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.

• while animal studies indicate that everyone is at risk for developing an addiction if the substance is ingested AT LEAST ONCE, not everyone does.

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

• For example, lots of people drink heavily during college, but this ends up being a passing phase - it will likely only become a persistent problem if you have a genetic predisposition to it

What are some examples of early exposures or genetic factors (diathesis)?

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 axis might be more easily triggered, or the reward system (dopamine/serotonin circuits) could become less responsive

• provide negative role models for managing stressors (a child might watch people have bad coping mechanisms/unhealthy substance dependence in their environment)

• increased risk for mood/anxiety disorders (low hedonic baseline or set point) —> normal life events feel less rewarding or more stressful

What are some examples of developmental crises (stress) in the diathesis-stress model? What makes adolescents and adults (at certain vulnerable points) more vulnerable to developing addictions?

Adolescence

• normally disrupts hedonic homeostasis via the stress of separation/individuation, identification with various social groups —> peers and social approval become a bigger priority or influence at this stage than parents

• mood dysregulation due to hormonal changes

• increased exploratory/risk-seeking behavior due to incomplete/still-occurring development of the frontal lobe + decreased parental supervision —> so kids might start experimenting with drugs

Adults

• major life events like divorce, death (of a loved one), or job loss

We also see influences from trauma, work-related stressors, lack of education, etc.

What does the diathesis-stress model suggest about treatments?

Treatments should be preventative in nature (focused on early education, surveillance, behavioral treatment)

What is the genetic model of addiction? How does it differ from the diathesis stress model?

The genetic model focuses on inherited genetic factors that increase vulnerability to addiction

• basically this model proposes that genes alone largely determine whether someone will develop addiction

• certain genetic variations (ex. risk-taking or reward-related impulsivity, negative urgency/negative affect, and executive function in PFC) make some people more prone to addictive behaviors

• environmental factors (stress, peer influence, drug availability) are often considered secondary or less critical

risk-taking: someone seeks out rewarding experiences quickly, without fully considering the consequences

• these people are more likely to try the drug in the first place

negative urgency/negative affect: the tendency to act impulsively when experiencing negative emotions, like stress, anxiety, or sadness

• these people have poor emotional regulation and have a compulsive drive to relieve stress through things like drug use

executive function in the prefrontal cortex (PFC): self-control, decision-making, planning, inhibitory control

• people find it harder to resist drug cravings or control their drug usage, which increases addiction risk

Risk-taking, negative urgency, and executive function variants can contribute to addiction under the genetic model of addiction. What else can?

• substance-specific gene variants (ex. variants in the genes that code for the enzymes that metabolize/break down alcohol)

• we also see a comorbidity or high co-occurrence between substance use disorders and psychiatric disorders (which may be because of the self-medication hypothesis, where people use substances to alleviate the distress they feel)

What do the concordance rates show for population-based twin studies, when we look at substance abuse/dependence?

If a disorder is completely genetic, monozygotic (identical) twins would have nearly 100% concordance - if one had the disorder the other would too, since they are genetically identical.

• DZ twins share 50% of their DNA, like other siblings

If a disorder is not genetic at all, monozygotic and dizygotic twins would have similar concordance rates

• what we see for substance use disorders, though, is that MZ twins have HIGHER concordance rates than DZ twins —> indicates that genetics play an important role

• DZ twins have a concordance rate that is more than the expected 50% of the MZ concordance (if only genetics played a role). This means that shared environment likely matters as well.

How does the metabolism of alcohol serve as an example of a substance-specific gene variant/how genetics plays a role? How does antabuse, a treatment given to alcoholics, work on a similar principle?

When breaking down alcohol, we go from EtOH (alc) —> acetylaldehyde —> acetate

• acetaldehyde (the intermediate) is toxic and causes flushing/palpitations, among other unwelcome physical sensations (alcohol dehydrogenase)

• acetate is the non-toxic, neutral product made when acetaldehyde is metabolized by ALDH (acetaldehyde dehydrogenase)

Some Asian populations have high levels of ADH (alcohol dehydrogenase) but low levels of ALDH (acetaldehyde dehydrogenase) due to variations in genetics (genetic polymorphisms)

This means that they suffer from an uncomfortable buildup of the intermediary substance acetaldehyde, and so even though they become intoxicated faster, it feels bad so they tend not to drink as much.

Antabuse works as an inhibitor of ALDH (alcohol dehydrogenase), meaning that whoever takes it will have acetaldehyde buildup in their system —> alcoholics end up feeling bad when they drink and associate negative feelings to alcohol, which leads them to stop drinking over time.

Talk more about co-morbidity - why anxiety usually precedes SUD (substance use disorder), and why depression usually follows.

The likelihood of substance use disorders increases with neuroticism or diagnosed mood/anxiety disorders.

• people with anxiety might use substances like alcohol or cannabis to reduce their anxious feelings or calm themselves, which can lead to dependence over time. They also might already suffer from serotonin/GABA dysregulation (too little GABA —> overactive amygdala/PFC)

• depression can often occur alongside or after drug usage

  • chronic substance use can reduce serotonin/dopamine receptor levels and sensitivity

  • it can also lead to social isolation and financial problems, which feed into depression

  • we also have the negative emotional states experienced during withdrawal to contend with as well

Do drugs cause brain damage, or is it that the people who already have deficits are the ones seeking them out? Or are both factors caused independently?

Drugs do cause brain damage, but it’s also true that people who have certain deficits already (poor judgment or emotional regulation) are more likely to use drugs.

We might also see another factor, such as poverty, cause both problems independently.

Compare the neurobiological model to the predispositional model of addiction.

1. neurobiological model of addiction: repeated drug use causes lasting changes in brain circuits (mostly those involved in reward, motivation, and control) —> this drives compulsive drug use and seeking.

   • changes have occurred in the prefrontal cortex and in stress systems like the HPA axis, which impairs self-control and increases cravings

   • so basically what this model is saying is that addiction is a brain disease caused by drug exposure —> the biological changes/changes in brain development occur AFTER drug use begins

2. predispositional model of addiction: focuses on how pre-existing biological/genetic factors BEFORE drug use influence addiction risk

   • genetic variants affect personality traits like impulsivity, risk-taking, and reward sensitivity —> this increases the likelihood that someone will gravitate towards, and try, drugs. So basically some people are biologically more vulnerable even before drug exposure.

How can we actually test the predispositional and neurobiological models?

1. longitudinal studies (before and after drug use) —> follow people or animals before any drug exposure and track who develops addiciton later

   • if brain or GENETIC differences predict who starts using and becomes addicted, that supports the predispositional model

   • if we see brain changes after drug use (in a way that shows that the brain adapted/has been causally altered), the neurobiological model is supported

2. genetic studies and family/twin studies

   • if genetic variants or family history predict addiction risk, that supports predispositional factors

3. animal models with controlled drug exposure

   • giving animals drugs and measuring brain changes isolates neurobiological effects —> how is the brain structure + function changing over time in response to drug exposure?

   • breeding/selecting animals with certain traits, like impulsivity, tests predispositional risk —> are these animals more likely to self-administer (give themselves) drugs? are they more prone to developing addictive behaviors, like compulsive drug-seeking?

4. neuroimaging studies in humans

   • look for preexisting brain differences in people who haven’t used drugs yet, but are high risk

   • compare to the brain changes in chronic users

Talk about a study in which monkeys could voluntarily and chronically drink alcohol in a longitudinal MRI study.

after drinking alcohol for 6 months/a year, the thickness of the cortex/hippocampus decreased.

• the size of the lateral ventricles increased, because of a loss of gray matter/neural tissue in the surrounding areas.

What is the Iowa Gambling Task?

This is a cognitive test designed to assess decision-making and risk-reward evaluation.

• participants choose cards from different decks, some “good” (small wins but overall profit) and some “bad” (large immediate rewards but bigger losses long-term)

• the goal is to learn to prefer decks that maximize long-term gain (the “good” decks)

• healthy participants exhibit subconscious stress reponses when hovering over bad decks before they are consciously aware of the difference in deck win probability

• marijuana/cannabis use is linked to impaired performance on the IGT because it might disrupt the functioning of the PFC/OFC and amygdala, which integrate emotional + cognitive info during decision-making

• use was correlated with cognitive test performance (heavy users did the worst, followed by moderate users and the control group)

Is there a change in cortical gray matter volumes in chronic marijuana users?

Yes (in the PFC/OFC or oribitofrontal cortex) and the hippocampus, which is critical for memory formation

What kind of correlation is there between cannabis use and amygdala volume?

Negative - chronic use decreases the volume of the amygdala

How is there a dose-response effect of cannabis use on IQ over time?

Basically, the more cannabis someone uses, the greater the impact on IQ over time (we see a bigger decrease)

• this was shown in a study where cannabis use was ascertained in interviews at multiple ages.

• most of this effect is seen in those who began using in adolescence

What is the integrated GINA model?

This explains how genetic predispositions (variants) and environmental factors (stress, trauma, drug exposure) interact to influence risk for disorders like addiction.

This model goes from exposure opportunity to the onset of use/experimentation, where we then go to occasional or casual use. This either leads to:

• cessation

• heavy episodic use (binge/intoxication), which leads to the three-stage addiction model

What is the anatomical model within the GINA framework?

The anatomical model focuses on specific brain regions and circuits involved in addiction (ex. the three-stage addiction model)

• prefrontal cortex is involved in preoccupation and craving, since the PFC is responsible for executive functioning

• striatum/midbrain is involved in heavy use (during binge/intoxication), which has to do with REWARD-related risk taking

  • we see polygenic risk here, meaning that multiple genes can contribute small effects that add up over time to influence traits (ex. vulnerability to addiction or risk-taking)

• limbic system is involved in the negative affect or withdrawal response

What are treatments for SUD?

Stopping usage cold-turkey is not treatment - while an inner core treatment plan that involves intake assessment, monitoring of substance use, and therapy/counseling can be developed, external/peripheral issues also need to be addressed in order for someone to “get clean” without relapsing.

• ex. child care services, vocational services, legal and financial services, transportation

While we can’t prevent all cases from beginning in the first place, we do harm reduction to avoid the more costly effects of SUD (overdose + death)

• ex. telling people not to use alone, only use one drug at a time, have a plan for if they OD, etc.

What are supervised consumption sites (which play a role in the harm reduction process)?

These are sites where drug users (ex. heroin addicts) can use in as safe of an environment as possible

• the heroin has been screened for fentanyl

• the point of these centers is to facilitate getting the person a hot meal or somewhere to stay for the night - to basically meet an addict where they are

• there is counseling and advice available for those who wish to begin the treatment/recovery process

What does it mean for drug use to be positively reinforced?

• addictive drugs have reinforcing effects - their effects include activation of the reinforcement mechanism (take this drug —> get the high; a learning signal is created through dopamine influx when VTA projects to nAcc)

• this activation strengthens the response that was just made - namely, taking the drug

• drugs with the most IMMEDIATE effects (the ones that reach the brain fastest) tend to be the most addictive - ex. nicotine through nose versus alcohol taken orally, heroin (intravenous drug) use compared to oral codeine/morphine use

How is drug use negatively reinforced?

Negative reinforcement in drug use happens when a person uses a drug to remove or reduce an unpleasant state, like anxiety, stress, withdrawal symptoms, etc.

• the relief that follows the use of the drug REINFORCES the behavior - it becomes more likely that the person will use again when they feel bad (so the behavior will increase in frequency)

• anticipation of these effects (ex. negative emotional states) can produce drug-taking before the negative feelings even occur

How can we measure addiction in the break point animal model?

• animals are trained to press a lever to receive a drug

• the more they press, the more motivated they are - which suggests drug-seeking behavior

• the break point is the maximum number of lever presses an animal is willing to make to receive a drug reward, as a measure of how “motivated” (addicted) it is.

• orexin is a neuropeptide that increases drug cravings - when we block it with an inhibitor/antagonist, we reduce those effects. The dopamine system becomes less responsive to drug cues, and the animal gives up sooner (has a lower break point)

• this particular antagonist (SB-5) selectively reduces ETHANOL responses

• we can test the break points for both ethanol and sucrose (comparing them to a water control group) to see how many times the lever is pressed.

  • sucrose vs water —> will the animals work for a natural reward

  • ethanol vs water —> to see addiction-like drug use

  • study showed similar responses for both; LOWERED breakpoint when orexin inhibitor was used

• we also see how much the rats are willing to press the lever EVEN WHEN THE DRUG HAS BEEN DISCONTINUED.

What is the difference in break point for long-acting (ex. morphine) and short-acting drugs

long-acting drugs = need to retake drug is reduced, not because the drug is less reinforcing but because the animal remains under the influence for longer, and its dopamine system remains saturated

• lower break point

short-acting drugs = animals come down quickly and will work harder to get back up, which means…

• they have a higher break point

What is conditioned place preference (in the context of measuring addiction in animal models)?

• learning to like the drug

• learning to associate the drug with salient cues (cues that were present during the high + can trigger drug cravings)

• respond to the cues alone

ex. in an experiment where a mouse is conditioned to get cheese from one side of a box, it will prefer to stay in the side where it got the cheese (meaning that the “drug” is being associated with the cues around it/the environment), even when the cheese has been substituted with a control stimulus (ex. saline solution)

How is mice CPP (conditioned place preference) affected by the preference of multiple drugs - do they provide an additive/summative effect?

Yes, we see a heightened place preference for cocaine + nicotine compared to just cocaine.

In an experiment, we also see that previous exposure to/experience with alcohol leads to an increase in cocaine-induced place conditioning (as in, cocaine is made available to the rats afterwards)

What happens to the nucleus accumbens (nAcc) and VTA after repeated cocaine self-administration (the rats are taking it voluntarily)?

We see LTP and synapse strengthening in the nAcc and VTA, mostly the glutaminergic inputs (from cortex) to dopamine neurons in the VTA (which are modulate the GABAergic MSNs in the nAcc, which express D1 or D2 receptors)

• other brain areas like cortex are also likely affected

• we also see dendritic branching/an increase in dendritic spine count in the PFC and nAcc

• this happens because the mice learn that the drug is rewarding

Does previous ethanol experience increase synaptic plasticity of NMDA receptors in the ventral tegmental area (VTA)?

Yes, ethanol exposure promotes NMDA/glutamate receptor plasticity (EPSPs) which leads to increased Ca2+ influx and IP3 sensitivity (which is important since IP3 is a second messenger that can release Ca2+ from intracellular stores)

What are the effects of early life stress in relation to addiction?

• stressful situations can cause a former addict to relapse

• also, stressful stimuli (even those that occur early in life) can increase an animal’s susceptibility to drug addiction in ways that can PARTIALLY MIMIC or SUBSTITUTE genetic risk.

• for example, taking infant rats away from their mother + littermates one hour per day for eight days caused them to take more drugs than non-stressed rats in adulthood

• basically, early life stress causes changes in the brain that persist into adulthood, and can make us more vulnerable to the development of disorders like addiction

Talk about the early life stress (isolated) rats versus the control rats - what difference was observed in their mean cocaine intake?

Control rats, at a certain low dosage of cocaine, showed little to no behavioral or neurochemical response - their reward systems didn’t detect the effect of the drug strongly.

• when dosage was low, intake also remained low because the rats had “no reason” to want it

In contrast, the isolated rats were much more sensitive to the same dose of cocaine (because even for low cocaine dosages, intake SPIKED)

• this indicates heightened sensitivity + reinforcing effects

• basically, the isolated rats showed a steeper dose-response curve (they consume more cocaine overall, and at lower doses)

What is the effect of stress and social satisfaction on susceptibility to developing addiction/substance use disorders? (hint: it has to do with D2 autoreceptors, which are located on the presynaptic terminal and inhibit DA release)

Animals that live in groups establish dominance hierarchies,

• dominant monkeys have more D2 receptors, and are less likely to self-administer drug —> demonstrate more resilience where addiction is concerned

• subordinate monkeys readily become addicted

• the question is whether early life stress affect D2 receptors

Can we conclusively state that drug use consistently lowers D2 receptor availability?

No, the results are mixed - stress may actually increase D2 receptors in some cases. This is theorized to be a compensatory (protective) mechanism, a result of the brain adapting to the stress.

Is there a negative correlation between D2 receptor count (in the nucleus accumbens) and the alcohol ingested?

Yes - low D2 receptor availability may mean the reward system is underactive or less responsive to natural rewards. This creates a kind of reward deficiency state, where individuals seek out STRONGER rewards to compensate

What is CRH, and how is stress associated with its release?

CRH is corticotripin-releasing hormone, (or factor). While it’s typically thought of as being released from the hypothalamus to the anterior pituitary (triggering the HPA axis)…

…it can also be released from the amygdala into the bed nucleus of the striatum.

• this is where it acts on the nucleus accumbens/nAcc (which is part of the striatum) and binds to CRHR1 and 2, which are CRH receptors.

• its release caused drug seeking REINSTATEMENT in rats that were formerly addicted.

How does CRH/CRF play different roles in acute stress versus chronic stress?

acute stress (adaptive function of CRH):

• the HPA axis is triggered, and leads to cortisol release

• alertness, arousal, and vigilance is initiated

• supports or enhances short-term memory, focused attention, and rapid decision-making (via the hippocampus and PFC)

chronic stress (maladaptive CRH overactivation):

• CRH signaling becomes dysregulated, which can damage the brain + body

• the amygdala is hyperactivated, which increases anxiety and fear

• prefrontal cortex is suppressed

the chronic stress can lead to a vicious cycle of stress that leads to brain changes and more stress sensitivity, which increases the risk of mental (psychiatric) illness or addiction

Do high responders to stress (animals or humans) release more extracellular DA ?

Yes - this means more dopamine gets dumped into the synapse under stress.

• the nucleus accumbens, which does have CRH receptors, is not responsible for this extracellular release. it’s the VTA, which also has CRH receptors + projects to the nAcc. HOWEVER, both start with the amygdala.

• CRH binds to CRH receptors on dopamine neurons in the VTA —> this increases dopamine neuron firing, which increases the RELEASE of dopamine on the postsynaptic neurons (PFC, nAcc)

  • in the VTA CRH acts like a dopamine release amplifier (increasing it)

• CRH is also released from the amygdala to the striatum (bed nucleus, potentially nAcc?), which modulates how dopamine is processed post-synaptically.

  • in the striatum CRH works to modulate the dopamine that has BEEN received

High responders to DA = they have a lot of CRH released from the amygdala (which may be overactivated under stress) onto the VTA, which will then release a LOT of dopamine onto the nucleus accumbens.

• sensitized (heightened) stress response, measured in DA release, is seen

Why do adrenalectomized (rats with their adrenal glands removed - think lobotomized) show low cocaine self-infusions across dosages, but control rats show a spike at a certain dosage?

Cocaine activates both

• the dopamine reward system (via blocking DAT and causing dopamine buildup in the synapses)

• the stress hormone system (amygdala activation, which leads to more CRH being released onto the VTA/binding to CRH receptors and increasing extracellular DA release)

  • in normal/control rats, the CRH release from the amygdala triggers the full HPA axis cascade: CRH —> ACTH from pituitary gland —> corticosterone (cortisol for rats) from the adrenal glands

  • in the adrenalectomized rats, the adrenal glands are missing. So while the upstream CRH release in the brain is intact, the downstream corticosterone release is NOT HAPPENING.

  • So we end up seeing the control rats ingest more cocaine (at a dosage that activates both the dopamine and stress pathways most optimally, and leads to the “best feeling”) than the adrenalectomized rats.

  • Basically, the control rats have their behavior reinforced more.

What effect does episodic activation of neural and hormonal stress mechanisms achieve?

Repeated stress activations/bursts of stress cause neural (beginning with CRH release from the amygdala) and hormonal (via corticosterone/cortisol release from adrenal glands) circuits to be activated MULTIPLE TIMES.

• these repeated stress activations cause CHANGES in brain chemistry and behavior

• the brain becomes more sensitive/sensitized to stress and drug-related cues

• this sensitization makes the person MORE LIKELY to seek out and take drugs in the future - even more than before.

• we can call this locomotor sensitization because in animal models, we can use increased movement as a measure of drug dosage

If CRF-R1 is overactive in the VTA, the brain might become sensitized (as in, overreact to cocaine)

• if an animal experienced social stress, like isolation, this could overact the CRH system (particularly in the VTA), which might make the animal more vulnerable to increased cocaine usage.

If we could block the stress response via CRF-R1 antagonist in the VTA, could we alleviate the effects of drugs and treat addiction?

CRF-R1 = excitatory/stress activating (and in the VTA, enhances dopamine release onto the nucleus accumbens)

• CRF-R2 is the modulatory/inhibitory receptor

There was an experiment where rats were randomized to 4 groups:

• non-stress (saline, or vehicle)

• non-stress (antagonist)

• stress (saline)

• non-stress (antagonist)

outcome variables (what we measure in a study to determine what effect the conditions have): locomotor sensitization (increased movement in response to repeated drug dosages), cocaine self-administration

Before exposing the animals to stress, some were given an antagonist (which blocks CRF-R1 receptors, which respond to the stress hormone CRF)

• this stops CRF-R1 from being activated

• they found that blocking CRF-R1 stopped this hyperactivity from developing (so NO stress-induced locomotor sensitization)

• also, animals under stress typically start taking more cocaine during a binge, but with CRF-R1 blocked, this increase in cocaine intake didn’t happen

Basically, CRF-R1 activation during stress is necessary for the brain changes (starting with more dopamine release) that make animals take MORE cocaine later

• so, since blocking the CRF (stress hormone) eceptor led to a reduction in cocaine intake, blocking the physiological effect of stress might be one way of treating

How do drugs affect the mesolimbic circuitry?

• nicotine activates dopaminegic neurons (class 2) via nicotinic acetylcholine receptors —> cholinergic neurons release acetylcholine (or we have nicotine as an agonist) and it binds to the nAChRs on dopaminergic neurons, which triggers a Ca2+ influx.

• alcohol inhibits GABAergic MSNs in the nucleus accumbens, but increases GABA transmission/signaling overall (class 2)

  • note: this works because these neurons both receive and release GABA. If they are receiving more GABA, they will be inhibited and release less GABA onto their own targets

• cocaine blocks the monoamine reuptake transporters (such as DAT, for dopamine), which keeps extracellular/synapse levels higher (class 3) —> class 3 drugs involve an increase in dopamine (in the VTA), which is for all addictive drugs.

• opiates inhibit GABAergic interneurons in the VTA that suppress dopamine neurons, leading to more activation.

Do we have an endogenous opioid system? What are examples of two endogenois opioids?

Yes. They are responsible for a lot of critical functions in the CNS and PNS, including but not limited to:

• reward and addiction

• mental illness

• mood states

• social bonding

• sexual activity

An example of two endogenous opioids are:

• enkephalins: bind to mu and delta opioid receptors and modulate pain, reward, mood, stress

  • found in the nucleus accumbens/nAcc

• dynorphins: bind to kappa opioid receptors, and produce stress effects. They COUNTERBALANCE the effects of enkephalins (work in the opposite direction

  • found in the striatum and hypothalamus

What are nociceptors and enkephalins?

These are (first order) sensory neurons in the PNS (their cell bodies are outside the spinal cord) with nerve endings in skin, muscles etc. Their job is to detect pain and harm.

• the nociceptors send signals to the spinal cord, which contains the neurons that process sensory information (second-order).

• Enkephalins bind to the mu and delta opioid receptors on these FIRST ORDER sensory neurons. This inhibits them from releasing neurotransmitter onto the second order neurons

  • this reduces the pain signal

  • so basically enkephalins play a modulatory role with pain (limiting pain)

  • exogenous opioids, like cocaine, can do what enkephalins do.

How do opioids and GABA relate to each other?

opiates like morphine or heroin bind to opioid receptors on GABAergic interneurons in the VTA.

• these opioid neurons are G-protein coupled and INHIBITORY (meaning that they open K+ channels when activated, sending in a hyperpolarizing current and REDUCING neurotransmitter release)

• if we inhibit the activity of the GABAergic neurons in the VTA….they will fire less….meaning they will inhibit their output less

• they modulate the dopaminergic neurons in

• So the nAcc DA neurons will release more

• however, destroying/inactivating the nucleus accumbens doesn’t take away heroin’s reinforcing effects (basically, heroin will still feel rewarding)

• the same is not true for amphetamine and cocaine - you DO need the nucleus accumbens to feel the reinforcing effects

Are there GABAergic neurons in both the VTA and the nucleus accumbens? Which type has opioid G-coupled receptors, and which type has D1 and D2 receptors?

There are GABAergic neurons in BOTH the VTA and nucleus accumbens/nAcc

VTA:

• interneurons; local circuit neurons that STAY within the VTA

• inhibit/modulate the dopaminergic neurons in the VTA itself

• have opioid receptors that are inhibitory (lead to opening of K+ channels)

nucleus accumbens:

• project to other brain structures (ventral pallidum, substantia nigra)

• receive dopamine input from the VTA and glutamate input from cortex/amygdala/hippocampus

• have D1 or D2 receptors

How is heroin different from amphetamines or cocaine in terms of needing the nucleus accumbens (or not!) in order to best feel the reinforcing effects?

cocaine and amphetamines

• increase dopamine in the nucleus accumbens

• so their rewarding effects DEPEND on the presence of the nucleus accumbens

heroin

• inhibits GABA neurons in the VTA

• this DECREASES their inhibitory output to dopaminergic neurons (which project to, and release DA in, the nucleus accumbens)

However, the GABAergic VTA neurons don’t JUST modulate the DA neurons - there are different ones can modulate other types of neurons too! So heroin is less “local” in its effects and getting rid of the nucleus accumbens won’t stop its reinforcing effects the same way it would for cocaine or amphetamines.

What is the opiate mechanism of negative reinforcement?

morphine usage leads to binding to opiate receptors meant for endogenous opioids.

• when these opioid receptors are activated (and remember, they are inhibitory - so not only will they open K+ channels, but they will also INHIBIT adenylyl cyclase which leads to LOWER cAMP levels), we see less protein kinase A activity

• if we don’t have enough protein kinase A, the cell will upregulate the signaling pathways being inhibited by morphine (as a compensatory mechanism) —> in order to restore cAMP levels to normal, we will need MORE adenylyl cyclase + protein kinase A

• this is basically tolerance

• when you remove the morphine, you end up with extra adenylyl cyclase/more PKA ready to phosphorylate their targets

• neurons fire more/become HYPEREXCITABLE. This drives negative reinforcement (i.e. taking the drug again to stop feeling so bad) because it creates symptoms like tremors and anxiety.

• physical symptoms are for locus coreulueus because it contains norepinephrine neurons, while the dysphoria (negative emotional state) is associated with the VTA

• This is because opioids (heroin, morphine) bind to GABAergic interneurons in the VTA that INHIBIT DA neurons —> without that inhibition, these neurons become hyperactive. So the brain eventually brings down their activity (while someone is using the drug) by downregulating dopamine receptor sensitivity/decreasing dopamine synthesis and release in the nucleus accumbens

• without the drug, your DA levels will crash (may go below baseline), leading to dysphoria and anhedonia (inability to experience pleasure from activities that would normally be pleasurable)

Why does heroin self-administration result in reduced mu receptor availability?

Because heroin is such a powerful agonist (has high affinity for mu receptors that are inhibitory/decrease cAMP and Ca2+ levels and bring in hyperpolarizing K+)…

…after a while the brain will internalize (pull into the cell) and downregulate the synthesis of mu receptors, in addition to desensitizing (so decreasing their effectiveness).

So over time we will end up seeing less receptors that might also be desensitized/completely nonfunctional

What is the difference between mu (μ) and kappa opioid receptors?

mu opioid receptors:

• meant for endogenous ligands like endorphins and enkephalins

• its role in reward is activating the reward circuit by disinhibiting the DA VTA neurons (by inhibiting the VTA’s GABAergic interneurons)

• it’s inhibitory, meaning it works by decreasing cAMP levels and increasing hyperpolarizing K+

kappa opioid receptors:

• meant for dynorphins (which are also endogenous opioids, but do the opposite of what you’d expect opioids to do) —> increase of dynorpins = decrease DA levels, increase dysphoria

• so activation of kappa opioid receptors —> occurs during stress, contributes to stress-induced relapse and negative reinforcement (ex. in the locus coeruleus

Both are found in many regions of the brain (nucleus accumbens/NAcc, amygdala, VTA, LC, etc.

How do cocaine and amphetamine behave? What is something amphetamine can do that cocaine can’t?

Both are DA agonists, not DA receptor agonists (so they increase the effects of dopamine). They bind to DAT (dopamine transporter) and prevent reuptake of DA from the synapse —> leads to DA buildup, more dopamine available to bind to D1 and D2 receptors.

• so they are indirect agonists, as opposed to being direct agonists

• crack cocaine has the same effects on dopamine release, but the effects are faster because you inhale it.

Amphetamine doesn’t just block the DAT like cocaine does, but also reverses its direction —> instead of dopamine being brought back into the cell from the synapse, we can have cytoplasmic dopamine being pumped INTO the synapse.

—> this makes amphetamines highly addictive/more intense than cocaine

What are the effects of cocaine/amphetamine abuse?

people who abuse these regularly experience:

• psychotic behavior

  • hallucinations

  • delusions of persecution

  • mood disturbances

  • repetitive motor behaviors

this is indistinguishable from schizophrenic episodes (which provided the earliest evidence that schizophrenia = caused by overactive dopamine terminals in the striatum

How does cocaine effect the epigenetic status of VTA neurons?

• dopamine receptor activation (indirectly achieved by cocaine, via blocking DAT) leads to intracellular signaling cascades that direct the binding of transcription factors to DNA

• this leads to an increase in transcription (and translation, as a result) of genes that are involved in neuroplasticity

• cocaine can increase HAT levels, which leads to an increase in acetylation (so the open/transcriptionally active chromatin conformation is favored) compared to a control, like a saline solution

• however, histone acetylation levels won’t increase “forever” —? eventually the HDACs will come back or become more active, leading to histone deacetylation and reducing gene expression

• this is a cycle (meaning that cocaine’s effects are dynamic/changing) —> addiction-related gene changes can be reversible

What is the difference between acute and chronic drug use, and what does that mean for gene regulation?

acute vs chronic drug use

• acute: single or limited exposure to drug use

  • leads to short-lived physiological and behavioral changes, rapid increase in dopamine

• chronic: repeated drug exposure over a longer time

  • includes the development of tolerance (you need more drug for the same effect) and epigenetic and adaptive changes in the brain

acute cocaine exposure:

• CREB phosphorylation

• CREB is a transcription factor, and promotes expression of pro-plasticity genes like FosB and BDNF (by binding to their promoters)

  • FosB: transcription factor that downregulates (DECREASES) dynorphin (which acts on kappa opioid receptors that are linked to stress/negative moods). FosB also binds to AMPA subunit and CDK-5 genes —> first enhances the response of postsynaptic cells to glutamate, the next enhances (mild) tau phosphorylation (which is necessary for it to bind to microtubules - it’s the hyperphosphorylation that is bad)

  • BDNF: strengthens synapses

How can we use epigenetic changes to work against the locomotor and conditioned place preferences of cocaine?

locomotor sensitization = stronger motor response with repeated exposure (ex. rat walking sober vs zipping around everywhere after receiving cocaine)

• basically cocaine induces hyperactivity (thru more dopamine in the substantia nigra, which activates the movement-promoting D1 MSNs)

If we increase (upregulate) histone deacetylase, this works against the increased acetylation (which causes neuroplasticity = drug-seeking behavior)

• consequently, if we use a HDAC inhibitor alongside cocaine, we can enhance conditioned place preference and locomotor sensitization (and HDAC inhibitors also mimic the effects of cocaine as well)

Do hard drugs account for more deaths than nicotine?

No, nicotine does. More people smoke than do any other drug. Most of the world’s smokers are from Asia

What works to prevent smoking:

• decrease in prevention

• advertising ban

• taxes on cigarettes

  • however, smoking is still around through vaping

How does nicotine work?

Nicotine stimulates acetylcholine receptors (it’s an ACh agonist)

• basically, VTA neurons receive this as an input and release dopamine as an output

• they project to the nucleus accumbens, so they release dopamine there

• blocking nicotinic receptors in the VTA inhibits the release of dopamine into the nucleus accumbens, which prevents reinforcement

• injection of a nicotine agonist into the VTA reinforces a CPP (preference for a specific place in accordance with the drug)

What effect does nicotine have on dopamine release?

Nicotine is a potent releaser of dopamine (because it activates nicotinic acetylcholine receptors on dopamine neurons in the VTA, leading to dopamine release in the nucleus accumbens) compared to a saline solution (control)

If you block nicotinic acetylcholine receptors with an antagonist, what happens when you try to activate them with nicotine?

Nicotine is prevented from activating nicotinic acetylcholine receptors (which stops the DA neurons from being excited, reduces their neuronal firing, and REDUCE dopamine release in the nucleus accumbens) in the VTA

• because remember, it would work on the VTA because the VTA DA neurons project to the nucleus accumbens

How does the mechanism of nicotine withdrawal work?

Nicotine does cause receptor activation, but it also leads to desensitization (since it can’t be degraded by acetylcholinesterase)

• normally AChE works by degrading acetylcholine so that it doesn’t remain too long in the synapse

• however, when receptors become desensitized (less effective when activated too long)…

• the brain compensates by upregulating (increasing) nicotinic acetylcholine receptors —> so this is the opposite of what we see with chronic activation of dopamine receptors (like what happens with cocaine)

• after abstaining or letting go of cocaine for a few weeks, the number of receptors does return to normal, but we keep seeing cravings

  • dopaminergic neurons in the VTA don’t only receive acetylcholine, but also glutamate (their main excitatory input)

  • glutamate is what directly excites the DA neurons, acetylcholine can depolarize neurons or enhance DA release

    • when both nicotine-induced depolarization and glutamate signaling happen together, NMDA receptors are activated (which strengthen the synapse thru Ca2+ influx —> AMPA receptor insertion) and LTP can happen, which enhances dopamine responses to cues

  • remember all addictive drugs (nicotine, cocaine, heroin) increase dopamine, so repeated use of one drug sensitizes the DA system + makes it more responsive to later drug exposure (and also reactivates the circuitry associated with past cocaine/heroin use and lead to relapse, which is known as cross-priming)

What is CHRNA-5? What does the genetic polymorphism involve?

It’s a subunit (in nicotinic acetylcholine receptors)

• with the genetic polymorphism, the receptor is less efficient and needs more stimulus to activate it, which leads to more cravings

What are the sites of action of alcohol?

• indirect agonist at GABA(A) receptors —> effect of GABA is enhanced —> hyperpolarization of the neuron via Cl-

• indirect antagonist at NMDA receptors —> which also works to increase GABA/inhibitory activity

Manipulation of BOTH of these systems trigger apoptosis via programmed cell death (since less firing = less activity = weakening of the synapse, leading to its loss (use it or lose it) = loss of BDNF (which promotes neuronal survival)

Also, the sedative effect of alcohol is from the GABA(A) receptor

Do neurons degenerate in rat cortex?

Yes. Brains were stained with an apoptosis marker, and we saw similar effects with GABA receptor agonist and an NMDA receptor antagonist (which both lead to an increase in neurodegeneration)

What are some important characteristics of fetal alcohol syndrome?

• leading cause of intellectual disabilities in the western world

• don’t meet cognitive milestones

• narrow forehead, small nose, long upper lip

What are the behavioral effects of alcohol?

At low doses alcohol produces mild euphoria and reduces anxiety (axiolytic), likely through inhibiting PFC activity

At higher doses alcohol produces uncoordination and sedation (via inhibition of activity in the cerebellum, necessary for motor coordination, and the parts of the brainstem that promote arousal and wakefulness)

Alcohol reduces the (punishing) effects of aversive stimuli (unpleasant experiences, like bright lights and loud noises) —> animals avoid these unpleasant experiences less, so they continue performing behaviors that would normally be suppressed by punishment

What provides positive and negative reinforcement for alcohol?

positive: mild euphoria

negative: anxiety relief (so if you stop drinking, your anxiety will return)

the combination of these effects is likely behind the high abuse (drinking) rates of alcohol

How does alcohol actually work in the brain?

• alcohol, like other addictive drugs, increases the activity of the dopaminergic neurons in the mesolimbic system (ex. VTA) and increases the release of dopamine in the nucleus accumbens

• the D2 dopamine receptor antagonist halperidol can block the euphoric effects of alcohol

What is the mechanism for alcohol withdrawal?

• alcohol antagonizes NMDA receptors (meaning that it can be an antagonist for NMDA receptors - not a very powerful one, but still)

  • this leads to the upregulation of NMDA receptors, and once you get off alcohol, you end up with a massive synchronized excitation that can lead to serious withdrawal symptoms (convulsions) —> so basically NMDA receptors are responsible for alcohol withdrawal seizures.

How does cannabis/marijuana work?

THC (active ingredient in marijuana) binds to a receptor in the brain that is meant for endogenous cannabinoids (known as CB1)

• CB1 is an inhibitory G-coupled receptor, and is found in lots of areas in the brain

• for example, marijuana can disrupt normal hippocampal functioning and lead to your memory being affected (via LTP/LTD effects —> long term cognitive decline?)

• loss of coordination (similar to what we see in alcohol) can happen with receptor activation in the cerebellum

What promotes the reinforcing effects of THC?

stimulated release of dopamine in the nucleus accumbens (because the VTA neurons project there) via inhibition of GABA

THC (marijuana) is addictve even though it doesn’t produce the same withdrawal symptoms as something like alcohol

• acute use = euphoria, chronic use = tolerance to behavioral effects (reduction in the production of endogenous cannabinoids)

• long term marijuana use can lead to bronchitis, slower choices in decision making tasks, minor impairments in attention and memory, subtle cognitive deficits

We see a shift from goal-directed (conscious) behavior with the reward circuit (VTA —> nucleus accumbens) being used less in favor of using the dorsolateral striatum (“I use it without thinking about it”)

• LTP happens in striatum to strengthen the formation of “automatic” habits

We might also see increased risk for psychosis or schizophrenia after chronic marijuana use