Addiction

drug addiction

chronic, relapsing brain disease that is characterized by compulsive drug seeking and use, despite harmful consequences (National Institute on Drug Abuse)

over __% of patients experience a relapse

40

over __% of the US population has a lifetime prevalence of drug use disorders

9

over ______ drug overdose deaths occurred in the 12 months ending in May 2020, the highest number of overdose deaths ever recorded in a 12-month period

81,000

drug addiction costs the US over $______________ dollars in law enforcement, healthcare, and lost wages

700 billion

DSM-V

gold standard text on the names, symptoms, and diagnostic features of mental illness, including addictions

according to DSM-V, when do substance use disorders occur?

when the recurrent use of a drug causes clinical and functional impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home

DSM-V: nine types of substance-related disorders

alcohol; caffeine; cannabis (e.g. marijuana); hallucinogens (e.g. lysergic acid diethylamide or LSD); inhalants (solvents, aerosols, ether, nitrous oxide); opioid (e.g. heroin), sedatives, hypnotics or anxiolytics (e.g. valium); stimulants (cocaine, methamphetamine); tobacco

most commonly abused substances

tobacco, alcohol, marijuana, opioids

substance-induced disorders (DSM-V)

intoxication, withdrawal, mental disorders (including psychosis, bipolar disorders, depression, anxiety, OCD, sleep disorders, sexual dysfunctions, delirium, cognitive disorders)

substance use disorders (DSM-V)

maladaptive pattern of substance use leading to clinically and functionally significant impairment, despite experiencing problems as a result, and occurring within a 12-month period

how many criteria must one meet to have a mild substance use disorder? (DSM-V)

2-3

how many criteria must one meet to have a moderate substance use disorder? (DSM-V)

4-5

how many criteria must one meet to have a severe substance use disorder? (DSM-V)

6-7

criteria for substance use disorders

1. taking the substance in larger amounts or for longer than intended
2. wanting to cut down or stop using the substance but not managing to
3. spending a lot of time getting, using, or recovering from the use of the substance
4. cravings and urges to use the substance
5. repeatedly unable to carry out major obligations at work, school, or home because of substance use
6. continuing to use despite persistent or recurring social or interpersonal problems caused or made worse by substance use
7. giving up important social, occupational, or recreational activities because of substance use
8. recurrent use of substances in physically hazardous situations
9. consistent use despite acknowledgement of persistent or recurrent physical or psychological difficulties caused or made worse by the substance
10. needing more of the substance to get the desired effect (tolerance)
11. development of withdrawal symptoms, which can be relieved by taking more of the substance

tolerance

* a need for markedly increased amounts of the substance to achieve intoxication or the desired effect
* markedly diminished effect with continued use of the same amount of substance

withdrawal

* the characteristic withdrawal syndrome for the substance
* the same (or closely related) substance is taken to relieve or avoid withdrawal symptoms

risk factors for addiction

genetics, sex, adolescence, mental disorders, route/pattern of drug administration, early life stress/abuse, community/social acceptance, personality traits

why are genetics a risk factor for addiction?

particular genes account for only a small amount of risk for addiction

why is sex a risk factor for addiction?

historically, females have not abused drugs to the degree that males do, but it is clear that being female (perhaps due to ovarian hormones) increases the likelihood to become addicted

how is adolescence a risk factor for addiction?

the earlier in life someone begins using drugs, the greater the likelihood of addiction

how is route/pattern of drug administration a risk factor for addiction?

smoking or injecting drugs increases addiction

how are early life stresses/abuse a risk factor for addiction?

growing up in difficult, stressful circumstances or explicitly suffering from abuse

how is community/social acceptance a risk factor for addiction?

environments of acceptance, either in the family or community, can increase the chances of addiction

how are personality traits a risk factor for addiction?

impulsiveness is a character trait that increases the likelihood of addiction

what neurotransmitter is involved with positive and negative reinforcement, as it relates to addiction?

dopamine

positive reinforcement

drug = good, rewarding effects in the brain

drugs → memory trace of euphoria → drug cravings and compulsive drug seeking

negative reinforcement

no drug = bad

where does the ventral tegmental area (VTA) project to?

nucleus accumbens

dopamine transporter function

dopamine reuptake, cleans the synapse

how does cocaine affect the synapse?

blocks dopamine transporters; dopamine stays in the synapse and increases in concentration due to block of reuptake

what type of receptors are dopamine receptors?

G-protein coupled receptors (GPCRs)

how do G-protein coupled receptors (GPCRs) act?

via a “signaling cascade”

ventral tegmental area (VTA)

a key source of “rewarding” dopamine

which part of the brain is the nucleus accumbens in?

ventral striatum, which is part of the basal ganglia

how does dopamine facilitate repetitive behavior?

when we get a reward, we have a peak of dopamine because our neurons release dopamine, which makes you feel good and excited; we want more of this

types and description of opioid receptors

mu-opioid, delta-opioid, kappa-opioid

all are Gi-coupled GPCRs and inhibitory

in which regions important for dopamine signaling are opioid receptors located?

ventral tegmental area (VTA) and nucleus accumbens

result of activation of opioid receptors

increased signaling through ‘reward circuitry’

how do opioid receptors act presynaptically?

decrease neurotransmitter release, often by inhibiting voltage-gated Ca+2 channels (results in decreased postsynaptic response

how do opioid receptors act postsynaptically?

cause hyperpolarization, usually by activation of K+ channels (e.g. GIRKS)

endogenous opioids examples

enkephalins, dynorphins, endorphins (play an important role in the pain system)

exogenous opioids

come from external sources; e.g. morphine, codeine, heroin, methadone, fentanyl

efficacy

how much of an effect a drug can have

potency

how much of the drug to get 1/2 max response of that drug

Which has a greater potency, morphine or fentanyl?

Which has a greater efficacy, morphine or buprenorphine?

fentanyl; morphine

cannabinoid receptors and description

CB1 and CB2; both are Gi-coupled GPCRs, both are inhibitory

endocannabinoid release

they simply diffuse across the membrane, which is distinct from other neurotransmitters, and are often used as “retrograde messengers”

retrograde

released from postsynaptic neuron to presynaptic neuron

where is CB1 found?

many different places in the brain, including the nucleus accumbens

how do CB1 receptors act presynaptically?

decrease neurotransmitter release, often by inhibiting voltage-gated Ca+2 channels

what is true of both opioid receptors and cannabinoid receptors?

* Gi-coupled GPCRs
* can be located pre- or post- synaptically
* inhibitory, presynaptically they inhibit neurotransmitter release
* can be expressed as interneurons that would normally inhibit reward signaling
* can caused increased reward signaling via disinhibition

what does nicotine bind to?

glutamate, GABA, serotonin, dopamine, opioids, cannabinoids, acetylcholine (ACh)

what two receptors can Acetylcholine (ACh) receptors be?

1. ligand gated channels; called “nicotinic,” because nicotine binds to them
2. G protein-coupled receptors (GPCRs); called “muscarinic,” because they bind a different drug called muscarine

are nicotinic acetylcholine receptors excitatory or inhibitory? which ion do they let in or inhibit?

excitatory, let Na+ in

what receptors does EtOH act on?

GABA(A); increases the release of GABA

what happens when GABA binds to GABA(A) receptors?

ligand-gated channels (GABA(A)) allow Cl- to follow into the cell, hyperpolarizing it, and making it less likely to fire an action potential

where all is GABA(A) found?

postsynaptic at the synapse; extra synaptically, where ambient GABA can activate them, (these receptors mediate a form of “tonic inhibition”); extra synaptic GABA(A) receptors are found in lots of places in the brain, including the cerebellum (motor), hippocampus (memory), and reward circuitry elements (reward)

why is EtOH considered a “dirty drug”?

acts in lots of places in the brain, sometimes with sweeping effects, sometimes with highly targeted effects

what happens when neurons in ventral tegmental area (VTA) are inhibited?

less dopamine released in the nucleus accumbens

what things does ACh play an important role in?

attention, theta oscillations

where are nicotinic ACh receptors found?

all over the brain, including on VTA neurons and their terminals in the nucleus accumbens

If Neuron A was GABAergic, and Neuron B was glutamergic, and Neuron B but not Neuron A expressed nAChRs, what would be the effect on Cell B if the neurons were exposed to nicotine?

there will be an excitatory response; when the nicotine joins to the nicotinic receptors, there will be increase

what causes the depression feeling when we drink?

when Cl- enters the cell, neurons are hyperpolarized

If Neuron A was GABAergic (and pretty active), and Neuron B but not Neuron A expressed both synaptic and extrasynaptic GABA(A) receptors, what would be the effect on Cell B if the neurons were exposed to alcohol EtOH?

neurons would hyperpolarize; alcohol inhibits the function and action of Neuron B

what can result from activation of opioid receptors?

increased signaling through ‘reward circuitry’

If Neuron A was GABAergic and expressed opioid receptors, and Neuron B expressed GABA(A) receptors but not opioid receptors, what would be the effect on Cell B if the neurons were exposed to morphine?

when Neuron A is exposed to opioids, opioids will inhibit the action of releasing GABA (less is released); Cell B is more active because inhibition is being inhibited (receiving less inhibitory GABA)

If Neuron A was GABAergic and expressed CB1 receptors, and Neuron B expressed GABA(A) receptors but not CB1 receptors, what would be the effect on Cell B if the neurons were exposed to THC?

THC is an exogenous cannabinoid, which means it is not released by neurons; THC will decrease release of GABA in Neuron A, so Neuron A’s inhibition is inhibited, so Neuron B will be more active

acute drug use can also cause longer lasting changes, including…?

(maladaptive) plasticity

Activation of mu opioid receptors allows the disinhibition of neurons (by inhibiting inhibitory interneurons) which can in turn dampen pain signaling via downstream actions. If this happened, and then you took an opioid again, would you have an increased or decreased response to that opioid? What would that be an example of?

decreased response; tolerance

what can occur when opioid receptors are strongly activated?

desensitize (stop signaling), be internalized (stop being where they can be activated), or change their signaling properties

negative reinforcement

the process by which removal of an aversive stimulus, (or aversive state, in the case of addiction), increases the probability of a response

three stages of addiction

1. binge/intoxication
2. withdrawal/negative effect
3. preoccupation/anticipation

drug pharmacodynamics

mechanism of action of a drug to produce the biological effects

drug pharmacokinetics

relation between drug intake and amount of drug active at the site

factors that determine the potency, side effects, and duration of a drug

absorption, distribution, metabolism, excretion

why does pharmacokinetic tolerance occur?

because a decreased quantity of the substance reaches the action; for example, the liver gets more efficient at breaking down the drug (e.g. alcohol) before it gets to the brain

treatment of drug addiction goals

help patient stop using drugs; help patient stay drug-free; help patient be productive with family, work, and society

treatments for drug addiction

medication, medical devices, behavioral counseling, treatment of comorbidities, long-term feedback to prevent relapse

opioid treatment options

methadone (full agonist), buprenorphine (partial agonist), naltrexone (competitive antagonist)

ligand

binds to a receptor

agonist

activates receptor

partial agonist

activates receptors, but less than a “full agonist”

antagonist

blocks/inhibits

competitive antagonist

binds at the same site as the agonist

medications to treat nicotine

patch, spray, gum, lozenges, varenicline, bupropion, TMS

varenicline

partial agonist of nicotinic acetylcholine receptors

bupropion

competitive antagonist of nicotinic acetylcholine receptors

alcohol treatment options

acamprosate (decreased withdrawal signs), disulfiram (decreased alcohol breakdown)

outpatient behavioral treatment includes

cognitive behavioral therapy, multidimensional family therapy, motivational interviewing, motivational incentives