Opioids: Reinforcement and Dependence Flashcards by Cambell Meier

Reinforcing effects of
opioids Animals readily acquire

operant self-administration of
opiates

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Self-administration increases over time to a

stable/optimal level in blood

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Reinforcing effects of
opioids Animals maintain a stable total level

separate
pretreatment with morphine will decrease self administration to reach the same approximate levels

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Animals readily develop

conditioned place preference for
opiate use

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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.

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Mesolimbic
dopamine pathway

Opioids function within the mesolimbic
dopamine reward pathway

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Dopaminergic projections from the
ventral tegmental area (VTA) project to

the Nucleus accumbens (NAc) providing
motivational salience to information
passing to the ventral palladium.

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In the absence of reinforcing stimuli Dopamine
release is under

r tonic inhibitory control of
GABA interneurons.

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Dopamine release in the NAc provides a

positive reinforcement to associated
behaviours

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Opioids function within the

mesolimbic dopamine reward
pathway

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Mesolimbic
dopamine pathway -Endorphin-secreting neurons
provide

inhibitory input to
GABAergic interneurons in the
VTA.

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Mesolimbic
dopamine pathway Endorphin release or MOR
activation results in

disinhibition
of NAc DA release

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Opiates act at

GABAergic
interneuron terminals (axoaxonal
transmission) to disinhibit NAc
dopamine release and increase
motivational salience.

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Mesolimbic
dopamine pathways Dynorphin provides

direct inhibitory
control over the mesolimbic DA
neurons.

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Mesolimbic
dopamine pathways Dynorphin release or KOR activation
results in

inhibition of NAc DA release.

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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)

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Reinforcing effects of opioid receptor agonists
Agonists at the κ receptor

r do not
acquire self-administration and will
actually induce conditioned place
aversion

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Reinforcing effects of opioid receptor agonists * Endogenous opioids provide

salience
through mesolimbic DA modulation

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Endogenous opioids provide salience
through mesolimbic DA modulation Opiates act principally through

μ-opioid
receptors to provide incentive salience

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Endogenous opioids provide salience
through mesolimbic DA modulation Dynorphins act through

κ-opioid
receptors to provide aversive salience

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Dopamine lesion using 6-OHDA

reduces but does not abolish opiate
self-administration

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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

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Relative intensity of reinforcement is thought to relate to the more

direct coupling of drug
administration with activation of reward circuitry

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Reinforcement increases with

different routes of drug administration

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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