lecture 6 & 7 - Neurobiology of Addiction

what is a drug? (plants, herbs, supplaments, medicine)

• is addiction a “Brain Disease”? A habit? Self-medication? 

• should we consider existence of “behavioral” addiction? (e.g., gambling, internet gaming, sex addiction)

• should governments care/have a say in what substances their citizens use?

• does culture matter? (e.g., religious practices)

• should all (or some?) currently illegal drugs be legalized? decriminaled? medical? recreational? harm reduction or prohibition?

drug regulation: some history

• Pure Food & Drug Act (1906) → required “patent” medicines to have labels, w/ contents

  • created the Food & Drug Administration (FDA)

• Harrison Narcotic Tax Act (1914) → regulated & taxed cocaine & opiates - (fun fact → in 1921, cigarettes were illegal in 14 states)

• Prohibition (1920-1933) → 18th Amendment to US constitution, prohibited production sale, & transport of “intoxicating liquors”

  • DID lower US drinking rate

  • repealed by 21st Amendment

• Marijuana Tax Act (1937): outlawed non-medical (untaxed) possession of opium, morphine, heroin & marijuana

•  Controlled Subtance Act (C.S.A., 1970): 

  • established D.E.A. (Drug Enforcement Administration), 5 drug “schedules”, based on medical use, abuse potential, risk of dependency

  • President Nixon declares the “War on Drugs”

• Federal Analogue Act (1986): due to appearance of “designer drugs” altered molecules would be technically legal

  • this act closed the loophole; any chemical “substantially similar” to a Schedule I or II drug intended for human consumption would be treated as Schedule I

CSA & DEA Substances

• Schedule I: Substances in this schedule have →

  • no currently accepted medical use in the US

  • a lack of accepted safety for use under medical supervision &

  • a potential for abuse

• Schedule II: substances have a high potential for abuse, which may lead to severe psychological or physical dependence

• Schedule III: Substances have less potential for abuse than substances in Schedules I or II & may lead to moderate or low physical dependence or high psychological dependence

• Schedule IV: substances have a low potential for abuse relative to substances in Schedule III

• Schedule V: substances have a low potential for abuse relative to substances listed in Schedule IV & consist primarily of preparations containing limited quantities of certain opiates

DEA Schedules: Shifting legality of “Kratom”

• supposed to help w/ opiate addiction

what drugs are the most “dangerous”?

• AD/LD vs. Dependence Potential

  • highest = heroin

  • lowest = LSD

Drugs harms beyond addiction - UK Drug Harms Study (2010)

• high score = most harmful

• ex: highest score → alcohol

HHS, SAMHSA, & the NSDUH

• US Govt. Dept. of Health & Human Services (HHS)

  • has a division called Substance Abuse & Mental Health Services Administration (SAMHSA)

    • & they produce the National Survey on Drug Use & Health (NSDUH)

“Downward Spiral” of Addiction Processes:

1. Preoccupation/Anticipation

2. Binge/Intoxication

3. Withdrawal

• taken in large amounts than intended

• preoccupation w/ obtaining

• persistant physical or psychological problem

• persistant desire

• tolerance/withdrawal

• social, occupational, or recreational activities compromised

• spiraling distress

• → addiction

DSM-5: Substance USe Disorder

• 11 criteria → 2-3 = mild, 4-5 = moderate, 6+ = severe

1. taking the substance in larger amounts or for longer than meant to

2. wanting to cut down or stop using the substance but not managing to do so

3. spending a lot of time getting, using, or recovering from use of substance

4. cravings & urges to use the substance

• ^^ impaired control

5. not managing to do what you should do at work, home, or school, because of substance use

6. continuing to use, even when it causes problems in relationships

7. giving up important social, occupational, or recreational activities bc of substance use

• ^^ social impairment

8. using substances again & again, even when it puts you in danger

9. continuing to use, even when you know you have a physical or psychological problem that could have been caused or made worse by the substance

• ^^ risky use

10. needing more of the substance to get the effect you want (tolerance)

11. development of withdrawal symptoms, which can be relieved by taking more of the substance 

• ^^ pharm dependence

Nucleus Accumbens (NAc), Motivation, & Addiction

• (Mesolimbic DA System)

• Olds & Milner (1954): rats allowed to self-stimulate their brain

  • medial forebrain bundle (MFB) → was a area they compulsively stimulated (hundreds of time/hr)

  • this bundle connects ventral tegmental area (VTA) to the → 

  • nucleus accumbens (NAc): contains high # of DA receptors, this turned out to be the key brain area for this effects

• “Reward”: pleasurable sensations or effects experienced from a substance or activity (e.g., food, sex, psychoactive drugs)

  • but NAc is NOT a “pleasure center” in the center

  • NAc is a motivation/seeking system

DA Levels in Response to Activities

• 50 n/dl = normal day

• 40 n/dl = worst day

• 100 n/dl = best day

• 94 n/dl = favorite food 

• 92 n/dl = sex

• Drugs & DA =>

  • 100-300 n/dl = alcohol, THC, heroin

  • 1,100 n/dl = metamphetamine

Dr. H. Research into Evo. of NAc

NAc: evolutionary old structure, some form of it present in all vertebrates (e.g., birds)

Mesolimbic Dopamine Systems in Addiction

• “Reward Pathway”: brain systems underlying motivation to seek, & getting pleasurable sensations form, or activities or substances (e.g., sex, food, drugs) 

  • two hypothesized phases of motivated behavior:

    • “Wanting” or Intcentive-Salience: stimuli that focus attention & trigger seeking behavior

    • “Liking or Hedonic Value: pleasurable sensations, satisfaction, euphoria

    • incentive → something to get you to do something

    • salience → something that stands out to get you to pay attention

    • hedonic → pleasurable

“Wanting” & “Liking” in the Addiction Process

1. Initial drug intake

2. experienced pleasure

3. repeated drug consumption

4. reduced pleasure (tolerance)

5. increased drug intake to acheive previous levels of “liking”

6. incentive sensitization of “wanting” circuits for drugs & their cues

7. Compulsive drug taking

8. abstinence/withdrawal

9. drug-associated cues act as potent trigger of craving & relapse

10. relapse

wanting (DA) ↔ liking (opiates, cannabinoids)

pharmacodynamics tolerance: role in withdrawal & tolerance

• neurons dynamically respond to drug-induced… over-active synapses by desensitizing or down-regulating

or 

• under-active synapses by sensitizing or up-regulating “Hangover” symptoms & withdrawal are the brain trying to rebound back to homeostasis 

Drug Craving, Cortical Glutamate & Relapse

• craving = “learned wanting”

• Prefrontal cortex, esp. Orbito Cortex (OFC): area in addicts becomes hypo-sensitive (less) to natural rewards, but hyper-sensitive (more) to drug-related cues

  • drug craving: drug experience memories & learned “triggers” lead to preoccupation w/ drug taking

  • driving cravings is OFC release of Glu, stimulating AMPA & mGluR receptors located on mesolimbic neurons (VTA & NAc)

Intoxication, Withdrawal, & Craving in the Brain

• wanting (incentive-salience) → mesolimbic system; release of DA

• liking (hedonic value) → mesolimbic system; release of endogenous opiods & cannabinoids

• withdrawal → amygdala; dysphoria, anxiety; release of dynorphin [makes you feel unpleasant] & CRF (Corticotrophin-releasing factor - stress inducing substance)

• craving (preoccupation, relapse): OFC & hippocampus; release of glutamate (stimulate Mesolimbic system) 

is addiction a brain disease? label matter

• “the message that addiction is a disease makes substance user less likely to seek help”

  • taking about addition as a disease => decrease self-efficacy 

Prefrontal Cortex (PFC) & Addiction Risk

“at risk” PFC → genetic predisposition, prenatal drug exposure, early-life stress (ACEs - adverse childhood experience, neglect)

variables that promote relapse

• in rat models of addiction, these factors lead to relapse (cocaine-seeking)

  • during cocaine = elevated reposne

  • during extinction = low or no response

  • during cocaine reinstatement = back to cocaine self-admistration response

• increase chance of relapse:

  • cocaine-related cues

  • small dose IV cocaine

  • mild stressor (brief shock)

  • ^^^ ex: cocaine or cue-induced reinstatement

agonists & antagonists drugs as treatment for SUD

• substitution treatment (agnoist - ex: methodone)

  • act similarly to opitates

  • stimulate opiate reception

  • alleviate or stop cravings for opiates

  • do not produce a rush (except for morphine or heroin)

  • can produce or maintain physical dependence (eventually wean them off)

• blocking or aversion treatment (antagonists)

  • block the action of opiates

  • block opiate reaction

  • do not produce a rush

  • do not produce physical dependence

pharmacologic approaches to drug use

• drugs for detoxification

  • rescue from overdose and/or reduce withdrawal symptoms

    • e.g., benzodiazepines for alcohol detoxification (i.e., reduce risk of seizures) 

• agonist substitution

  • activate same drug pathways but less intensely, goal to “wean off” drugs

    • e.g., methadone for heroin

• partial agonist substitution

  • similarly conceptually to using full agonist

    • e.g., varencline (Chantix) for nicotine

• antagonists

  • block effects of abused drug, but may produce withdrawal, or unpredictable overdose in relapse

    • e.g., naltrexone for opioid or methamphetamine

treating addictions: naltrexone + buproprion for Meth Use Disorder

• randomly drug test them

• ~5% of placebo participants had negative urine samples

• ~30% of naltrexone-bupropion had negative urine samples

pharm approaches to drug abuse

• anti-craving approaches

  • GABA agonists, glutamate antagonists: potential for reducing reinforcement & cravings, relapse

    • e.g., topiramate (Topamax) off-label: alcohol, cocaine abuse

      • (originally anti-seizure medication)

• “new directions in treatment”

  • vaccines: create drug-specific antibodies to “immunize” a person against relapse, prevent drug from crossing BBB

  • Psychedelic-Assisted Psychotherapy (e.g., psilocybin, ayahuasca) may potentially be helpful, but research is mixed on long-term benefits

  • GLP-1 → may also potentially help treat drug addiction

Treating Addictions: Topiramate for Cocaine Use Disorder

• Placebo group → don’t change much from baseline

• topiramate group → ~60% to ~75% → increase in recovery