Despite significant efforts cocaine abuse remains a continuing public health problem. Chronic cocaine use is accompanied by neuroadaptations in multiple neurotransmitter systems, as well as enduring changes in brain functional activity. To date there are no FDA approved medications for treatment of cocaine dependence. Drug development efforts are hampered by the lack of understanding of the neurobiological basis of potential pharmacotherapeutic strategies. The goal of these studies proposed is to characterize at a systems level the neurobiological effects of potential treatment drugs that have shown positive signals in current clinical trials, drugs approved for use In humans being considered for use in treatment;and mechanistic drug treatments for which preliminary animal studies suggest may be useful in reducing cocaine reinforcement based on their mechanisms of action. The convergence of Information from these different strategies will provide critical Information about the neuropharmacological mechanism of effective treatment and guide future drug development.
Aim 1 will evaluate the consequences of chronic administration of candidate medications and then assess the neurobiological effects of these medications in rodent models of chronic cocaine self-administration in neurochemical systems as established in Project 1 We will measure changes in the function of dopamine systems using microdialysis in freely moving rats and voltammetry in brain slices and assess changes in functional brain activity with the 2-deoxyglucose method and the expression of immediate early genes consequent to chronic treatment with candidate medications.
Aim 2 will make use of established nonhuman primate models of cocaine self-administration to evaluate the consequences of these potential pharmacotherapies on brain transmitter systems and to characterize the sites of changes in functional activity accompanying responses to cocaine-associated cues and cognitive processes as established in Project 1 It is only through a systems level analysis with clinically relevant models of substance abuse as proposed in this application that a greater understanding of the neurobiological basis of treatment can emerge. Thus, the systems approach of Project 2 provides a bridge between behavioral evaluations in Project 1 and the cellular approaches in Project 3.
By combining multiple drug strategies in this Project, areas of convergence will be identified that characterize relevant mechanisms of drug action showing positive clinical signals and help delineate specific neuropharmacological mechanisms that can serve as targets for medications development.
|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|
|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|
|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|
|Siciliano, Cody A; McIntosh, J Michael; Jones, Sara R et al. (2017) ?6?2 subunit containing nicotinic acetylcholine receptors exert opposing actions on rapid dopamine signaling in the nucleus accumbens of rats with high-versus low-response to novelty. Neuropharmacology 126:281-291|
Showing the most recent 10 out of 310 publications