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Before We Start

Before We Start. Rapper ’ s Paradise https://www.youtube.com/watch?v=-YCeIgt7hMs Caution and Danger T. Szasz Focus on symptoms and not diagnoses https://www.youtube.com/watch?v=Qj7GmeSAxXo. Impulsivity and D 2/3 Receptors cont.

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Before We Start

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  1. Before We Start • Rapper’s Paradise • https://www.youtube.com/watch?v=-YCeIgt7hMs • Caution and Danger • T. Szasz • Focus on symptoms and not diagnoses • https://www.youtube.com/watch?v=Qj7GmeSAxXo

  2. Impulsivity and D2/3 Receptors cont. Baseline-Dependent Effects of Cocaine Pre-Exposure on Impulsivity and D2/3 Receptor Availability in the Rat Striatum: Possible Relevance to the Attention-Deficit Hyperactivity Syndrome Caprioli, Hong, Sawiak, Ferrari, Williamson, Jupp, Carpenter, Aigbirhio, Everitt, Robbins, Fryer, and Dalley. 2013. Neuropsychopharmacology. 38: 1460-71

  3. Supporting Articles • 2° Besson et al. 2010 • “Dissociable Control of Impulsivity in Rats by Dopamine D2/3 Receptors in the Core and Shell Subregions of the Nucleus Accumbens.” • 3° Archer et al. 2012 • “Neurogenetics and Epigenetics in Impulsive Behaviour: Impact on Reward Circuitry.”

  4. Defining Impulsivity • Cliff • Phenotypic Impulsivity • Negative consequences, Risky Behavior, Repetitive*, Not able to discern want from need, Underdeveloped PFC, less feedback from PFC to limbic, impatience, make choices even recognizing the negative consequences for that choice

  5. Impulsivity Defined (cont.) • Justin • Impulsivity- a predisposition toward rapid, unplanned reactions to internal or external stimuli with diminished regard to the negative consequences of these reaction to the impulsive individual or to others

  6. Adding to the Discussion • °1 ø attempt at defining impulsivity (assumed) • °2 Impulsivity is a multidimensional behavioral construct involving rash or risky behavior and a strong tendency toward spur-of-the-moment, poorly judged decisions and actions (Besson et al. 2010: 560) • °3 Impulsiveness is a personal attribute characterized by the individual’s tendency to engage in behaviors without adequate forethought as to the consequence of the actions.

  7. Archer on Characteristics of Impulsivity • Epigenetics=study of heritable changes in genome function without DNA sequence alteration. • Impulsivity • Act on impulses on spur-of-the-moment • May be expressed through pos or neg urgency (acting rashly when in a pos or neg mood state). • Motor Impulsivity = Anxiety and Depression • Cognitive Impulsivity = Not related as above

  8. Archer on D2 (it all comes back to BDNF) • Only associates with addiction, aggression, eating disorders, and impulsivity • Gambling, Internet, etc. • Associated with DRD2 Gene and D2A1 Allele • Reduced D2 availability in bilat dorsal caudate and R putamen • Suggest DA Agonist Therapy effective and saw craving, total play time, & cue-induced DLPFC activation in gaming addiction subjects. • Reported similar findings in other studies of addiction

  9. Striatal D2 and DAT in Impulsivity • From James • Stice et al. • Proposes three theories to explain conflicting findings • Individuals at risk experience ↓ reward from eating, leading to compensatory over-eating and hyper-responsivity of reward circuitry via conditioning – Reward Deficit Theory • Individuals at risk initially show ↑ responsivity to reward value of food cues, leading to over-eating and a reduction in DA signaling in response to food intake – Reward Surfeit Theory • Individuals at risk initially experience ↑ reward from eating, leading to overeating that reduces DA signaling in response to food intake and hyper-responsivity of reward circuitry to food cues, both of which may drive further overeating - Synthesis • Narayanaswami • D2 • DAT outcome of DIO

  10. Background (D2/3 Receptors) From Wikipedia

  11. DA from CNS Forumhttp://www.cnsforum.com/imagebank/section/Dopaminergic/default.aspx

  12. Dopamine Agonists and Antagonists http://wings.buffalo.edu/aru/Agonists&Antagonists.html

  13. Besson et al. • NAcbs D2/3 mediates HI in rats •  D2/3 density in VS via PET (Bari et al. 2008; Dalley et al. 2007) • May include NAcbsC and NAcbsS • Previous work: intra-NAcbsC infusions of D2/3 antagonists  impulsive behavior on 5CSRTT • Purpose of Study= Investigate role D2/3 in NAcbsC and shell in mediating inter-individual differences in impulsive behavior • H1: HI rats nafadotride  impulsive behavior (admin to NAcbsC)

  14. Besson et al. Results • Nafadotride (D2/3 antagonist) • Exerts impulsivity state dependent, dissociable effect in NAcbsS & NAcbsC (HI rats) •  impulsivity when infused in NAcbsS •  impulsivity when infused in NAcbsC • Ø∆ when administered systemically, but  omissions  correct response latencies

  15. Besson et al. Results cont. • Aripiprazole (D2/3 partial agonist) • Ø effect on impulsivity with NAcbsS/NAcbsC infusion •  impulsivity  perseverative but omission & correct response latencies when systemically administered

  16. Archer et al (2012) • ELS  Impulsivity through epigenetic regulation of stress response, behavioral disinhibition, cognitive-emotional systems • Polymorphisms affecting BDNF • Eating disorders, addiction, and indiscriminate social behavior

  17. Neural Basis for Impulsivity • 1° • Abnormalities in fronto-striatal ganglia circuitry • Impaired dopamine (DA) neurotransmission in fronto-striatal networks • Further compromised by drug abuse, but not caused by • +Animal Models & +Human Studies

  18. Fronto-Striatal Pathway

  19. FSP-cont

  20. 1° Research Questions • RQ1: What are the consequences of cocaine exposure on D2/3 receptor availability in the ventral striatum (VS) in relation to behavioral impulsivity on the 5CSRTT? • 5CSRTT as analog for Cont. Performance Test • RQ2: What is the relationship between HI and LI rats and D2/3 availability in VS following discontinuation of cocaine self-administration?

  21. Why does it matter? • May be relevant in use of stimulant drugs for impulse control disorders (e.g. ADHD).

  22. M&M

  23. Timeline for Study

  24. Animal Model • 96 adult male Lister-hooded rats 2-3 m/o • HI n=10; LI n=12 • Experiment: HI n=6; LI n=8 • Control: HI n=4; LI n=4 • Housed individually rev 12hr light/dark • Off (red)=0700 • Restricted diet; weight reduced to 85-90% of free-feed

  25. Training • ~50 sessions/day; 6 sessions/week • Training complete when: • 75% accuracy with omissions on fewer than 20% of trials • ITI = 5s • Computer controlled • Reward reduction to reach training objective • Omission, Incorrect Response, Premature Response • 5s TO and loss of food reward for that trial

  26. HI vs LI assignment • HI assignment due to >50% premature response rate on long-ITI challenge sessions (3 sessions=100 discrete trials-1wk apart). • LI selected from remaining rats and responded prematurely in <30% of trials.

  27. Screening for HI

  28. Effects of IV Cocaine SA on 5CSRTT Performance

  29. Selective Correction of Impulsivity in HI rats following withdrawal from IV cocaine SA

  30. [18F] Fallypride Advanced Accelerator Applications www.adacap.com/prodotti.php?c=00002&a=00013&l=eng

  31. Figure 4 Figure 4 Selective remediation of deficient D2/3 receptor availability in the left ventral striatum of HI rats by prior exposure to intravenous cocaine self administration. (a) 3D depiction of regions of interest showing the ventral striatum (blue), anterior dorsal striatum (green), and posterior dorsal striatum (red). (b) Horizontal section through [18F]fallypride BPND maps for HI and LI rats overlaid on the coregistered MR template (left (L) and right (R)). The images are 7mm below the dorsal brain surface (BPND threshold.14). (c) Binding potential (BPND) of [18F]fallypride in the left and right ventral striatum of LI (square symbols, n.8) and HI (circle symbols, n.6) rats before (‘pre-cocaine’) and after (‘post-cocaine’) cocaine self-administration. It can be seen that [18F]fallypride BPND is significantly reduced in the left ventral striatum of HI rats compared with LI rats before cocaine exposure (**Po0.01) and that cocaine selectively normalises [18F]fallypride BPND in HI rats in this brain region (*Po0.05). Neuropsychopharmacology (2013) 38, 1460-1471; doi:10.1038/npp.2013.44

  32. Figure 5 Binding potentials of [18F]fallypride in the left (a, c) and right (b, d) anterior and posterior dorsal striatum of LI (square symbols, n.8) and HI (circle symbols, n.6) rats before (‘pre-cocaine’) and after (‘post-cocaine’) cocaine self administration. There were no significant baseline differences in[18F]fallypride BPND in either brain region between LI and HI rats. Prior cocaine exposure also had no significant effect on [18F]fallypride BPND in the anterior and posterior dorsal striatum of LI and HI rats. Neuropsychopharmacology (2013) 38, 1460-1471; doi:10.1038/npp.2013.44

  33. Figure 6 Figure 6 Relationship between the percentage change in [18F]fallypride BPND in ventral and dorsal striatum before and after the exposure of LI and HI rats to cocaine as a function of baseline (ie, pre-cocaine) [18F]fallypride BPND. With the exception of [18F]fallypride BPND in the ventral striatum of LI rats, the results show that the effects of cocaine on D2/3 receptor availability depend in an inverse manner on baseline [18F]fallypride BPND. The horizontal dotted line depicts no net effect of cocaine on [18F]fallypride BPND. Pearson product moment correlation coefficients and P-values are given in each panel. Neuropsychopharmacology (2013) 38, 1460-1471; doi:10.1038/npp.2013.44

  34. Take Home #1 • Behavioral Inhibition present in ADHD, Addiction, etc. • Behavioral Inhibition = Relative deficiancy in D2/3 Availability in VS • Prior cocaine exposure restores D2/3 availability &  impulse control • D2/3 agonists improve response inhibitory control in stimulant addicts • Relevant to past findings  D2/3 availability in NAcbs and Caudate Nucleus in unmedicated adults

  35. Take Home #2 • “The clinical efficacy of stimulant drugs such as methylphenidate in ADHD may depend, in part, on restoring D2/3 receptor signaling in the VS of impulsive individuals”(Caprioli 2013:1469)

  36. Take Home #3

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