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Neurobiology of drug action and addiction. Richard Palmiter Dept Biochemistry. Prefrontal cortex. Hippocampus. Nucleus accumbens. Substantia nigra (SN) Ventral tegmental area (VTA). The dopamine reward system . Striatum. Wise (2002) Neuron . Some dopamine circuit details. D1R.

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Neurobiology of drug action and

addiction

Richard Palmiter

Dept Biochemistry


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Prefrontal cortex

Hippocampus

Nucleus accumbens

Substantia nigra (SN)

Ventral tegmental area (VTA)

The dopamine reward system

Striatum

Wise (2002) Neuron


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Some dopamine circuit details

D1R

GABAAR

DA

D2R

GABAAR

GABA

NAc

VTA


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Some dopamine signaling details

Glu

Glu

D1R

GABA

Low affinity

DA

D2R

NAc

High affinity

VTA

1 sec

burst


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Drugs release dopamine

Cocaine, amphetamine

DA

D1R

Morphine, heroin, nicotine

DA

D2R

Ethanol ?

NAc

VTA



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Glu

Animals like dopamine

self stimulation



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Animals like the effects of drugs happen

drug

Conditioned place preference

Animals learn to like the place where they experience the effects of drugs


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Drugs usurp to dopamine system happen

Drugs have greatest effect when given in a novel environment


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Voluntary drug administration is more addictive than involuntary administration

Voluntary drug

administration

Involuntary drug

administration

‘yoked situation’


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Chronic drug exposure changes the brain involuntary administration


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Medium spiny neuron morphology in NAc changes involuntary administration

Distal spines

Robinson, TE (2004)

amphetamine


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Drugs produce stable involuntary administration

changes in the brain

cortex

What are these changes and do they explain addiction?

Glu

Glu

D1R

Glu R

DA

Glu

DA

D2R

  • Morphological

  • Receptors

  • Signaling pathways

  • Transcription

  • [Glutamate]

glial

cells

NAc

VTA


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Imagining the brain on drugs involuntary administration

Reduced D2R availability & blood flow correlate with addiction

Volkow (2004) Nat Rev.


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Drug-induced changes produce sensitization involuntary administration

locomotion

days 1 2 3 4 25

PBS

Drug

Sensitization reflects stable changes

Cross -sensitization


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Presumably, some of the drug-induced changes in neural plasticity in VTA and/or NAc underlie enhanced responsiveness to drugs and some of those changes may result in compulsive drug taking

Which changes are addictive?

Are they reversible?


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self administration plasticity in VTA and/or NAc underlie enhanced responsiveness to drugs and some of those changes may result in compulsive drug taking

self administration

Bodily state influences drug-taking activity

self administration

self administration

Hungry (stressed) animals will lever press more for drugs or electrical stimulation than fed animals

How does stress enhance responding?

Lever presses

fedfasted


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Reinstatement of drug taking activity plasticity in VTA and/or NAc underlie enhanced responsiveness to drugs and some of those changes may result in compulsive drug taking

reinstatment

  • Cue

  • Stress

  • Drug (i.v)

extinction

Lever presses

training

drug

saline

cue


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What happens during reinstatement? plasticity in VTA and/or NAc underlie enhanced responsiveness to drugs and some of those changes may result in compulsive drug taking

Memories (associations) are recalled

  • Long-term memories require protein synthesis

  • Memories become labile when recalled

  • Restoring memories requires protein synthesis

  • again !!

Conditioned place preference for morphine can be

erased by blocking protein synthesis after recall

Alberini (2006) JN


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Problems with the VTA-dopamine hypothesis of addiction plasticity in VTA and/or NAc underlie enhanced responsiveness to drugs and some of those changes may result in compulsive drug taking

  • Dopamine receptor agonists are not addictive

  • Some drugs that release dopamine are not addictive

  • Some aspects of reward learning are intact in mice lacking dopamine

  • Mice without dopamine can still learn a conditioned place preference for morphine or cocaine

  • Other neurotransmitters are involved


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Drugs release dopamine, but… plasticity in VTA and/or NAc underlie enhanced responsiveness to drugs and some of those changes may result in compulsive drug taking

Cocaine, amphetamine

DA

D1R

Morphine, heroin, nicotine

DA

D2R

NAc

VTA

Dopamine receptor agonists are not drugs


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Is dopamine action in nucleus accumbens critical for the pleasurable effects of drugs and drug/place association ?

Mice without DA can learn CPP for morphine & cocaine

Mice without the cocaine receptor (DAT) can learn CPP for cocaine

Serotonin

Hnasko (2005,2007) Nature, JN; Jones (2005) PNAS


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Other neuromodulators are also required pleasurable effects of drugs and drug/place association ?

Mice without

Norepinephrine (NE)

do not learn CPP for morphine

Olson (2006) Science

NE action in pre-frontal cortex may be necessary for drugs to activate dopamine neurons


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extinction pleasurable effects of drugs and drug/place association ?

Lever presses

training

reinstatment

drug

saline

  • Cue

  • Stress

  • Drug (i.v)

cue

Drug taking does not necessarily lead to addiction

3 months

Deroche-Gamonet..Piazza, 2004 Science


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  • Hallmarks of Addiction pleasurable effects of drugs and drug/place association ?

  • Subject has difficulty limiting drug intake

    • persistence

  • Subject has high motivation to take drug

  • motivation

  • Subject continues to take drug despite adverse consequences

  • resistance


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    Many days of self administration, 5 days withdrawal, reinstatement with cocaine, then divide into groups based on response

    motivation

    persistence

    resistance

    Piazza (2004)


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    Many days of self administration, 30 days withdrawal, reinstatement with cocaine or cue

    All rats self-administered the same amount of cocaine

    cue

    Piazza (2004)

    very low doses


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    56 rats trained for a long time at self administration reinstatement with cocaine or cue

    Three tests: persistence, resistance, motivation

    Consider rats ranking in top 1/3rd of group on each test: thus, individual rat could get score of 0, 1, 2 or 3

    All rats self-administered the same amount of cocaine

    Piazza (2004)


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    Conclusions: reinstatement with cocaine or cue

    • Rat addiction as described here:

    • Requires long self-administration paradigm

    • Independent of amount of cocaine delivered during training

    • Independent of motor activity

    • Vulnerability is function of individual

    What are those individual differences???


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    Addiction correlates with impulsivity rather than novelty seeking

    • Identify high and low impulsive rats

    • Identify high and low reactivity to novelty rats

    Persistence, Resistance, Motivation

    Belin…. Everitt (2008)


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    Conclusions from Belin…Everitt paper seeking

    • High correlation between impulsivity and transition to compulsive drug taking

    • Impulsivity precedes drug use

    • Independent of initial propensity to acquire

    • cocaine self administration

    • Impulsivity correlates with low D2 receptor abundance in ventral striatum

    • Early vulnerability to take cocaine correlates better with novelty seeking