiology of addiction?

• Long-term potentiation (LTP) occurs in regions that are repeatedly activated, strengthening neural connections

• Incentive salience is linked to positive reinforcement of drug-related memories and feelings, making cues associated with the drug more motivating.

• Cues related to the drug become stronger triggers for drug-seeking behaviour.

How does dopamine play a role in the neurobiology of addiction?

• Initial effect: Drugs that cause rapid, intense dopamine release in the nucleus accumbens/ striatum lead to a stronger reward and reinforcement of drug use.

• With repeated exposure, dopamine circuits shift from the mesolimbic pathway (motivating behaviour toward goals) to the nigrostriatal pathway (driving habitual, compulsive drug-seeking behaviour).

  • Mesolimbic pathway: Involved in motivation and reward prediction, guiding goal-oriented drug-seeking behaviour.

  • Nigrostriatal pathway: Drives habitual compulsivity and arousal behaviours, pushing individuals toward repeated drug use, even in the absence of reward → contributes to habitual compulsivity

What role does the prefrontal cortex (PFC) play in addiction?

• PFC is involved in decision-making and inhibitory control

• In addiction, the PFC, OFC and anterior cingulate cortex (involved in reward and decision making) become impaired, reducing the ability to inhibit impulses and make sensible decisions about drug use.

• The loss of inhibition leads to compulsive drug-seeking behaviour.

What is the role of the amygdala and hippocampus in addiction?

• Amygdala processes emotional responses, including stress and cravings, contributing to emotional memory related to drug use.

• Hippocampus is involved in consolidating drug-related memories, which contribute to cravings and stress → increase the likelihood of relapse.

How do brain regions interact in addiction?

• Prefrontal cortex (decision-making), amygdala (emotion), and hippocampus (memory) all interact in a dysregulated manner in addiction.

• Loss of inhibition in decision-making, emotional memory of cravings, and drug-related memories combine to promote impulsivity and compulsivity in drug use.

What is the Role of Synaptic Plasticy in the Addiction Cycle?

• Addiction involves maladaptive synaptic plasticity across muliple brain regions

• Both long term potenitation (LTP) and long term depression (LTD) occur

• Plasticty alters dopamine signalling, decision making and habit formation

• These changes shift control from goal directed behaviour to compusive drug seeking

How Does Synaptic Plasticity Drive the Addiction Cycle?

• Addiction involves maladaptive synaptic plasticity across multiple brain regions

• LTP occurs in the VTA DA neurons via glutamatergic input and in the NAc (in GABAergic neurons) and other dopamine-innervated regions

• LTP shifts dopamine neuron firing from tonic → phasic burst firing, strengthening drug-associated cues

  • This promotes a circuit shift from mesolimbic (reward) to nigrostriatal (habit) pathways

• LTD and impaired LTP in GABAergic NAc neurons disrupt prefrontal cortex function

• These changes underlie poor decision-making and compulsive drug seeking

What Molecular Changes Underlie Synaptic Plasticity in Addiction?

• Altered AMPA/NMDA receptor expression

• ↑ AMPA receptors and specific subunits at potentiated synapses

• Increased neuronal excitability and firing

• Activation of intracellular signalling pathways:

  • ↑ cAMP

  • ↑ CREB phosphorylation

  • ↑ kinase activity

• These changes promote maladaptive neural circuits in addiction

How Does Synaptic Plasticity Contribute to the Development and Persitence of Addiction

• Repeated drug exposure strengthens specific synaptic connections (between the VTA and NAc neurons), within the mesocorticolimbic pathway

• These changes are gradual and depend on the neurotransmitter and circuit involved

• Each substance produces a distinct pattern of plasticity and altered activity (not a global brain response)

• These gradual, substance-specific changes drive compulsive drug-seeking and relapse

What are the initial synaptic plasticity changes in the VTA during addiction?

• First changes occur at glutamatergic synapses onto VTA dopamine neurons

• ↑ AMPA/NMDA receptor-mediated EPSCs

• ↑ AMPA: NMDA ratio

• Impaired LTP at GABAergic synapses onto VTA DA neurons and PFC neurons

• Potentiation of some GABAergic synapses onto VTA neruons→ net disinhibition of DA neurons in VTA

• Result: increased dopamine release to maintain drug effects

How does synaptic plasticity across the mesocorticolimbic pathway drive addictive behaviour?

• Maladaptation across multiple brain regions disrupts Glutamatergic and GABAergic control, driving addictive behaviour.

• Plasticity begins in the VTA and triggers subsequent synaptic plasticity in other parts of the mesocorticolimbic pathway.

• The nucleus accumbens receives glutamatergic input from PFC and amygdala, where repeated substance exposure induces LTP in PFC and striatal medium-spiny neurons.

• Changes in NMDA/AMPA receptor subunits, balance of currents, and Ca²⁺ sensitivity all contribute to changes in synaptic activity and reinforce addiction-related circuitry.

What Physical Changes in Neurons Are Seen in Addiction and SUD?

• Decreased size of dopamine cell boides in the VTA

• Increasde dendrtic growth and branching within the NAc to mximise DA interaction

What determines the addictive potential of different drugs?

• While many drugs can be addictive, their potential for addiction depends on drug-specific pharmacological and pharmacodynamic properties, including receptor binding, transporter interactions, signalling profiles, and receptor cellular localisation.

• These factors can underline the effects seen and explain why some drugs are more addictive than others.

• Spatial bias (e.g., opioids: MOP/DOP ligands, 5HT2A ligands) can also influence drug-specific pharmacological effects.

What common effects do addictive drugs have, and what determines their intensity?

• Addictive drugs have primary effects on the reward system by increasing dopamine release.

• This produces effects such as hedonic (pleasure), stimulation or sedation, calming, mood elevation, intense euphoria, acute rush, and prolonged high.

• The extent and combination of these effects depend on the specific drug taken.

How do drugs of abuse influence the reward pathway beyond directly acting on dopamine neurons?

• Drugs of abuse modulate the reward pathway not only by acting on DA neurons but also via other neurons that synapse onto them.

• Glutamatergic inputs, GABAergic interneurons, and opioid-containing neurons in the VTA can all affect DA neuron activity or connect directly to the nucleus accumbens, providing multiple routes through which drugs alter dopaminergic signalling.

How Does The Psychostimulant Cocaine Exert Its Effect

• The psychostimulant binds to and inhibits noradrenaline (NAT/NET), serotonin (SERT) and dopamine (DAT). transporters present on the presynaptic terminal, preventing MOA reuptake in the NAc

  • Pleasure effects: achieved by DAT and SERT inhibition → excess DA and SE present in the synapse

  • Stimulant effects: achieved by NAT/NET inhibition → excess NA

• Post-synaptic mechanisms eventually remove the MOA, but there is prolonged exposure at the NAc neuron level by the MOAs before they are removed

• Smoking leads to a rapid uptake, producing a quick and intense high within seconds, followed by a rapid, intense crash with severe withdrawal effects, which drives the addiction cycle.

How Does The Psychostimulant Amphetamine Exert Its Effect

• The psychostimulant binds to and inhibits dopamine (DAT) transporters

• It acts as a substrate and competitively inhibits DA uptake into the presynaptic terminal

• It is taken up into the presynaptic terminal and inhibits VMAT and the filling of vesicles with the transmitter → prevents MOA uptake into vesicles for release

  • More DA present in DA neuron cytoplasm

• Reversal of DAQT (DAT) direction with cytoplasmic DA released intothe synapse

• Minor effect at NAT/NET and SERT → mild stimulant effect

How Does The Psychostimulant MDMA ( Methylenedioxy-methamphetamine) Exert Its Effect

• Inhibits DAT, NAT/NET, SERT

• Primary effects through the release of 5-HT – blocks SERTs, resulting in an increased release of SERT

• Gives rise to Serotonin syndrome

  • Profound hyperthermia

  • Altered mental status

  • Movement disorders

How Do The Psychostimulants Cathinones (Bath Salts) Exert Their Effects?

• Increase the release of NA, DA and 5-HT

• Inhibit transporters NAT/NET, DAT, SERT –

  • At lower doses, stimulant effects and effects on SNS are seen

• Not easily detected in urine and toxicology screens

How Do Cannabinoids e.g. Cannabis and D 9-THC Exert Their Effects

• Act via CB1 and CB2 receptors (Gi-coupled GPCRs) to modulate DA activity.

• CB1 receptors: on VTA GABAergic & glutamatergic inputs → can increase or decrease DA release depending on which neurons are affected.

  • On GABAergic neurons → disinhibition of DA release→ ↑ DA in nucleus accumbens (NAc).

  • On glutamatergic neurons or DA neurons → ↓ DA release.

• CB2 receptors: on DA neurons (cell body & presynaptic) → modulate DA directly.

• Hedonic or avesive effect determined by CB1:CB2 receptor ratio

  • Explains the lower addictive potential of cannabis compared to other drugs.

How does acute ethanol ingestion affect the mesolimbic dopamine pathway?

• Increases GABA release → reduces inhibition → initial pleasurable effects.

• Inhibits NMDA receptors on VTA GABA neurons.

• Increases β-endorphin release, activates mu-opioid (MOPR) receptors on GABA neurons in VTA.

• This leads to disinhibition of DA neurons → ↑ DA release in nucleus accumbens → pleasurable effects and behavioural inhibition.

How do opioids affect the mesolimbic dopamine pathway and neuronal excitability?

• Act on Gi-coupled opioid receptors (Mu, Delta, Kappa) and can reduce neuronal excitability depending on location.

  • Action on VTA GABAergic neurons causes disinhibition and increased DA release in the nucleus accumbens (NAc).

  • Direct effect on Mu-opioid receptors in the NAc, which modulates projections to PFC, hippocampus, and amygdala.

• This leads to cellular effects of

  • Reduced cAMP production

  • Closure voltage-gated Ca²⁺ channels

  • increased K⁺ efflux

• Activation of MOPR on GABAergic neruons → reduced inhibition of DA neurons (disinhibits) → increased DA in NAc → rewarding effect

What is spatial bias for mu-opioid (MOP) receptor ligands and how does it differ between peptide and non-peptide agonists?

• Receptor signalling depends on the location of MOPRs, not just ligand type.

  • provides spatial dimension to the receptor signalling

• Peptide agonists: signal at

  • Plasma membrane (easily accessible) → activate G-proteins or β-arrestin

  • Endosomes (after receptor internalisation)

• Non-peptide agonists: signal at

  • Plasma membrane

  • Golgi-localised MOPRs

• Opioid receptors can also signal from intracellular organelles (endosomes, Golgi), contributing to spatial bias.

What is the Spatial Signalling Observed With MOPR Receptors

• Opiond receptors typically signal through

  • G-protein pathway → decreased excitability

  • beta arrestin pathway → Opoid receptor internalisatio nand recycling → fewer receptors for opoids to have and effect

• The beta arrestin pathway can be promoted in response to certain ligand and cay contribute to the toelrance seen with opiod receptors

What is the Effect of Spatial Bias With MOPR Signalling In the Golgi?

• It can result in

  • Changes in gene expression

  • Altered mitogenic signalling

  • Modified intracellular trafficking (e.g., receptor reinsertion into the plasma membrane)

  • Calcium regulation

• The activation of this spatial bias is drug-dependent, varying with different opioid ligands.

How do patterns of abuse, withdrawal, and addiction differ between psychostimulants, cannabis, ethanol, and opioids?

• Psychostimulants:

  • Intense binge/intoxication

  • Intense withdrawal (depends on length of binge)

  • Can develop a strong craving

• Cannabis:

  • Significant intoxication (often chronic during waking hours)

  • Craving generally mild

• Ethanol:

  • Less intense binge & withdrawal

  • Effects accumulate over repeated use, intensifying over time

• Opioids:

  • Intense effects at all stages (binge, withdrawal, craving)