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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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slide1

Neurobiology of drug action and

addiction

Richard Palmiter

Dept Biochemistry

slide2

Prefrontal cortex

Hippocampus

Nucleus accumbens

Substantia nigra (SN)

Ventral tegmental area (VTA)

The dopamine reward system

Striatum

Wise (2002) Neuron

slide3

Some dopamine circuit details

D1R

GABAAR

DA

D2R

GABAAR

GABA

NAc

VTA

slide4

Some dopamine signaling details

Glu

Glu

D1R

GABA

Low affinity

DA

D2R

NAc

High affinity

VTA

1 sec

burst

slide5

Drugs release dopamine

Cocaine, amphetamine

DA

D1R

Morphine, heroin, nicotine

DA

D2R

Ethanol ?

NAc

VTA

slide7

Glu

Animals like dopamine

self stimulation

slide9

Animals like the effects of drugs

drug

Conditioned place preference

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

slide10

Drugs usurp to dopamine system

Drugs have greatest effect when given in a novel environment

slide11

Voluntary drug administration is more addictive than involuntary administration

Voluntary drug

administration

Involuntary drug

administration

‘yoked situation’

slide13

Medium spiny neuron morphology in NAc changes

Distal spines

Robinson, TE (2004)

amphetamine

slide14

Drugs produce stable

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

slide15

Imagining the brain on drugs

Reduced D2R availability & blood flow correlate with addiction

Volkow (2004) Nat Rev.

slide16

Drug-induced changes produce sensitization

locomotion

days 1 2 3 4 25

PBS

Drug

Sensitization reflects stable changes

Cross -sensitization

slide17

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?

slide18

self administration

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

slide19

Reinstatement of drug taking activity

reinstatment

  • Cue
  • Stress
  • Drug (i.v)

extinction

Lever presses

training

drug

saline

cue

slide20

What happens during reinstatement?

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

problems with the vta dopamine hypothesis of addiction
Problems with the VTA-dopamine hypothesis of addiction
  • 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
slide22

Drugs release dopamine, but…

Cocaine, amphetamine

DA

D1R

Morphine, heroin, nicotine

DA

D2R

NAc

VTA

Dopamine receptor agonists are not drugs

slide23

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

slide24

Other neuromodulators are also required

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

slide25

extinction

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

slide26

Hallmarks of Addiction

  • Subject has difficulty limiting drug intake
      • persistence
  • Subject has high motivation to take drug
  • motivation
  • Subject continues to take drug despite adverse consequences
  • resistance
slide27

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

motivation

persistence

resistance

Piazza (2004)

slide28

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

slide29

56 rats trained for a long time at self administration

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)

slide30

Conclusions:

  • 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???

slide31

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)

slide32

Conclusions from Belin…Everitt paper

  • 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
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