Projed 3 combines the research efforts of Dre. Scott Hemby, Steve Childere and Allyn Howlett. The overall goal is to identity biochemical adaptetions with chronic cocaine self-administration and determine the degree to which topiramate and other candidate medications can reveree or attenuate cocaine-induced alterations in specific brain regions. Studies will utilize a combination of procedures to evaluate neuronal plasticity in receptore and their signal transdudion resulting from cocaine administration and the effeds of potential b-eatment agents. The studies will determine changes in gene and protein expression as well as fundional fine-tuning manifested as phosphorylation modifications in discrete brain regions from rodents and nonhuman primates following cocaine self-administration and treatment with the candidate medications. Numerous studies indicate dysregulation of dopaminergic pathways and signaling in humans and animal models, yet pharmacotherapies that diredly target dopamine signaling have proven only moderately successful. An alternative strategy Is to identity medications that target neuroti^ansmitter systems that augment dopaminergic signaling diredty and/or indiredty. Identification of key biochemical processes associated with efficacious medications will provide the basis for development and optimization of next generation pharmacotherapies that can better target cocaine abuse as well as further our underetanding of neurobiological basis of cocaine reinforcement.
Specific Aim 1 (Childere and Howlett labs) will charaderize the effeds of candidate medications on the biochemical neuroadaptations associated with chronic cocaine exposure in rodent models by 1) determining changes in receptor binding properties of ionotropic and metabofropic receptore as well as fondional adivation of GPCR's using GTPyS binding and 2) examining changes In signal transdudion via activation of protein kinase pathways.
Specific Aim 2 (Hemby lab) will assess biochemical neuroadaptations of candidate medication efficacy associated with chronic cocaine exposure in riiesus monkeys by 1) examining mRNA and protein expression of ionotropic glutamate and GABA receptore and related synaptic proteins, as well as targeted proteomic analysis of receptor subunit complexes to provide a more compreliensive underetanding of coordinate synaptic protein alterations and 2) assess mRNA and protein expression of BDNF, frkB and related signaling pathway alterations (akt, PLCg, ERK) in the nucleus accumbens and caudate/putamen.

Public Health Relevance

Identifying the molecular and neurochemical targets that mediate the actions of potential pharmacotherapies to reduce cocaine reinforcement will provide a better understanding of the neurobiological mechanisms of cocaine addiction, as well as provide ways to develop therapeutic agents with higher efficacies and less side effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA006634-20
Application #
8268937
Study Section
Special Emphasis Panel (ZDA1)
Project Start
Project End
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
20
Fiscal Year
2011
Total Cost
$436,308
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Ding, Huiping; Kiguchi, Norikazu; Yasuda, Dennis et al. (2018) A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci Transl Med 10:
Chen, R; McIntosh, S; Hemby, S E et al. (2018) High and low doses of cocaine intake are differentially regulated by dopamine D2 receptors in the ventral tegmental area and the nucleus accumbens. Neurosci Lett 671:133-139
John, William S; Martin, Thomas J; Solingapuram Sai, Kiran Kumar et al. (2018) Chronic ?9-THC in Rhesus Monkeys: Effects on Cognitive Performance and Dopamine D2/D3 Receptor Availability. J Pharmacol Exp Ther 364:300-310
Siciliano, Cody A; Saha, Kaustuv; Calipari, Erin S et al. (2018) Amphetamine Reverses Escalated Cocaine Intake via Restoration of Dopamine Transporter Conformation. J Neurosci 38:484-497
Ilyasov, Alexander A; Milligan, Carolanne E; Pharr, Emily P et al. (2018) The Endocannabinoid System and Oligodendrocytes in Health and Disease. Front Neurosci 12:733
Melchior, James R; Jones, Sara R (2017) Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo. Mol Cell Neurosci 85:93-104
Namjoshi, Sanjeev V; Raab-Graham, Kimberly F (2017) Screening the Molecular Framework Underlying Local Dendritic mRNA Translation. Front Mol Neurosci 10:45
Gould, Robert W; Czoty, Paul W; Porrino, Linda J et al. (2017) Social Status in Monkeys: Effects of Social Confrontation on Brain Function and Cocaine Self-Administration. Neuropsychopharmacology 42:1093-1102
Karkhanis, Anushree; Holleran, Katherine M; Jones, Sara R (2017) Dynorphin/Kappa Opioid Receptor Signaling in Preclinical Models of Alcohol, Drug, and Food Addiction. Int Rev Neurobiol 136:53-88
Luessen, D J; Sun, H; McGinnis, M M et al. (2017) Chronic intermittent ethanol exposure selectively alters the expression of G? subunit isoforms and RGS subtypes in rat prefrontal cortex. Brain Res 1672:106-112

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