Drug Addiction 2

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Drug Addiction 2
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KC Berridge, 2003, Pleasures of the brain, Brain
Cognition, 52106-128.

• One sign of positive vs. negative affect facial
  expression in response to various tastes

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Animals play

• 50kHz vocalizations tickle-induced laughter
  in rats (Panksepp, 2000, Curr. Dir. Psych. Sci.,
  9183-186)
• Produced during play, just before expected
  rewards, during tickling. (The article doesnt
  mention this, but 50kHz calls are also produced
  by both male female rats before and during
  copulationdifferent from 22kHz postejaculatory
  song.)
• Berridge notes such calls also occur during
  aggressive encounters not JUST pleasure

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Animal humor (Rubber Chicken), J. Panksepp,
2005, Sci. 30862-3
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Brain areas associated with pleasure

• Orbitofrontal (prefrontal) cortex
• Both and emotions
• Human fMRI and PET activity in response to
• Cocaine other drugs
• Pleasant tastes odors
• Pleasant touch
• Pleasant music
• Winning money

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Brain areas associated with pleasure

• Orbitofrontal (prefrontal) cortex responses
• Monkeys (single-cell recording, E.T. Rolls, 2000)
• Tasty food
• Cue predicting tasty food
• Changes when prediction changes
• Changes when value changes (hungry vs. full)
• Cocaine, heroin

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Brain areas associated with pleasure

• Orbitofrontal (prefrontal) cortex
• But probably not a necessary cause of positive
  (or negative) emotion
• Axons to NAcc may ? positive affect
• Important for expectation, voluntary regulation
  of emotion, strategies to reach goal.

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Brain areas associated with pleasure

• Anterior cingulate cortex
• Activated during both and - emotions
• Lesions may treat intractable pain or OCD
• Lesions in rats still approach rewards normally
• Therefore, not necessary for or - emotion

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Cingulotomy to treat OCD
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Brain areas associated with pleasure

• LH septal area
• Electrical stim. ? work for more (Olds Milner,
  54)
• Increased liking???
• Increased wanting???
• Berridge incentive salience (wanting)
• Nonhedonic
• Elect. Stim. ? no more, maybe less, hedonic
  facial responses, but did eat more.
• Therefore, wanting does not imply liking.

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Brain areas associated with pleasure

• LH septal area
• Human brain stimulation (R. Heath, 72, 96)
• Ventral thalamus, ventral pallidum, lat. septal
  area, NAcc.
• Felt more positive re. people surroundings
• I just feel good.

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Brain areas associated with pleasure

• LH septal area (cont.)
• Human brain stimulation (R. Heath, 72, 96)
• One patient (depressed, suicidal, epilepsy,
  delusions)
• approaching orgasm, but cant quite get
  there (stim. 1200, 1500, 900 times on different
  occasions did ejaculate if he could also
  masturbate or have therapy with a prostitute)
• Stimulation made him want to do sexual acts,
  he responded to a wider range of arousing stimuli
  (heterosexual, not just homosexual)
• True pleasure? Equivocal

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Brain areas associated with pleasure

• LH septal area (cont.)
• Human brain stimulation (Portenoy et al., 86)
• Woman patient (intractable pain vent. post-lat.
  thalamus)
• Helped a bit with pain
• Compulsive stimulation at expense of personal
  hygiene, family commitments.
• Intense thirst (with drinking), anxiety, erotic
  sensations, hot cold.
• Effects sound more negative than positive!

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True brain substrates for liking

• NAc shell
• Opioid receptors in medial caudal NAcc shell may
  ? true liking.
• Morphine in post. NAcc shell increased () facial
  reactions to bittersweet taste (Pecina
  Berridge, 2000).
• Also later caused more wanting of that taste.
• Also suppressed negative reactions to bitter
  tastes suppressed pain.
• Rats work for opiate admin. there.

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Fig. 3. Fos plumes (?) A Morphine increases
hedonic responses (B) Mapping positive site (C)
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True brain substrates for liking

• PFC connections with NAc shell
• May allow thoughts to ? liking
• May allow PFC to modulate liking wanting.

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Liking circuitry
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True brain substrates for liking

• Parabrachial nucleus (in pons)
• GABA/benzodiazepine receptors ? liking
• Connected with NAc shell
• Receives taste visceral input
• (Im not sure whether this would be important for
  non-taste stimuli.)
• Also input from PFC and LH Part of
  interconnected circuit that could allow conscious
  influence of affect and vice versa.

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True brain substrates for liking

• Ventral pallidum
• Necessary, as well as sufficient, to ? liking
• Adjacent to lateral hypothalamus (LH)
• Lesions abolish () taste response
• Also a site for food, cocaine, brain
  stimulation reward
• Humans stimulation ? affective mania for several
  days
• Sexual arousal in men ? PET activation
• Part of direct indirect pathways (target of NAc)

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Pleasure One pathway or many?

• Evidence for shared pleasure pathways for food,
  drugs, sex
• Opioid receptors in NAc shell for liking
• Dopamine receptors (in NAc core???) ? wanting
  drugs, sex, food, elect. stim., maternal
  behavior, videogames for humans.

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Final thoughts

• Kent Berridge (03) Liking is mediated by
  opioid receptors in medial caudal shell of NAc,
  as well as GABA/benzodiazepine receptors in
  parabrachial nucleus of the pons and neurons in
  the ventral pallidum.
• Recall that ventral pallidum gets output from the
  NAcc as part of the direct and indirect pathways.
• Therefore, tolerance probably results from
  decreased activation in these areas.

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Really Final Thoughts

• Craving (wanting), then, probably results from
  increased activation of the indirect pathway of
  the NAcc core.
• Dependent on glutamate via NMDA receptors to
  activate ?FosB, since D2 receptors inhibit
  adenylyl cyclase (and therefore cant increase
  ?FosB).

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S. Robinson et al., (2005) Distinguishing whether
dopamine regulates liking, wanting, and/or
learning about rewards. Behav. Neurosci. 1195-15

• Dopamine-deficient mice (lack TH in DA neurons
  require daily L-DOPA, wh. makes them hyperactive
  and hyperphagic for 6-9 hr, after wh. they become
  hypoactive and hypophagic again)
• Exp. 1 T-maze 12 days to learn to find food
  then position and cues are reversed for 12 days
• All mice injected with lo-dose L-DOPA 30 before
  test
• Phase 1 liking Minor diff. in of rewards eaten
• Phase 1 wanting DD mice reached goal faster, but
  took longer to consume reward.
• Phase 1 learning no difference

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Dopamine-deficient mice (Fig 1)
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Exp. 1, phase 1 (Fig. 2)
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Dopamine-deficient mice

• Phase 2 (reversal) learning Control mice learned
  quickly, DD mice did not (Fig. 3A,below)
• Not clear why, since all animals had L-DOPA.
• Phase 2 liking Both groups ate similar of food
  on correct trials similar liking (but since DD
  mice had fewer correct trials, they had less
  food, Fig. 3B).
• Phase 2 wanting DD mice shorter latency to
  intersection, longer to start eating(Fig.3D-F)

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DA-deficient mice, Exp. 1, phase 2 (cue reversal,
Fig. 3) DD mice did not learn reversal.
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Dopamine-deficient mice

• Summary of Exp. 1
• Phase 1 DD mice given L-DOPA can learn, like,
  want similarly to control mice (a few minor
  diffs.)
• Phase 2 DD mice did not learn the reversal.
• Both too much and too little DA in striatum can
  impair the ability to learn a reversal
• DD mice may have used hippocampus strategy
  (extra-maze cues, which did not change), not
  striatum strategy.

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Dopamine-deficient mice

• Exp. 2. Caffeine used to activate DD mice w/o
  L-DOPA (Otherwise, DD mice are inactive.)
• Caffeine (adenosine receptor antag.) does not ?
  Fos-ir therefore, action is different from DA
• 3 grps of DD mice
• Phase 1 Saline/Phase 2 L-DOPA (SAL-LD)
• Phase 1 caffeine/phase 2 LD (CAF-LD)
• LD-LD

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Dopamine-deficient mice

• Exp. 2 results
• Phase 1 learning
• SAL mice hypoactive needed help getting to goal
• LD mice learned
• CAF mice as active as LD mice, but did not
  improve (Fig 4A, left, below)
• Phase 2 learning (all received LD, Fig.4A, rt.)
• SAL-LD no diff from LD on Phase 1 Therefore, no
  learning in Phase 1 (Fig.4B).
• Both CAF-LD LD-LD were better on first trials
  of Phase 2 therefore, both had learned in Phase
  1 (Fig.4 C,D).
• DA is not necessary for learning about goal.

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Dopamine-deficient mice (Fig. 4)
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Dopamine-deficient mice

• Exp. 2 liking
• Phase 1 CAF mice consumed somewhat fewer rewards
  (as a of correct choices) than LD mice (Fig.
  5B).
• (It seems to me that this shows decreased
  liking!!!)
• Phase 2 (all had LD) No differences (Fig. 5D).

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DA-deficient mice Fig. 5. Phase 1 CAF mice ate
less Phase 2 (LD) no diffs.
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Dopamine-deficient mice

• Exp. 2 wanting (Fig. 6, below)
• Phase 1 CAF mice had longer latencies to
  intersection and to eat than LD mice. (less
  wanting)
• Phase 2 no diffs, except increased lat. to begin
  to eat on day 12 in SAL-LD CAF-LD mice (6F).
• LD-LD mice began to eat sooner in Phase 2 than in
  Phase 1 they had learned to eat quickly in Phase
  1 (6 I).
• DA contributes to wanting.
• (But DA is NOT NECESSARY, as authors claim!!!!!)

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DA-deficient mice (Fig. 6) Wanting
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Dopamine-deficient miceSummary

• DD mice could learn about rewards and liked
  rewards (although there were some deficiencies in
  CAF-treated mice, compared to LD-treated mice in
  both measures).
• But CAF-treated DD mice took longer to begin to
  eat after they reached the reward Less wanting.
  (Note that even CAF-treated mice did eat and did
  run to goal. Therefore at least SOME wanting,
  even without DA!)
• It seems to me that DA CONTRIBUTED TO, but was
  NOT ESSENTIAL FOR all 3 measures!!!

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Overall Summary

• Liking is mediated by
• Opioid receptors in med. caudal shell of NAc
• GABA/benzodiazepine receptors in parabrachial
  nucleus of the pons (at least for tastes)
• Neurons in the ventral pallidum.
• One or more of these may be down-regulated in
  drug (or other) tolerance, possibly by increased
  production of dynorphin.

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Overall Summary (cont.)

• Wanting is enhanced by DA, which may also
  contribute to some measures of liking learning.
• Sensitization of motor activity and of wanting
  may require glutamate NMDA receptor activation of
  ?FosB in Indirect Path of NAc core.
• Stress and novel cues may contribute to
  sensitization via either CRH in the brain or
  glucocorticoids, both peripherally (to increase
  blood glucose) and in brain (to stimulate
  directly).

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Overall Summary (cont.)

• Sensitization to motor effects of cocaine is
  enhanced by estrogen in females.
• Locomotor sensitization to environmental cues
  associated with cocaine may require increases in
  AMPA receptors in VTA.
• But locomotion response to cocaine itself was not
  affected.