Human subjects who are dependent on methamphetamine (MA) exhibit functional and structural abnormalities within frontostriatal circuitry that most likely contribute to behavioral sequelae of MA abuse. Still little is known about the specific neurochemical adaptations that result from MA abuse and how they contribute directly to impaired neurobehavioral function. Project 3 will employ a non-human primate model of MA dependence to explore the neurochemical mechanisms contributing to impaired response inhibition (as indexed by a reversal learning task) that results from drug exposure (Aim 1). Using both in vivo and ex vivo measures of brain catecholamine function, we will generate insights about the molecular and neurochemical adaptations that contribute directly to functional brain abnormalities revealed in Project 1. These studies will then be extended in two important ways. First, we will explore the mechanisms of action of modafinil, a drug that improves response inhibition in humans and which may, through this mechanism, have therapeutic efficacy in the treatment of stimulant dependence. We will deliver modafinil to control and MA-experienced monkeys and will test the hypothesis that this agent exerts pro-cognitive effects by indirect stimulation of a-2 adrenergic receptors (Aim 2). These complex pharmacological experiments, which are not readily performed in human subjects, will allow us to define a mechanism of action for modafinil and will, in turn, provide a greater understanding of how modafinil produces specific behavioral effects being studied in Projects 1 and 2. Our final goal is to identify more specific targets for pharmacological interventions. As noted above, modafinil may produce indirect stimulation of a-2 adrenergic receptors and multiple lines of evidence now supports the notion that direct a-2 adrenoceptor agonists can improve cognition. We will therefore conduct experiments to test the idea that selective activation of a-2 receptors facilitates response inhibition in MA-exposed monkeys (Aim 3);these results will be compared with effects of subtype-specific dopamine receptor agonists or antagonists, based upon direct evidence supporting their involvement in reversal learning. These experiments have the potential to drive a new phase of medication evaluation in a mature translational research center. Through these Aims, Project 3 proposes to provide a mechanistic foundation for clinical data and to direct future hypothesis testing in clinical populations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory Grants (P20)
Project #
5P20DA022539-04
Application #
7880747
Study Section
Special Emphasis Panel (ZDA1)
Project Start
Project End
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
4
Fiscal Year
2009
Total Cost
$191,454
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Dean, Andy C; Morales, Angelica M; Hellemann, Gerhard et al. (2018) Cognitive deficit in methamphetamine users relative to childhood academic performance: link to cortical thickness. Neuropsychopharmacology 43:1745-1752
Kong, Xiang-Zhen; Mathias, Samuel R; Guadalupe, Tulio et al. (2018) Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium. Proc Natl Acad Sci U S A 115:E5154-E5163
Kohno, Milky; Morales, Angelica M; Guttman, Zoe et al. (2017) A neural network that links brain function, white-matter structure and risky behavior. Neuroimage 149:15-22
Jones, Hannah W; Dean, Andy C; Price, Kimberly A et al. (2016) Increased self-reported impulsivity in methamphetamine users maintaining drug abstinence. Am J Drug Alcohol Abuse 42:500-506
Okita, Kyoji; Ghahremani, Dara G; Payer, Doris E et al. (2016) Emotion dysregulation and amygdala dopamine D2-type receptor availability in methamphetamine users. Drug Alcohol Depend 161:163-70
Okita, Kyoji; Ghahremani, Dara G; Payer, Doris E et al. (2016) Relationship of Alexithymia Ratings to Dopamine D2-type Receptors in Anterior Cingulate and Insula of Healthy Control Subjects but Not Methamphetamine-Dependent Individuals. Int J Neuropsychopharmacol 19:
Okita, Kyoji; Petersen, Nicole; Robertson, Chelsea L et al. (2016) Sex Differences in Midbrain Dopamine D2-Type Receptor Availability and Association with Nicotine Dependence. Neuropsychopharmacology 41:2913-2919
Kohno, M; Okita, K; Morales, A M et al. (2016) Midbrain functional connectivity and ventral striatal dopamine D2-type receptors: link to impulsivity in methamphetamine users. Mol Psychiatry 21:1554-1560
Okita, Kyoji; Mandelkern, Mark A; London, Edythe D (2016) Cigarette Use and Striatal Dopamine D2/3 Receptors: Possible Role in the Link between Smoking and Nicotine Dependence. Int J Neuropsychopharmacol 19:
Ballard, Michael E; Dean, Andy C; Mandelkern, Mark A et al. (2015) Striatal Dopamine D2/D3 Receptor Availability Is Associated with Executive Function in Healthy Controls but Not Methamphetamine Users. PLoS One 10:e0143510

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