Opioids: Reinforcement and Dependence Flashcards
Reinforcing effects of
opioids Animals readily acquire
operant self-administration of
opiates
Self-administration increases over time to a
stable/optimal level in blood
Reinforcing effects of
opioids Animals maintain a stable total level
separate
pretreatment with morphine will decrease self administration to reach the same approximate levels
Animals readily develop
conditioned place preference for
opiate use
Heroin self-administration reaches steady-state levels and are
self-regulated by rats. Heroin SA contrasts sharply with
cocaine SA in which use is erratic and subject mortality is
high.
Mesolimbic
dopamine pathway
Opioids function within the mesolimbic
dopamine reward pathway
Dopaminergic projections from the
ventral tegmental area (VTA) project to
the Nucleus accumbens (NAc) providing
motivational salience to information
passing to the ventral palladium.
In the absence of reinforcing stimuli Dopamine
release is under
r tonic inhibitory control of
GABA interneurons.
Dopamine release in the NAc provides a
positive reinforcement to associated
behaviours
Opioids function within the
mesolimbic dopamine reward
pathway
Mesolimbic
dopamine pathway -Endorphin-secreting neurons
provide
inhibitory input to
GABAergic interneurons in the
VTA.
Mesolimbic
dopamine pathway Endorphin release or MOR
activation results in
disinhibition
of NAc DA release
Opiates act at
GABAergic
interneuron terminals (axoaxonal
transmission) to disinhibit NAc
dopamine release and increase
motivational salience.
Mesolimbic
dopamine pathways Dynorphin provides
direct inhibitory
control over the mesolimbic DA
neurons.
Mesolimbic
dopamine pathways Dynorphin release or KOR activation
results in
inhibition of NAc DA release.
Reinforcing effects of opioid receptor agonists Agonists at μ and δ receptors are
reinforcing and readily lead to self-administration and conditioned place
preference (CPP)
Reinforcing effects of opioid receptor agonists
Agonists at the κ receptor
r do not
acquire self-administration and will
actually induce conditioned place
aversion
Reinforcing effects of opioid receptor agonists * Endogenous opioids provide
salience
through mesolimbic DA modulation
Endogenous opioids provide salience
through mesolimbic DA modulation Opiates act principally through
μ-opioid
receptors to provide incentive salience
Endogenous opioids provide salience
through mesolimbic DA modulation Dynorphins act through
κ-opioid
receptors to provide aversive salience
Dopamine lesion using 6-OHDA
reduces but does not abolish opiate
self-administration
Reinforcement
Opiates and other drugs of abuse are considered to engage natural reward circuitry in a manner
that bypasses the need for sensory input / processing
Relative intensity of reinforcement is thought to relate to the more
direct coupling of drug
administration with activation of reward circuitry
Reinforcement increases with
different routes of drug administration
Heroin is more reinforcing than
morphine due to more rapid transit across the BBB
IV administration is more reinforcing than
oral or IM administration due to more rapid access to the BBB
Drugs available by inhalation (esp. nicotine) have very
rapid access to the brain and are highly reinforcing
- In humans reinforcement by drugs of abuse is thought to be
far stronger than natural rewardS
Reduced self-care is common among
drug users – including poor or insufficient diet
Rebound hyp eractivity
As opiates are depressants (in that they depress CNS
function) their withdrawal results in CNS hyperactivity
Withdrawal symptoms can be described as
rebound
hyperactivity as neural circuits operate at a disturbed
homeostatic level
Withdrawal effects contrast/oppose
acute effects of
intoxication
acute action
what the drug does
withdrawal sign
opposite of acute action
Acute action Analgesia withdrawal sign
Pain and irritability
Acute action Respiratory depression withdrawal sign
Panting and yawning
Acute action euphoria withdrawal sign
dysphoria and depression
Acute action relaxation and sleep withdrawal sign
restlessness and insomnia
Acute action tranquilization withdrawal sign
fearfulness and hostility
Acute action decreased blood pressure withdrawal sign
increased blood pressure
Acute action constipation withdrawal sign
Diarrhea
Acute action pupil constriction withdrawal sign
pupil dilation
Acute action hypothermia withdrawal sign
hyperthermia
Acute action drying of secretions withdrawal sign
tearing, runny nose
Acute action reduced sex drive withdrawal sign
spontaneous ejaculation
Acute action flushed and warm skin withdrawal sign
chillness and goosebumps
parts of the brain and receptors responsible for Analgesia
MOR– Cortex, 11
Thalamus, PAG,
Raphe Nucleus
KOR– spinal
parts of the brain and receptors responsible for respiration depression
Medulla
parts of the brain and receptors responsible for euphoria
Mesolimbic DA
parts of the brain and receptors responsible for relaxation and sleep
MOR
KOR
parts of the brain and receptors responsible for tranquilization
KOR
parts of the brain and receptors responsible for decreased blood pressure
MOR
parts of the brain and receptors responsible for constipation
MOR in the GI
parts of the brain and receptors responsible for pupil constriction
KOR
parts of the brain and receptors responsible for hypothermia
Medulla
parts of the brain and receptors responsible for drying of secretions
σ-receptor
parts of the brain and receptors responsible for reduced sex drive
Hypothalamus
parts of the brain and receptors responsible for flushed and warm skin
MOR
In humans behavioural tolerance contributes
to the decreased effects of
opiates
- Tolerance and dependence are
reversible
adaptive changes to drug use
Learning and memory processes can be
demonstrated to contribute to
tolerance in
animal models
NMDA receptor antagonists (MK801,
dizocilpine) reduce
tolerance to analgesia as
measured by tail
-flick latency
Physical dependence model
Establishment and maintenance of addictions
manifests from development of dependence
Abstinence (withdrawal) results in craving,
leading to
relapse
Posits addiction is a result of
negative
feedback in trying to eliminate unpleasantness
of abstinence
Models of drug addiction
initial drug use -> repeated drug use -> physical dependence -> attempts at abstinence -> withdrawal symptoms -> relapse then relapse back to attempts at abstinence
Limitations of physical dependence model (3)
Addiction results from physical dependence
Relapse results from withdrawal
Model fails to account for psychological contributions to relapse and craving
Addiction results from physical dependence Some addictive drugs do not
demonstrate dependence e.g. cocaine
Addiction results from physical dependence Dependence can be demonstrated without
addiction - Normal dependence in clinical use of opiates
Dependence only explains
persistent use, not initial use
Relapse results from withdrawal - * Relapse can occur well after
detoxification
Relapse results from withdrawal - Role of classical conditioning in relapse is not well
demonstrated in humans – mostly anecdotal
evidence
Positive reinforcement model
Drug addiction results from
positive feedback – compulsive
desire to experience drug-related
euphoria
Euphoria resulting from initial drug
use serves to
reinforce additional
use
Limitations of positive reinforcement model
- Craving increases with prolonged use
- Many users voluntarily stop using drugs that are strongly
reinforcing
Limitations of positive reinforcement model - Craving increases with prolonged use
euphoric effects tend to diminish with use due to tolerance
- Many users voluntarily stop using drugs that are strongly
reinforcing
individual differences in susceptibility to addictions is not
explained by the reinforcing effects of drug-induced euphoria
Positive reinforcement model steps
initial drug use -> positive reinforcement -> repeated drug use -> attempts at abstinence -> compulsive desire to re-experience drug-induced euphoria -> relapse then relapse back to attempts at abstinence
Incentive-sensitization model steps
initial drug use -> positive reinforcement -> repeated drug use -> sensitization of drug wanting but not drug liking -> attempts at abstinence -> compulsive desired for the drug due to sensitized incentive salience system -> relapse then relapse back to attempts at abstinence
Incentive-sensitization model
Distinguishes drug liking (drug ‘high’) and drug
wanting (craving)
Incentive-sensitization model Increased use occurs with
increased wanting even
though drug liking remains the same or decreases
Increased use occurs with increased wanting even
though drug liking remains the same or decreases - Proposes two distinct
underlying neurobiological
processes for liking and wanting
Incentive-sensitization model - Drug wanting system undergoes
sensitization - Mesolimbic DA system readily sensitized
Incentive-sensitization model Drug liking system undergoes
Tolerance
Opponent-process model
Affective processes responsive to strong
stimuli (e.g. euphoria) are balanced by
opposing affective responses that is
experienced after initial response ends
Affective stimuli would be the _____ opponent process would be the ______
High - Withdrawal
- Repeat presentation of strong stimuli results in
strengthening of the opponent process
Adaptive processes lower
r hedonic set point
such that chronic users experience dysphoria
in the absence of drugs
Limits of incentive-sensitization and opponent process models (Both)
Both address neural mechanisms of drug abuse
- Both explain different aspects of addiction
Limits of incentive-sensitization and opponent process models (Both) - * Both explain different aspects of addiction
- Incentive-sensitization provides an explanation of drug craving
- Opponent-process provides an explanation of dysphoria during
withdrawal
Limits of incentive-sensitization and opponent process models (neither)
Neither model addresses initial drug use
Limits of incentive-sensitization and opponent process models - Limited incorporation of
psychosocial factors contributing to
addictive patterns of use
Disease models of addiction
Propose that drug addiction results
from inherent differences in
susceptibility
Propose that drug addiction results
from inherent differences in
susceptibility - Exposure to
drug in some individuals
results in loss of control over intake
Disease models of addiction -Most widely accepted for
alcoholism
Disease models of addiction Alternate explanation is that
drug
exposure alters brain function leading
to loss of control
Disease models of addiction Drug use initiation is
necessary but not
sufficient for development of a
substance-use disorder
Disinhibition (predisposition to
impulsivity, hyperactivity, antisociality)
s a predictive risk of substance-use
(regardless of the substance)
Disease model removes the
moral
aspects of addictions
