final prep

  • intoxication

    • Aside from these sites of action what happens when drugs are taken durring intoxication?

      • changes in dominant frequency bands

        • EEG (elctric changes in scalp)

        • Diff drugs (wih diff effects) differentally alter these frequencies

          • nicotein shifts towards more alter (higher)

          • alcohol shifts towards less alert (lower)

        • Increases in alpha frequencies may underline the feelings of eupohoria durring acute intoxication

      • Changes in glucose metabolism

        • 10-30% decrease in metabolism with alcohol

        • shifts glucose metabolism towards nucleus accumbens and amygdala (these regions see an increase in glucose metabolism)

      • changes in blood flow (shifting where in the brain gets more or less blood)

      • changes in functions of brain regons assocated with cognitive ablities

        • aligns with intoxication: for alchol regions associated with attention, spatial reasoning, motor control, emotional processing

        • includes anterior cingulate, basal ganglia, amygdala

    • Distrabution: How do drugs effect brain

      • Many mechamisms to move drugs across blood brain barrier

      • More lipophilic drugs will have more success crossing blood brain barrier

      • Transporters pump drugs out of the cell back into the blood

  • Blood brain barrier

    • interactions with the endothelium and glia

    • permiablity changes as a result of local signaling, including inflamation

    • ???can change peramablity to stop drugs from getting to brain??? may be a way to stop brain from feeling drugs

  • Agonist spectrum-ligana gatted ion channles

    • angonist fully opens channle

      • drug & nerotranmiter

    • Partial agonist open channle some

    • Antagonist block receptor but it might open a little sometimes (basline level of iron flow)

    • Anti angonist stop any flow

  • Mechanisms of action

      • Drugs of abuse hijack dopamine system

        • either changes in how much dopamine neurons (that relaease sopamine atb their synapses) have action potentials

        • or changes how that dopamine works in the synapse- preventing reuptake, increasing amount of released dopamine, binding to dopamine, ect.

      • This gen a change between in the stength of connections between these regons

        • In the non-addicted brain the top down

          control provided by ACC, PFC, and OFC can

          override the drive towards rewarding stimuli

          • Juice

          • Paraphernalia for an addict

        • As addiction makes structural and

          functional changes to how these systems

          interact the drive towards drug related

          stimuli overwhelms the ability to regulate

          behavior

          • IIncreased drive from VTA and Nac towards action

          • OFC, amygdala, and hippocampus also drive activity towards drug related behavior

          • PFC increasingly is unable to regulate the activity in these other systems

  • Alchol

    • where does it exert its effect

      • widespread interactio

        • no one recpetor that it binds too

        • ion channles

    • The impact on dopamine neurons

      • NMDA receptors help inhibit VTA dopamine

        • alchol disninhibits VTA

        • NMDA antagonists can mimic alcohol (rat discrimination test)

      • Voltage gated potassium channles regulate (reduce) exitablity of VTA dopamine neurons

        • alchol reduces that regulation

    • Chronic exposure

      • NMDA channles up regulate overtime- more channles get stuck in membrane b/c they are chronicly inhibited

      • This can cause sesure durring withdrawl

        • delerum tremens (the shakes)

        • 3 days into withdrwal lasts 2-3 days

        • can result in death

  • Nicotine

    • Receptors adapt over time and exposure

      • Desensitization: with the continuous presence of the agonist, over time leads to another conformational change where the receptor essentially stops responding to the agonist even though the agonist is still present

        • can be reversed quickly by removal of the agonist

      • Inactivation: if the agonist stays much longer, on the order of hours, the receptor converts from a state of simple desensitization to one of inactivation

        • This state does not reverse simply upon removal of the agonist, since it also takes hours in the absence of agonist to revert back to the resting state where the receptor is again sensitive to new exposure to agonist

      • Natral break down cant happen with nicotine so ions stop getting thro, receptors are inactivated and takes an hour before they can handle acytocoline again

      • Increasing recpetors at synapse so brain can handle acytocoline

      • over activates actoylonine they then then crash out and dont work anymore temoparilly

      • ROLE in addiction circut:

        • 2 locations where dopamine is modulated:

          • VTA

          • NAc

        • VTA: Nicotine activates and then inactivates presynaptic glutamate terminals -> increased excitation of VTA dopamine

        • NAc: Nicotine activates and then inactivates nicotinic Acetylecholine Receptors (nAChRs) on VTA dopamine neurons and modulates the firing of VTA neurons

          • Ach synapses on dopamine neuron terminals to increase dopamine

      • in the VTA

        • gliutamate excites VTA

        • GABA inhibits VTA

        • Differences in inactivation across receptor types means gaba is stopped while glutamate is increased

        • Dopamine is increased

      • Accumbens dopamine also increased

        • Presynaptic ach receptors in Nac increase dopamine release

    • Steps of response

      • Initially, the brain is free of nicotine, and nAChRs should be responding normally to cholinergic synaptic activity

      • When nicotine first arrives, nAChRs are activated, causing the neurons to depolarize and fire action potentials

      • DA neurons are activated, contributing to the increase in DA in the nucleus accumbens

      • As the nicotine from the cigarette lingers, desensitization of nAChRs begins.

        • more than a few cigs in a row

        • There is considerable variability in desensitization of the various nAChR subtypes

  • STIMULANTS

    • Caffine

      • Adenosine 2A receptor antagonist

        • Prevents the inhibition of VTA dopamine by

        adenosine

        • Metabolism (glucose and ATP) leads to adenosine

        build up over the day.

        • This build up inhibits VTA activity and makes us

        tired.

        • Blocking the adenosine leads to more dopamine

        and more motivation/ energy/ effort

    • Cocaine / methylphenidate (Ritalin)

      • Reuptake transporter inhibitor

        • Monoamines (serotonin, norepinephrine, dopamine)

        • Drugs bind outside of the cell to prevent the reuptake of the neurotransmitter

      • Reuptake transport

        • After the vesicle releases neurotransmitter into the cleft

          • The neurotransmitter is floating in the fluid of the synapse

          • Channels on the presynaptic membrane take up the neurotransmitter for re use or recycling within the pre-synaptic cell

          • This is reuptake transport

      • The effect

        • Same story as anti depressents

        • taken back thro cell thro uptake

        • When those are blocked more nerotranmiters left to bind

    • Amphetamine

      • Laboratory-manufactured stimulant drugs

        • Examples: Amphetamine, dextroamphetamine, methamphetamine

        • pill/ capsule form

      • Reverse the dopamine transporter rather than blocking it

        • Prevent vesicles from filling with dopamine

        • No dopsamine being taken from vessicles

        • cosses contraintion gradent into cell

      • Misuse common among college students

        • Almost 1 in 10 undergraduates acquire amphetamines or related stimulants without prescriptions.

      • Once neurotransmitters are taken into the cell they get recycled

        • Transporters are also used to put previously used neurotransmitters into vesicles

        • Therefore, these transporters can directly affect how much neurotransmitter is available in the synapse

          • through reuptake and thro vescicle content

  • Opiods

    • methodone

    • fentanal

    • Bilogical mechanisms

      • Opioids are agonists to the μ-opioid receptor

        • Involved in pleasure and in reducing pain

        • Therapeutic pain sites are in the spinal cord and thalamus where pain signals get relayed from the body into the brain

          • Opioids are highly effective at stimulating second messengers from g-protein coupling

    • Role in addiction circut

      • Mu opioid receptors are on the pre-synaptic gaba neurons in the VTA

      • Activation of the opioid receptors reduce gaba release

      • Reduced inhibition from gaba leads to increased dopamine to the Nucleus accumbens

  • Cannabionids

    • Many forms of THC

    • Major active ingredient: Δ9-Tetrahydrocannabinol (THC)

      • When smoked, produces a mixture of hallucinogenic, depressant, and stimulant effects, known as cannabis intoxication

      • Targets the CB receptors (retro messengers)

      • Most of the effects last 2 to 6 hours.

    • Other forms of THC

      • Delta 8 THC

      • THCA

        • These gat converted into THC when heated

          • Syntehtic THC

          • legal loop holes

      • Cannabidiol (CBD)

        • no high

        • potential medical benefits

      • Terpenes

    • Role in addiction circut

      • Cannabinoids increase dopamine

      • Also increase endogenous (natural) opioid release (so the role of opioids in addiction is also part of the story here too!)

      • Cannabinoids as a retromessenger affect glutamate excitation in the VTA

    • Role in VTA

      •  Retro messengers reduce firing

        rates

      • Can suppress excitation

        • If GABA interneurons are hit they will inhibit less

        • If glutamate neurons that excites GABA interneurons are hit they will excite inhibitors less

  • Hallucagions (unlikely)

  • Withdrawl and cravings

    • why is craving hard to mesure

    • HPA AXIS

      • CHonicaly overactive in states of chronic use

      • Balance highs and lows (When stop taking no more highs so left with a chronic low)

      • Changes in how the hypothalamus triggers this system at baseline leads to more stress during withdrawals

      • Leads to heightened stress response

      • Blocking corticotropin-releasing factor (CRF) that the hypothalamus uses to activate the pituitary gland can alleviate some of the anxiety and stress of withdrawal

      • Slow to regain a pre-addiction baseline

    • Protracted withdrawal

      • Changes in activity across frequency bands

        • Changes in sychronous activity in the brain

        • Just like with intoxication the patterns of these changes differ between drugs

    • Pharmacological solutions

      • Drugs that block opioid receptors

        • Buprenorphine or Naloxone

        • Can cut relapse rates by 50%

      • AEF0117 that inhibits only a subset of intracellular activity resulting from THC activation of the receptor.

        • No withdrawals or negative effects

        • People who received the drug consumed less cannabis

      • Financial incentives can cut relapse

      • Counseling (like mindfulness training)

    • Treating withdrawal

      • Buprenorphine is a partial agonist at the µ-opioid receptor and is used to treat withdrawal from opioids

      • Clonidine, an α2-adrenergic agonist, produces cellular effects similar to opioid receptor activation, and dampens many of the physical signs and symptoms of opioid withdrawal

      • Alcohol facilitates (GABA) receptor function, benzodiazepines (or other medications that modulate GABA systems) are now used routinely to prevent the life-threatening side effects of alcohol withdrawal.

    • Blockade of drug targets as part of treatment

      • Prevent the drug from reaching the target in the brain

      • The blockade needs to also not cause activation

      • Naltrexone is a good example of this

        • naltrexone blocks the ability of opioids to produce their many effects

        • BUT it also blocks endogenous opioids which can lead to depressed moods

        • It works for alcohol and nicotine as well given that their withdrawals are related to endogenous opioids

      • We don’t have a good option like this for stimulants like cocaine or meth

        • We would need a molecule that would stop cocaine or meth from binding to the dopamine transporter but would allow it to function properly fir dopamine

        • this is hard to develop

      • Some work has been done that could block cocaine from crossing the blood brain barrier

        • Use immununological approches to changes the permeability of the blood brain barrier

        • this has worked in animals, but timeline for people

        • specific to cocaine

    • mimicry of drug action

      • A way to alleviate drug use but minimize the negative impacts of drastically altered brain chemistry

      • Provide a drug that activates the same system as the drug of abuse but that has less of the “high”

      • Methadone is an example here

      • Buprenorphine as a partial agonist for opiod receotors also fits the bill

      • Nictine or lozenges for tobacco addiction

      • working on partial agonists for nicotinic cholinergic receptor that might better than low levels of nicotine

      • Dopamine antagonists

        • blocking dopamine should reduce the effect of drugs of abuse that ramp up dopamine

        • dont seem to reduce drug craving or use long term

        • changes in dopamine signaling might increase self administration in animals

      • Dopamine agonists

        • having a pharamacological effect that increases dopamine negates the need for the drug

        • D1 agonists and D2 partail agonists both show promise in animal studies

        • Not using in people yet

    • Acerylchloine is important for paying attention

      • nicotine occupies & desentitizing receptors that should be used for attention

      • when norm Ach activity occurs there is less bandwith for nautrual signals and therefore attention can suffer

      • Upregulation of ach receptors can cause side effects during withdrawal

        • Agitation, unrest, Can be resolved through nicotine

      • Acute tolerance (during the day as nicotine concentrations build)

      • Long term tolerance as the system adjusts (less reward, and agitation)

    • Cue- elecited craving

      • present a cue

        • alcholol sent

      •  Ask abstinent addicts to report subjective craving

      • Can do this in an MRI

        • See changes in activity in the brain associated with the cue

        • Relate those changes to the subjective reports of craving

      • For alcohol- cerebellum, amygdala

    • EEG can also shed light on craving

      • We see those same elevated (higher frequency) shifts in activity that are associated with craving (in addition to predicting withdrawal)

        • Cocaine, Nicotine

      • Event related potential sizes are also related to craving

        • Larger ERPs associated with attention orienting are associated with increased craving

  • Treatment

    • Factors that lead to Variability in outcomes and response to treatment

      • I

  • Settings

    • Lots of variability here

      • Prisions

      • Private/expensive

      • Hospital / social workers – often just detox and referal

    • This can end up in a healthcare insurance nightmare

      • networks

      • underinsurance

      • lifetime caps

    • Four levels of care

      • General outpatient

      • Intensive outpatient or day hospital

      • Medical monitoring in inpatient residential setting

      • Medically managed inpatient care

  • Social context

    • I

  • Animal models of initiation

    • Modeling behavior

      • Housed with a rat who has a cocaine problem leads to faster acquisition

      • Social peer can either increase or inhibit acquisition relative to isolated controls

    • Social stress

      • Rats who had a social defeat developed cocaine addiction twice as fast as control rats

    • Social rewards are additive with drug rewards

      • Conditioned place preferences

      • Contingency of social interaction can enhance drug use

  • Escalation

    • A progression towards increased use

    • Behavioral and biological factors

    • Animal studies suggest modeling behavior and social stress in this phase are strong facilitators of behavior

      • Binging, using drugs to the exclusion of other rewards, progressive responding across reward schedules

    • Human research

      • More use in social settings is related to more use at the individual level

      • More social use is tied to more solitary use

  • Animal models of recovery

    • Social rewards are competitive vs drugs

      • Access to a social connection is sometimes more valuable than drug access

    • Cues of social defeat can trigger relapse in animals

    • Social contact with a rat that used to be associated with drug use can reinstate drug use