Addiction clinical + neurobio

What are disability adjusted life years?

DALYs = total number of years lost due to illness, disability, or early death in a population, and act as a measure of economic burden. Substance abuse comes second after depression.

In terms of the actual costs of substance abuse, what comes first, second, and third? Which account for the worst/highest costs, legal or illegal drugs.

• tobacco

• alcohol

• illicit drugs

So legal costs account for the worst costs, likely due to how normalized they are/how widespread their availability is.

The fact that substance abuse CONTINUES to create high, long-lasting economic costs (in healthcare, lost productivity, criminal justice expenses) shows how STRONGLY addictive and rewarding these substances are.

Define two DSM-V definitions: substance intoxication and substance withdrawal.

Substance intoxication: the development of reversible, substance-specific syndrome due to recent ingestion. One example of a substance-specific syndrome is being drunk when you drink alcohol - the symptoms wear off when your BAC drops.

• not only that, but we see clinically-significant and problematic behavioral or psychological changes

• symptoms are NOT attributable to another medical or psychiatric disorder

Substance withdrawal occurs when a person STOPS taking a substance

• we see clinically-significant, problematic behavioral, cognitive, or physiological changes with the reduction (or cessation/STOPPING) of prolonged or heavy use.

• This causes significant distress or impairment in social/occupational fields

• The symptoms are not attributable to another medical or psychiatric disorder

What are the criteria you have to meet to fulfill the DSM’s substance-specific use disorder (which differs from addiction because it is specific to the substance that someone has an issue with)? Are there gradations/variations in severity for this?

This is basically a problematic pattern of use that leads to 2 or more of the following:

1. take more of the drug, for longer than intended

2. Desire/effort to cut down or control use

3. Much time spent using or recovering

4. Craving

5. Results in repeated failure to fulfill role obligations (i.e. we see interference with daily life tasks)

6. Continued use despite recurrent problems due to use

7. Reduce important activities due to use (and positive activities are less or not prioritized)

8. Recurrent use in physically hazardous situations

9. Tolerance (need more to achieve the same effect)

10. Withdrawal

We have three gradations or variations in severity:

• mild - 2 or 3 symptoms met

• moderate - 4 or 5 symptoms met

• severe - more than 5 symptoms met

Self-reports can be unreliable because the victim is in denial about the severity or frequency of their substance usage.

What is the most commonly used illicit drug?

Marijuana (made up 40% of illicit drug users), followed by cocaine, ecstasy, LSD, and meth. Heroin and crack made up the smallest numbers, likely because of the significant stigma associated with using these drugs (ex. used by those who are visibly addicts/homeless) - the drugs are seen as extreme and risky, so fewer people ever start them.

How much of the population meets the criteria for having a substance use disorder in the past year? What were the two categories?

16.5% of the population, alcohol or drugs (in terms of what kind of substance use disorder they could have)

How do drug overdose deaths differ by ethnicity? Did the COVID-19 pandemic cause a decrease or increase in the number of ODs?

• black and hispanic groups (and indigenous people) had the highest ODs per 100,000 people

• hispanic and AAPI groups had the lowest

• however, every group saw an increase of ODs during the pandemic (due to increased isolation meaning that more people used drugs alone, which leads to a higher risk of fatal overdose. There was also a huge strain on mental health caused by the pandemic)

What is the 3-stage model of addiction?

Substance use disorders develop early in life and operate via a relapsing model.

1. Preoccupation/anticipation (craving) - the “wanting” phase

   • this is when a person thinks about or desires the drug, like seeing friends use at a party, remembering how good it felt before, or just craving the high

   • the prefrontal cortex activates, involved in planning, decision-making, and impulse control (though over time you stop showing a regard for the consequences of use)

   • in early use, it’s often social or curiosity driven, and later it becomes compulsive craving

   • so, basically this stage motivates the drug seeking behavior.

2. Binge/intoxication - the “taking” phase, involving the high a person gets/the pleasure they experience shortly afterwards

   • this person uses the drug, experiencing the rewarding effects (ex. a surge in dopamine)

   • this activates the basal ganglia, reinforcing the drug-taking habit through positive reinforcement

   • the pleasurable feeling encourages repetition of use

3. Withdrawal/negative affect - “avoiding bad feelings” phase

   • after the drug wears off, unpleasant withdrawal symptoms kick in like anxiety, irritability, and dysphoria

   • the extended amygdala activates, which produces negative emotions and stress

   • motivation shifts from “feel good” to “avoid feeling bad”

   • now, negative reinforcement drives continued use to relieve the discomfort of withdrawal

   • you experience physical and/or psychological pain if you can’t acquire the drug

What is hedonic homeostatic dysregulation?

A. The individual experiences a drug or rewarding stimulus for the first time.

• STRONG activation of reward pathways (dopaminergic signaling in the mesolimbic pathway, ESPECIALLY the nucleus accumbens)

• The brain hasn’t adapted, so there is a NET INCREASE in pleasure with little to no opposition

• The experience feels euphoric or intensely pleasurable (we go far above the baseline during the primary affective reaction, and experience a crash or low during the affective after-reaction)

B. The stimulus is encountered frequently

• the brain begins to DOWNREGULATE reward responses (ex. desensitization on the part of the dopamine receptors to the response, decreased dopamine release). The A-process is smaller in magnitude (so we see reduced pleasure, while the B-process has anti-reward symptoms like dynorphin begin to ramp up).

C. Chronic use leads to neuroadaptations

• the brain establishes a new hedonic baseline that is lower, instead of returning to original homeostasis. Things that used to feel good no longer do - and they have to use more of the drug just to feel NORMAL.

• the reward system is hypofunctional, while the anti-reward system is hyperactive

• use is now largely to avoid withdrawal and dysphoria, NOT to get high. so here we see a shift from positive to negative reinforcement

D. Long-term cessation of the stimulus (spending time without the drug)

• the low hedonic set point may persist for weeks, months, or even longer

• the brain’s reward system is slow to recover, and stress systems remain hyperactive (ex. corticotropin-releasing factor, or CRF).

• there is increased risk of relapse due to PERSISTENT negative affect and stress-triggered cravings

• if the drug IS reintroduced, it can shock the reward system and lead to an intense initial euphoria (caused sensitization)

• the positive reinforcement spike might be more prominent than before, but this is short-lived. The upcoming crash or B-process will be even lower than before

Talk about the reward/stress circuitry, which promotes survival. Which is the positive reinforcement pathway, which is negative reinforcement, and which is mixed? And what modulates each of these pathways?

This involves the dopamine VTA neurons that project to the (meso)limbic system - nucleus accumbens and amygdala - as well as the cortex.

• drugs hijack this pathway and make it easy to get addicted

Positive reinforcement: VTA and nAcc system

• activated during eating, social affiliation, threat avoidance, pair-bonding, and mating (sex)

• the pleasure associated with these behaviors positively reinforces continuing or initiating these behaviors, because they promote survival or continuation of the species

Negative reinforcement: extended amygdala

• activated by stressors (food deprivation, threat, loss)

• associated pain/negative affect negatively reinforces behavior that avoid or manage stress —> you will do things just to avoid feeling bad, NOT to feel good (ex. taking drugs to escape withdrawal symptoms)

How are the dorsal striatum/basal ganglia involved in habit mediation, which is relevant during repeated binges/intoxications?

Early on, behavior is goal-directed and mediated by the ventral striatum + prefrontal cortex

• I do this because I want X outcome

With repetition, control shifts to the dorsal striatum, which makes behavior more AUTOMATIC

• I do this because it’s a habit, regardless of outcome

This shift is known as the transition from action-outcome (working towards a goal) to stimulus-response (things you don’t have to think about, because you do them all the time)

• as behaviors (like taking a drug) become more repetitive and less sensitive to outcomes, they increasingly begin to rely on this region

How do drugs limit normal negative feedback of reinforcement?

Repeated use (at first) downregulates the neuropeptides that would usually inhibit it - so the high is more intense because you aren’t properly shutting off the reward system.

1. Normally the brain self-regulates dopamine signaling - after a rewarding event, negative feedback mechanisms (ex. inhibitory neurotransmitter GABA and inhibitory neuropeptides like dynorphin) to stop the reward system from being overstimulated

2. When you first start using drugs, the brain is flooded with dopamine FAR beyond natural levels. This leads to the downregulation of dopamine receptors in the beginning (ex. the D2 dopamine receptors) because the brain is allowing you to feel the high. Also, the expression of inhibitory neuropeptides like dynorphin is downregulated.

   • dynorphin normally inhibits dopamine release in the nucleus accumbens

3. In chronic/dependent use (or overuse), the brain senses things are out of balance - there’s too much dopamine for too long. So the inhibitory systems (dynorphin and CRF) become upregulated as an overcorrection measure.

   • because the baseline mood drops as a result, and withdrawal gets worse, use becomes about avoiding pain more than seeking pleasure

If dynorphin and GABA are inhibitory, why are they released from the D1 MSNs (nucleus accumbens) which are involved in the excitatory pathway?

Basically the MSNs in the nAcc (the D1-type) modulate the VTA - not by stopping it. This is what it means:

• D1 MSNs = stimulated by dopamine

• D2 MSNs = inhibited by dopamine

The names - excitatory or inhibitory - don’t have to do with what the MSNs release THEMSELVES, but by what effect DOPAMINE has on them.

D1 MSNs, when activated by dopamine, release:

• GABA

• dynorphin

So more dopamine (from the VTA) —> more D1-MSN activation in the nAcc —> more dynorphin (which inhibits dopamine release from the VTA) —> LESS dopamine

So D1 MSNs are not STOPPING VTA activity, but rather toning it down and applying the brakes, regulating the system’s gain, and preventing runaway dopamine signaling.

• basically, D1 MSNs are regulators: so even though they are excited by dopamine, their outputs can include inhibitory feedback

What is CRF, and how does it play a role in the withdrawal/affect stage?

This is the negative reinforcement pathway in the extended amygdala - the entire circuit makes us feel worse.

• leads to activation of the autonomic nervous system (via physical stress signals), which can lead to sweating, shaking, etc.

• This is because the central amygdala and BNST (bed nucleus), also in the amygdala, have CRF-expresing neurons.

• These neurons project to the hypothalamus, which triggers the HPA axis and leads to the release of cortisol.

• So basically, CRF or corticotropin-releasing factor leads to cortisol (stress hormone) release when the hypothalamus talks to the adrenal cortex (via the pituitary gland)

What does the preoccupation stage involve - what parts of the brain?

• basolateral amygdala (BLA): critical for associative learning and memory (emotional memories)

• prefrontal cortex (PFC): executive control, decision making, and evaluating consequences

• nucleus accumbens (nAcc): receives glutaminergic input from the PFC and BLA —> when it receives dopamine from the VTA, it heightens motivation and craving

• hippocampus: works with the BLA to strengthen cue-triggered cravings

Basically

• glutamate (from the BLA and hippocampus) + dopamine (from the VTA) —> sent to the nAcc, which creates a STRONG motivational signal to seek the drug

• the PFC, which should regulate this impulse, is compromised by CHRONIC drug use. Basically, self-control weakens, and cravings increase.

• stress pathways (the CRF in the extended amygdala) intensify this effect by INCREASING how bad you feel, which makes relapse more likely.

How can we use neuroimaging to study addiction?

• fMRI - can show changes in oxygenation and blood flow associated with brain activities (ex. increased acvitation in the BLA, nAcc, and PFC when a person sees drug-related images)

• PET scans and SPECT - looks at biochemical and pharmacological processes (glucose metabolism, drug distribution + kinetics, receptor/ligand interaction, enzyme targeting)

Is chronic drug use associated with brain matter loss - and if so, what kind? Which regions does this primarily occur in?

Yes, loss of gray matter (neuronal cell bodies and synapses, not white matter or myelinated axons).

We see the greatest loss of gray matter in the frontal and parietal lobes (via MRI scans) in meth-addicted individuals - ex. prefrontal cortex which is responsible for executive control/decision making/reigning in impulses.

In amphetamine users, we see a reduction (decrease!) in the volumes of the temporal and hippocampal areas, along with the anterior cingulate cortex (in the limbic system) and prefrontal cortex. This correlates with a decline in cognitive performance.

Does how high a person feel correlate well with how much cocaine is available in the striatum?

Yes - kind of. Everything matches up except for later on, when the high (reported by the patients via questionnaire) wears off before the cocaine is out of the person’s system (as detected through PET scans).

• this means that the dopamine system has become saturated (when all receptors are taken/have been activated). After a point, more cocaine won’t make you feel higher because the max response has been hit.

• This is known as the ceiling effect

When people are given a visual cue, do we see a lot of activation in the anterior cingulate cortex in cocaine users compared to a control?

Yes - this is because the ACC is involved in pain, but is especially active during emotional pain (i.e. social rejection or shame) - basically, users feel emotional stress/distress when seeing the drug, especially because chronic cocaine use impairs mood regulation.

Why do we see reduced orbitofrontal/prefrontal cortex activity in a cocaine abuser?

(The orbitofrontal cortex is part of the prefrontal cortex).

Repeated cocaine use leads to less responsiveness of the PFC, which means that judgment becomes worse. So the user might ask themselves whether what they are doing is worth it, but they won’t be able to give the right answer/will overvalue the rewards of the drug.

Why do we see reduced D2 receptor activity in the striatum of those who use cocaine (as seen in a PET scan)

Chronic drug use lowers D2 (inhibiting) receptor count in the striatum.

• (might be useful to know - while the dorsal striatum has D2 receptors that are involved in movement control, the ventral striatum/nAcc has receptors that are involved in motivation, reward, and addiction)

Reduced D2 receptors = less control, less regulation of motivation, more compulsive drug-seeking.

Why D2 receptor numbers go down is that, when the brain gets overwhelmed from excess dopamine, it will end up downregulating (reducing) the number of receptors that are activated by dopamine - D2 receptors, in this case - and making existing receptors less sensitive to dopamine as well - so their response to activation will be blunted (which leads to tolerance)

Why do we see reduced levels of monoamine oxidase in the organs of a smoker (PET study) - so not only the brain, but also throughout the body?

monoamine oxidase (MAO) breaks down monoamine neurotransmitters like dopamine, serotonin, and norepinephrine.

Cigarette smoke contains compounds that inhibit MAO - and if we are thus inhibiting the breakdown of monoamines like dopamine, we are raising their levels in the brain. This paves the way for downregulation of dopamine receptors + desensitization of these receptors’ responses as well.

What effect does MDMA have on the brain over time? What is the role of SERT? What is the effect of MDMA on net serotonin signaling?

• because MDMA acts as a monoamine releaser, it increase the amount/activity levels of three monoamine neurotransmitters (dopamine, serotonin, norepinephrine)

• prolonged release of serotonin = overactivation of axon terminals/synapses = degradation of the serotonergic neurons’ axon terminals with chronic use, which leads to a loss of function

Damage/degradation to presynaptic axon terminals leads to a reduction in serotonin transporter (SERT) protein levels, since this is embedded in the axon terminal.

• SERT’s job is to transport serotonin from the synaptic cleft BACK into the presynaptic neuron.

• Obviously, if levels of SERT go down, we will see excess serotonin in the synapse and temporary overactivation of postsynaptic receptors - though axon terminal damage = less release of serotonin long-term. Net serotonin signaling is DECREASED.

• After 10 weeks of post-MDMA use, rats show an increased anxiety response as well (since serotonin has inhibitory control over anxiety circuits)

What is the diathesis-stress model?

A disorder develops when a person with a certain vulnerability, or diathesis, experiences enough stress to trigger it.

• you need a genetic/biological predisposition ON TOP OF an environmental trigger for a disorder to develop. Just one usually isn’t enough.

Early exposures (which can function similarly to a genetic weakness) or biological factors:

• sensitize reward and/or HPA stress response system (basically, make these systems hyper-reactive) —> the HPA

• provide negative role models for managing stressors

• increased risk for mood/anxiety disorders (low hedonic baseline or set point)