JD

Substance Abuse & Addiction Notes

Substance Abuse & Addiction

  • Commonly abused drugs:
    • Cocaine
    • Alcohol
    • Opiates (Pain drugs + Heroin)
    • Marijuana
    • Depressants
    • Tobacco
    • Hallucinogens
    • Inhalants
    • MDMA
    • Methamphetamine

Addiction Definition

  • National Institutes of Drug Addiction defines addiction as:
    • A chronic disease characterized by drug seeking and use that is compulsive, or difficult to control, despite harmful consequences.
    • The initial decision to take drugs is voluntary for most people, but repeated drug use can lead to brain changes that challenge an addicted person’s self-control and interfere with their ability to resist intense urges to take drugs.
    • These brain changes can be persistent, which is why drug addiction is considered a "relapsing" disease—people in recovery from drug use disorders are at increased risk for returning to drug use even after years of not taking the drug.
    • It's common for a person to relapse, but relapse doesn't mean that treatment doesn’t work. As with other chronic health conditions, treatment should be ongoing and should be adjusted based on how the patient responds. Treatment plans need to be reviewed often and modified to fit the patient’s changing needs.

Cycle of Addiction

  • Initial drug use
  • Abuse
  • Tolerance & Escalation
  • Dependence (& Withdrawal)
  • Addiction or Substance Use Disorder
  • Relapse
    • Note: DSM-V uses the term substance use disorder instead of addiction

Initial Drug Use vs. Abuse

  • Some substances are legal (licit) while others are illegal (illicit).
  • Drug Abuse: The use of illegal drugs or use of prescription drugs for purposes other than those for which they are meant to be used, or in large amounts.

Tolerance, Escalation, Dependence

  • Repeated use of drugs leads to habitual consumption and changes in brain circuits.
  • Tolerance: ability to derive pleasure from drugs decreases over time. This is associated with pharmacological changes, i.e., more drug is required to activate neurons in the same way.
  • Escalation: As a result, the amount of drug consumed increases over time.
  • Drug dependence: when one’s body adapts to having the drug on board. This involves neural and peripheral adaptations. If one stops using the drug, they experience negative physical and psychological symptoms, called withdrawal.

Dependence, Addiction, and Withdrawal

  • Addiction: physical dependence & habitual and compulsive drug seeking and drug use that interferes with one’s life.
  • Characterized by 3 shared features:
    • Habitual drug taking (controlled to uncontrolled intake)
    • Compulsion to seek and take drugs (increased craving/motivation & consumption despite negative consequences)
    • Emergence of negative emotional states (dysphoria, anxiety, and irritability)
  • Relapse: return to drug taking because of compulsion to consume - inability to resist urges to consume and desire to alleviate negative withdrawal symptoms. (Positive and Negative reinforcement of drug consumption)

Risk Factors for Addiction

  • Fortunately, most people are able to resist the short-term effects; only a minority of people who try highly-reinforcing drugs go on to abuse them.
  • Although cocaine has one of the highest abuse potentials of all recreational drugs, only about 15 percent of people who use it, escalate their use of the drug to the point of substance abuse (Wagner and Anthony, 2002).
  • Risk factors:
    • Genetics
    • Environment
    • Neurodevelopmental predisposition
    • Psychological traits (and associated neural correlates):
      • Impulsivity (dysregulation of prefrontal executive control)
      • High sensation seeking (reduced thickness of ACC)
      • High stress reactivity (reduced corticolimbic regulation of HPA axis)

Dopamine in Addiction

  • Activation of the mesocorticolimbic dopamine pathway is necessary for initial reward and continued reinforcement.
  • Drugs that are abused trigger the release of dopamine in the nucleus accumbens (NAc), as measured by microdialysis (Di Chiara, 1995).
  • Different drugs stimulate the release of dopamine in different ways.
  • Repeated use of drug continues to engage mesolimbic dopamine and mesocortical dopamine (mesocorticolimbic dopamine).

Neurobiological Basis of Addiction

  • Changes at the synaptic level:
    • Changes in type and number of receptors, amount of neurotransmitter released, strength of synapses (LTP, LTD)
  • Changes to areas of the brain involved in 3 shared features:
    • Reward and Habit:
      • Basal ganglia (nucleus accumbens -> dorsal striatum)
    • Executive control, attention, and decision making:
      • Prefrontal cortex, orbitofrontal cortex, and ACC
    • Emotion & Affect:
      • Limbic system, especially amygdala

Dopamine Neuroadaptations across Addiction Cycle

Use
* LTP in VTA
* increased mesocorticolimbic dopamine transmission
Abuse
* LTP and LTD in NAc and PFC
* High dopamine levels
Dependence
* Impairment in NMDAR-LTD in NAc
* Low D2 and D3 receptors
Escalation
* Impairment in mGluR-LTD in PFC
Withdrawal
* hypodopaminergia

Neuroadaptation to Learn

  • D2 receptors in the striatum are lower across many classes of drugs (and in obesity).
  • Thought to reflect a homeostatic response to overstimulation of the receptors
  • PET Scans: using change in radioactive ligand binding as a proxy for receptor density

Addiction & Neurotransmitters

  • Addiction depends on more than JUST dopamine.

Neurotransmitter Systems

Binge/Intoxication
* Dopamine (Increase)
* Opioid peptides (Increase)
* Serotonin (Increase)
* \gamma-aminobutyric acid (Increase)
* Acetylcholine (Increase)
Withdrawal/negative affect
* Corticotropin-releasing factor?? (Increase)
* Dynorphin (Increase)
* Norepinephrine (Increase)
* Hypocretin (orexin)" (Increase)
* Substance P (Increase)
* Dopamine (Decrease)
* Serotonin (Decrease)
* Opioid peptide receptors (Decrease)
Preoccupation/Anticipation
* BNST-bed nucleus of the stria terminals.

Molecular Neurocircuits of Addiction

Binge/intoxication
* Ventral tegmental area (Increase - circuit 1)
* Ventral tegmental area (Increase - circuit 2)
* Dorsal striatum (Increase - circuit 3)
* Dorsal striatum (Increase - circuit 4)
Withdrawal/negative affect
* Ventral tegmental area (Decrease - circuit 5)
* Central nucleus of amygdala (Increase - circuit 6)
* BNST (Increase - circuit 7)
* Nucleus accumbens shell (Increase - circuit 8)
* Habenula (Decrease - circuit 9)
* Central nucleus of amygdala (Increase - circuit 10)
* Central nucleus of amygdala (Increase - circuit 11)
Preoccupation/anticipation
* Prefrontal cortex (Increase - circuit 12)
* Prefrontal cortex (Decrease - circuit 13)
* Hippocampus (Decrease - circuit 14)
* Basolateral amygdala (Decrease - circuit 15)
* BNST (Increase - circuit 16)
* Insula (Increase - circuit 18)

Cocaine

  • Well-studied and highly-abused drug.
  • Mechanism: binds to the dopamine and norepinephrine transporter.
  • Route of administration modulates speed of intoxication/reinforcement.

Self-Administration of Cocaine

  • Helps model voluntary consumption and the impact of cues on drug taking & seeking as well as relapse.
  • Self Administration: Pavlovian & operant conditioning
  • Extinction: Abstinence; new learning
  • Reinstatement: Drug or cue reinstates responding (relapse)

Relapse

  • Relapse is often driven by cues.
    • Dopamine in the nucleus accumbens is important for initial reward/reinforcement.
      • Links drugs to drug cues (pavlovian) and drug seeking actions (operant).
      • Over time, this develops into a habit (that engages the dorsal striatum).
      • Predictive cues (and unexpected drugs) can still stimulate dopamine release and invigorate drug-seeking and relapse.
      • Emotional stimuli & CRH can also trigger reinstatement.
    • Self Administration: Pavlovian & operant conditioning
    • Extinction: Abstinence; new learning
    • Reinstatement: Drug or cue reinstates responding (relapse)

Role of Prefrontal Cortex in Reinstatement and Relapse

  • Rodents:
    • Stimulation of the vmPFC with an infusion of AMPA blocked reinstatement of responding following a free shot of cocaine or the cue that was previously associated with cocaine reinforcement.
  • Humans:
    • During abstinence, the activity of the mPFC of people who abused cocaine was lower than that of non-cocaine-using participants.
    • In another study, the amount of mPFC activation during tasks that normally activate the mPFC was inversely related to the amount of cocaine people normally took each week.

Note on Research

  • The conceptual ideas described are mostly based on cocaine and amphetamine research. More recent work with other classes of drugs (alcohol, nicotine, opioids and now hallucinogens) have found similarities and differences in psychological/ neurobiological correlates and risk factors.

Treatment

  • Substance Abuse Treatments Must Engage Physical and Psychological Symptoms
  • After the first few experiences with a drug, most people (between 70% and 95% depending on the drug) either maintain a recreational use of the drug or do not continue to consume it.

Stress

  • Stress is adaptive while chronic stress is harmful.
  • Adrenaline/noradrenaline have subtle differences in effects.
  • Stress can have enhancing and impairing effects on hippocampal memory.
  • The majority of individuals exposed to early life or long-term stress maintain healthy brain and psychological functioning.