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Hoplight et al Neuropharmacol Hoplight et al

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Hoplight et al Neuropharmacol Hoplight et al Powered By Docstoc
					     Addiction:
Transition from Molecular to
  Behavioral Understanding



           John Neumaier, M.D., Ph.D.
            Department of Psychiatry
           Harborview Medical Center
                       and
            University of Washington
                 Goals
– How does a psychiatrist think about
  addiction?
– Review some psychological and learning
  aspects of addiction theories
– Review some molecular events associated
  with addiction
– Consider the substrates of enduring
  addiction and risk for relapse
Impaired Response Inhibition and
       Salience Attribution




      Goldstein and Volkow (2002) Am J Psychiatry 159:1642
Rostral Anterior Cingulate Cortex activation
 in Stroop task (tests executive function)




         Bolla et al. (2004) J Neuropsychiatry Clin Neurosci 16:456.
  What are the psychological
    aspects of addiction?

– Emotional (liking)
– Motivational (wanting)
– Learning (cognitive and associative)




      Robinson and Berridge (2003) Annu Rev Psychol 54:25-53.
                  Wanting
• Motivation to obtain a reward (such as a
  drug)
  – Can be independent of “liking” the reward
• Pathological wanting = craving
• The importance of the reward grows with
  repeated exposure (sensitization)
• Can be inferred by how hard someone will
  work to obtain the reward
                                    Learning
                              dorsolateral   dorsomedial
Sensory, insular ctx inputs                                  PFC inputs
    S/R associations                                       S/R associations
     Sensorimotor?                                             Limbic?
Molecular adaptations associated
 with addiction are likely to be
         stage specific
 – Sensitization
 – Tolerance
 – Escalation
 – Withdrawal
 – Extinction
 – Relapse
            sensitization




tolerance
What are the neural plasticity events
associated with these adaptations?
“Incubation” of craving




                     Yavin Shaham
What are the effects of social
      stress on drug
   self administration?
Stress Induced Reinstatement




      Shalev et al (2002) Pharmacol Rev 54:1-42.
Escalation
       What might pharmacological
    treatments for addiction look like?
•   Prevent initial drug events?
•   Shift balance of + and - features?
•   Prevent reinstatement?
•   Facilitate extinction learning?
•   Deconstruct reconsolidation of memory?
•   Shift from out of control to regulated
    use?
      Serotonin and Reward
                     SEROTONIN RECEPTOR SEQUENCE HOMOLOGY

                                              5-HT 2A
                                              5-HT 2A
                                              5-HT 2C
                                              5-HT 2C   Gq
                                                        Gq
                                              5-HT 2B
                                              5-HT 2B

• Many different                              5-HT 1A
                                              5-HT 1A
                                              5-HT 1B
                                              5-HT 1B
                                              5-HT 1D   Gi
                                              5-HT 1D   Gi
  receptors implicated                        5-HT 1E
                                              5-HT 1E
                                              5-HT 1F
                                              5-HT 1F
                                              5-HT 5A
                                              5-HT 5A
                                              5-HT 5B   ?
                                                        ?
                                              5-HT 5B
                                              5-HT 7
                                              5-HT 7    Gs
                                                        Gs
                                              5-HT 6
                                              5-HT 6    Gs
                                                        Gs
• 5-HT1B and 5-HT6
  have roughly
  opposing effects
Andrews and Lucki Psychopharm. (2001) 155:221–229
Neumaier et al (2002) J Neurosci 22:10856.
                                EtOH consumed (g/kg)
                                                              *
                                                        4
                                                       3.5
                                                        3
                                                       2.5
                                                        2
                                                       1.5
                                                        1
                                                       .5
                                                        0
                                                             1B   GFP   UNH




Hoplight et al (2006) Alcohol 38:73.
        5-HT1B & “Binge Cocaine”
• 3 weeks of noncontingent cocaine injections
    – 15 mg/kg ip every hour X 3 injections daily
•   or 1 day of 3 cocaine injections
•   Saline controls
•   Unhandled cage controls
•   5-HT1B mRNA by ISHH
Hoplight et al (2006) Neuropharmacol
Hoplight et al (2006) Neuropharmacol
                 Study Design



Guide cannula            Gene transfer Behavioral testing


                Food restriction                   sacrifice
Mitchell et al (2007) Neuropsychopharm EPub
      Operant Conditioning

• 1st session
  – 10 sucrose pellets presented
    noncontingently
  – 50 trials of stimulus cue light with lever
    presentation, response within 10 sec
    rewarded with sucrose pellet
• 2nd and 3rd session, same except 3
  noncontingent sucrose pellets
% successful trials   60%



                      40%

                                                                             *
                      20%



                      0%
                            no surgery      sham       GFP-only     5-HT6/GFP

                                day 1                day 2                 day 3

                                         Mitchell et al (2007) Neuropsychopharm EPub
         Is learning deficit due to
        increased 5-HT6 activity?
• SB258585 or BGC20-                             80%

  761 given immediately
                                                 60%
  after 2nd day session


                           % successful trials
  had no effect
                                                 40%


• SB258585 (5 mg/kg ip)                          20%                  *
  or saline vehicle
  immediately before 1st                         0%
                                                       GFP-only 5-HT6/GFP GFP-only 5-HT6/GFP
  and 2nd sessions                                           saline               + SB258585

                                                          day 1           day 2            day 3
         Is effect of 5-HT6 receptor
     overexpression subregion specific?

                                                       80%



                                                       60%




                                 % successful trials
                                                       40%


                                                                               *
                                                       20%



                                                       0%
                                                             GFP-only   5-HT6/GFP     GFP-only    5-HT6/GFP
                                                                 dorsomedial                dorsocentral


                                                                day 1               day 2              day 3


Voorn et al TINS (2004) 27:468
5-HT6 overexpression in NAcc shell

• No significant effects on locomotor
  sensitization
• Conditioned place preference, compared
  HA6/GFP to GFP injected animals
Conditioned place preference to cocaine (20 mg/kg)



        900




        450




          0
5-HT6 antagonist & cocaine reward

• Ro4368554 or vehicle given before
  subthreshold doses of cocaine (5 mg/kg)

           *




               Ferguson et al 2007 Biol Psych in press.
                  Implications
                                             Glu
• Impaired… or stable?
                           5-HT
• Dopamine and Serotonin
                                          striatum
  - opposing factors?              GABA
                           5-HT6
• 5-HT6 receptors and ACh
                                             ACh
                            DA

				
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posted:10/11/2012
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