1. J. David Jentsch, PhD, Associate Professor Departments of Psychology and Psychiatry & Biobehavioral Sciences University of California, Los Angeles Impulsivity: Causes and Consequences

2. Cognitive Control  “Learning” and “memory” reflect the acquisition and persistence of experience-dependence modifications in behavior; however, these mechanisms are often not sufficient to permit adaptive, flexible behavior  Cognitive control is rubric that describes another set of processes that contribute the ability to voluntarily modulate behavior, either in the service of future plans, changing conditional rules or complex and variable contextual influences

3. Cognitive Control  Requires multiple domains of cognitive function, including:  Working memory (ability to maintain internal representations of distant goals)  Ability to update the contents of our internal representations as contingencies shift  Contributes to our ability to execute planned behavior  Inhibitory control of pre-potent responding

4. Implications of Poor Cognitive Control  Inability to delay gratification, integrate complex outcomes in decision making, stop reward-directed behavior (addiction)  Generally, the impulsive aspects of substance abuse can be thought of as a loss of the ability to maintain internal representations of future goals and to inhibit immediately gratifying behavior

5. Questions  What are the determinants of individual variation in cognitive control and impulsivity?  What neuropharmacological targets emerge as important mechanisms for the modulation of cognitive control?

6. Pathways to Deconstructing a Complex Phenotype  Recent studies from Lynn Fairbanks (UCLA) have identified impulsive approach and aggression as a heritable trait in non-human primates  Heritability supports search for genetic mechanisms that may be common to those driving the phenotype in humans

7. Trait Impulsivity  Rapid, unplanned, inflexible approach to novelty (social or non-social) or to rewards; exploratory (image right) or aggressive (highly risky) in nature  Orthogonal to anxious aspects of temperament, leading to at least 4 categories of phenotypic responses to challenge

8. Impulsivity: A Stable Indicator of Temperament Males (n=70) Females (n=56) Data represent two challenge tests separated by 16 months Fairbanks et al. (2004) Biol. Psychiatry, 55: 642-7 r=0.83 r=0.89 Impulsivity

9. Genetic Determinants?  48-basepair, exon 3 variable number tandem repeat polymorphism in the DRD4 (dopamine D4 receptor) gene  In humans, 4 and 7 repeats are the most common alleles  7-repeat allele associated with greater risk for ADHD and higher impulsivity/novelty-seeking  Vervets carry 5 or 6 repeats, with the 5-repeat version being associated with greater impulsivity  This polymorphism accounts for 13% of the variance in impulsive responding in the impulsivity tests (Bailey et al. 2007; Psychiatric Genetics, 17: 23-7)

10. Is Impulsivity an Indicator of Poor Cognitive Control in Monkeys?

11. Experimental Design  Adolescent (4 year old) male vervet monkeys, living in social groups  Drawn into the study according to the following criteria:  Common DRD4 allele (DRD4.6)/low impulsivity  Common DRD4 allele (DRD4.6)/high impulsivity  Rare DRD4.5 allele

12. Spatial Delayed Response  Maintenance of information in working memory  Relies upon DLPFC (amongst other circuits) Curtis and D’Esposito (2004) Cog. Affec. Behav. Neurosci., 4: 528-39

13. Spatial Delayed Response Performance James et al. (2007) J. Neurosci., 27(52):14358-64.

14. DRD4 and Working Memory  These studies that DRD4 genotype modulates working memory in the hypothesized direction (rare allele associates with high impulsivity and poor working memory)  This genotype contributes in a non-unique fashion as compared with the as-of-yet unknown genotypes also driving this super-phenotype that spans the temperamental and cognitive domains

15. What about other genes? Pedigree-wide assessment for working memory (and other cognitive control- related processes) for whole-genome linkage analyses

16. What about other aspects of cognitive control? Executive control over behavior (reversal learning)

17. Reversal Learning and Cognitive Control  Subjects (rodents, monkeys or humans) learn a discrimination based upon positive and negative feedback, alone  Once learned, the contingencies change, and behavior must be flexibly altered in order to obtain desired outcomes  Reversal, as compared with acquisition, selectively measures the ability to change or inhibit a conditioned response

19. Reversal Learning and the Orbitofrontal Cortex Dias et al. (1996) Nature, 380: 69-72

20. Impulsivity and Discrimination Learning and Reversal Subjects were n=12 juvenile (~2 ½ year old subjects)

21. Impulsivity  In young subjects (juveniles and adolescents), impulsive temperament is a strong predictor of working memory maintenance and flexible responding, two key aspects of cognitive control  The impulsive youngster exhibits a spectrum of cognitive control impairments that depend upon variation in AD/HD risk genes…

22. Genomic/neurochemical determinants?

23. Catecholamine Mechanisms  Role for the DRD4 gene in modulating impulsivity and cognitive control suggests that catecholamine mechanisms, generally, remain important targets for neuropharmacological interventions  We know D1-like receptors play a critical role in working memory  What about other dimensions of cognitive control, such as the ability to update behavior in response to reinforcement shifts (reversal learning?)

24. D1/D5 Mechanisms Do Not Modulate Reversal Learning Performance Lee et al. (2007) Neuropsychopharmacol., 32(10):2125-34 SCH 23390 = D1-like antagonist Dose = 0.03 mg/kg

25. D2/D3 Mechanisms Selectively Modulate Reversal Learning Performance Raclopride = D2-like antagonist Dose = 0.03 mg/kg Lee et al. (2007) Neuropsychopharmacol., 32(10):2125-34

26. Dopaminergic Mechanisms  Differently from working memory (maintenance of central representations), reversal learning (flexible responding) depends more on D2-like than D1-like receptors  We propose that D1- and D2-like receptors dissociably contribute to the maintenance vs. updating of central representations and behavior  New emphasis on D2-like mechanisms in cortex for cognitive control is needed

27. Cortical D2 Receptors and Cognitive Control  Ideal strategies include mechanisms that selectively increase, in an activity-dependent manner, extra- cellular levels of dopamine, which then can act on D1-like and D2-like receptors to facilitate working memory and executive control over behavior  Inhibition of the noradrenaline transporter??

28. Atomoxetine Improves Reversal Learning in Monkeys *

29. Conclusions  Progress on the genetics of individual variation in cognitive control in experimental animals  Including the identification of subjects that naturally exhibit a range of psychiatric disorder-related symptoms and endophenotypes  Pharmacological studies reveal a critical role for dopamine D2-like and alpha-adrenergic mechanisms in flexible responding

30. Collaborators and Students  Lynn Fairbanks (primatology)  Nelson Freimer (genetics)  Eydie London (molecular imaging)  Emanuele Seu (post-doc), Alex James (graduate student), Stephanie Groman (graduate student)

31. Acknowledgements  National Institute on Drug Abuse  P20-DA22539 (Methamphetamine Abuse, Inhibitory Control: Treatment Implications)  National Institute of Mental Health  P50-MH77248 (CIDAR: Translational Research to Enhance Cognitive Control)  RL1-MH83270 (Translational Models for Memory and Cognitive Control)  Tennenbaum Center for the Biology of Creativity at UCLA