Intravenous drug use continues to be a major public health problem which has become a significant vector for the spread of AIDS. The combined use cocaine and heroin (speedball) has proven to be a significant challenge for the treatment of cocaine and heroin abuse. This application proposes investigation of the brain processes underlying speedball self- administration. Recent data from the laboratory suggests a potential mechanism for the enhance reinforcing effects of speedball compared to either drug alone that is observed in drug abusers. The self-administration of cocaine/heroin combinations resulted in large increases in the extracellular fluid levels of dopamine ([DA]e) in the nucleus accumbens (Nacc) above that with cocaine self-administration, while heroin self- administered alone has no effect. The research proposed in this application is designed to test the hypothesis that the potentiation of heroin of cocaine's elevation of [DA]e in the Nacc are through opioid receptors perhaps on GABA neurons and this potential is the basis of the enhanced reinforcing effects of speedball. Experiments will initially assess the loci and opioid receptor subtypes necessary for this potential by determining the effects of selective alkylation on the reinforcing efficacy (with progressive ratio schedules) and self-administration thresholds (with fixed ratio schedules) for speedball. Experiments will initially assess the loci and opioid receptor subtypes necessary for this potentiation by determining the effects of selective alkylation on the reinforcing efficacy (with progressive ratio schedules) and self-administration thresholds (with fixed ratio schedules) for speedball. In addition, the association between the dose intake relationship for cocaine and speedball and Nacc [DA]e will be assessed throughout the dose-intake curve. Additional experiments will determine if treatments that attenuate the potentiation of reinforcing efficacy and threshold lowering effects of heroin on self-administered cocaine also attenuate the potentiation of Nacc [CA]e. Experiments will determine whether the potentiation is through opioid receptors that impact GABA releasing neurons by injecting selective GABA agonists and antagonists into identified brain regions and assessing effects on self-administration thresholds; and, if effective, on Nacc [DA]e. In addition, experiments will assess whether direct injections of selective opioid receptor agonists into identified brain regions is sufficient to enhance the reinforcing efficacy and lower thresholds for cocaine self-administration. In this manner, the neurobiological mechanisms of this potentiation can be determined.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA012498-05
Application #
6702538
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (01))
Program Officer
Volman, Susan
Project Start
2000-02-20
Project End
2006-12-31
Budget Start
2004-02-01
Budget End
2006-12-31
Support Year
5
Fiscal Year
2004
Total Cost
$245,389
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
McIntosh, Scot; Sexton, Tammy; Pattison, Lindsey P et al. (2015) Increased Sensitivity to Cocaine Self-Administration in HIV-1 Transgenic Rats is Associated with Changes in Striatal Dopamine Transporter Binding. J Neuroimmune Pharmacol 10:493-505
Pattison, Lindsey P; McIntosh, Scot; Sexton, Tammy et al. (2014) Changes in dopamine transporter binding in nucleus accumbens following chronic self-administration cocaine: heroin combinations. Synapse 68:437-44
Bough, Kristopher J; Amur, Shashi; Lao, Guifang et al. (2014) Biomarkers for the development of new medications for cocaine dependence. Neuropsychopharmacology 39:202-19
McIntosh, Scot; Howell, Leonard; Hemby, Scott E (2013) Dopaminergic dysregulation in prefrontal cortex of rhesus monkeys following cocaine self-administration. Front Psychiatry 4:88
Pattison, Lindsey P; McIntosh, Scot; Budygin, Evgeny A et al. (2012) Differential regulation of accumbal dopamine transmission in rats following cocaine, heroin and speedball self-administration. J Neurochem 122:138-46
Pattison, Lindsey P; Bonin, Keith D; Hemby, Scott E et al. (2011) Speedball induced changes in electrically stimulated dopamine overflow in rat nucleus accumbens. Neuropharmacology 60:312-7
Tannu, N S; Howell, L L; Hemby, S E (2010) Integrative proteomic analysis of the nucleus accumbens in rhesus monkeys following cocaine self-administration. Mol Psychiatry 15:185-203
Hemby, Scott E (2010) Cocainomics: new insights into the molecular basis of cocaine addiction. J Neuroimmune Pharmacol 5:70-82
Hemby, Scott E; Tannu, Nilesh (2009) Modeling substance abuse for applications in proteomics. Methods Mol Biol 566:69-83
Martin, Thomas J; Coller, Michael; Co, Conchita et al. (2008) Micro-opioid receptor alkylation in the ventral pallidum and ventral tegmental area, but not in the nucleus accumbens, attenuates the effects of heroin on cocaine self-administration in rats. Neuropsychopharmacology 33:1171-8

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