reward circuits and drug addiction

intracranial self-stimulation

instrumental learning with rats

• brain regions that support this are the mesolimbic dopamine system

• DA system - projection neurons, VTA sends them to PFC, amygdala and NAc in striatum

• self-stimulation increases DA

• DA plays a role in reward related behaviours, and drugs also increase it

principles of drug action: tolerance, withdrawal, sensitization

tolerance: decreased sensitivity to drugs

• metabolic: body gets rid of it faster

• functional: altered sensitivity in synapses (decrease or increase # of receptors to counteract drug)

conditioned tolerance: more tolerance in the context you took the drug before, body is prepared to counteract it

withdrawal: rebound reaction to drug after exposure

• opposite of what drug did

• longer exposure = greater withdrawal

• physical dependence

conditioned withdrawal: more withdrawal symptoms in the place you took the drug, body is trying to compensate the effects of drug

sensitization: repeated exposure increases sensitivity to behavioural effects of drugs

• higher DA release usually, with same dose

• all drugs of abuse

Addiction criteria

1. habitual drug use

2. drug seeking behaviour

3. physical dependence

marijuana

active ingredient: THC

• receptors found all over the brain

• anandamide - endogenous, works as a retrograde messenger to inhibit transmitter from presynaptic terminal

• inhibits GABA/GLUT

• affects memory processing —> cognitive impairment in challenging tasks

• chronic use: reduced activation in PFC and amygdala in response to emotional faces

therapeutic effects:

• medicinal use

• analgesia

• appetite stimulant

• anti-nausea

alcohol

biphasic action - depresses neural firing but diff brain areas get affected with diff doses

• low doses: inhibits GABA, disinhibits cortex

• high doses: cortical inhibition with inhibiting bigger neurons

• somehow increases DA

• positive modulator to GABA

• reduces functioning in NMDA glut. receptors

• blocks calcium and other ion channels

nicotine

stimulates nicotinic acetylcholine receptors on DA pathway

over time: aversive affects develop tolerance

• rewarding effects may sensitize

• being alert, enhanced cognition

withdrawal: anxiety, restlessness

therapeutic effects:

• better attention/cognition

• help with alzheimer’s/schizophrenia

• can prevent parkinsons

opiates

agonists for endogenous opiod receptors

• enkephalin and endorphine —> inhibit neural firing

• inhibit GABA in VTA and disinhibit dopamine

• analgesia

withdrawal: hyperactivity

long term use: OD, long term cognitive deficits from heroin abuse

psychostimulants - cocaine, amphetamine

affect monoamine systems → reinforcing actions mediated by DA system

• cocaine - blocks DA transporter and prevents reuptake

• amphetamine - reverses transporter and releases more DA, while also preventing reuptake

• increased confidence, energy, alertness, less sleep, fidgety

• withdrawal: crash, fatigue

long term use: damage to monoamine systems

• psychosis

• too much noradrenaline → strokes

• DA-induced toxicity

• deficits in PFC cognitive functions

therapeutic effects - small doses:

• promote wakefulness

• enhance cognition

physical dependence model

users take drugs to escape withdrawal symptoms

limitations:

• users take drugs after drug is detoxified

positive rewards model

users take drugs to feel pleasure

limitations

• pleasure is gone after tolerance builds

• some drugs are not pleasurable

dopamine and animal models

reducing DA transmission reduces self-administration

• also blocks conditioned place preference for drugs

• da release also increased by reward-associated cues

so, dopamine activates brain’s natural reward pathways, but more higher

• blocking dopamine receptors doesnt change experience of drug euphoria

dopamine involved in approach behaviours of drug and wanting, but not involved in liking the drug

pavlovian approach to reward related stimuli

blocking DA receptors blocks approaching the cue, but not consumption of reward

dopamine promotes behaviours directed towards reward related stimuli

giving rat amphetamine makes rat approach the cue more

in hyperdopamine state, the cues have much more influence over behaviour

incentive sensitization hypothesis

cues associated with drug taking take over behaviour

• drug use makes the DA system sensitized

• develop an unconditioned response to drug cues

• associative memories become amplified in a hyperdopaminergic state and trigger more behaviour to seek drug

Dopamine and addiction

1. drugs increase mesolimbic DA levels

2. your brain makes associations with external stimuli and drug taking

3. reward-associated cues (stress, taste of drug) release DA in NAc

4. prolonged drug use induces sensitization for drugs