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 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

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.”

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

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

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.

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

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

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

Background (D2/3 Receptors) From Wikipedia

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

Dopamine Agonists and Antagonists

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

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)

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

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

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

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

Fronto-Striatal Pathway

FSP-cont

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?

Why does it matter?

May be relevant in use of stimulant drugs for impulse control disorders (e.g. ADHD).

M&M

Timeline for Study

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

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

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.

Screening for HI

Effects of IV Cocaine SA on 5CSRTT Performance

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

[18F] Fallypride

Advanced Accelerator Applicationswww.adacap.com/prodotti.php?c=00002&a=00013&l=eng

Neuropsychopharmacology (2013) 38, 1460-1471;doi:10.1038/npp.2013.44

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)). Theimages are 7mm below the dorsal brain surface (BPND threshold.14). (c) Binding potential (BPND) of [18F]fallypride in the left and right ventral striatum ofLI (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

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

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.

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

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)

Take Home #3