Cocaine abuse and addiction continue to be a serious problem in the world. Currently, there is no effective pharmacological treatment for this mental disorder. Our long term goal is to understand the mechanism of cocaine addiction in order to develop effective treatments for this disorder. Cocaine has three known high affinity targets, the dopamine (DA) transporter (DAT), the serotonin (5HT) transporter (SERT), and the norepinephrine (NE) transporter (NET). When cocaine enters the brain it blocks all three transporters and thus increases extracellular DA, 5HT, and NE in various brain regions, resulting in complex cocaine effects. One way to study the role of each transporter is to generate knockout mice with individual transporters deleted. The potential problem with this approach is that adaptive changes to compensate for the complete removal of the critical transporter may alter the reward pathway significantly. We are employing an alternative approach. We are generating knock-in mouse lines carrying a transporter mutant that is insensitive to cocaine inhibition while maintaining functional monoamine uptake. We have generated a knock-in mouse line carrying a cocaine-insensitive DAT mutant that retains substantial uptake activity. In these mice, cocaine no longer produces reward, suggesting that DAT blockade is necessary for cocaine reward. However, DAT mutant mice do not provide information about the roles of NET and SERT in cocaine effects.
The specific aims of the proposed study is (1) to construct mutants of SERT and NET that are functional but insensitive to cocaine inhibition;(2) to generate 2 mouse lines with their SERT or NET replaced by the cocaine-insensitive transporter mutants;and (3) to analyze the cocaine responses by the knock-in mice. This study will tell us whether NET or SERT blockade is also necessary for cocaine reward, or it enhances or dampens cocaine reward. Precise knowledge on how DA, 5HT, and NE systems modulate cocaine reward and aversion may suggest potential drug targets to modulate the intensity and dynamics of cocaine reward and aversion. Compounds that dampen the cocaine-induced euphoria and prolong cocaine dysphoria may discourage cocaine seeking and abuse. These compounds would be excellent drug candidates for the development of pharmacological treatment for cocaine addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA020124-04
Application #
7664307
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Pollock, Jonathan D
Project Start
2006-09-30
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$320,669
Indirect Cost
Name
Ohio State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Thirtamara Rajamani, Keerthi; O'Neill, Brian; Han, Dawn D et al. (2015) Inactivation of the catalytic phosphatase domain of PTPRT/RPTP? increases social interaction in mice. Autism Res 8:19-28
O'Neill, Brian; Tilley, Michael R; Han, Dawn D et al. (2014) Behavior of knock-in mice with a cocaine-insensitive dopamine transporter after virogenetic restoration of cocaine sensitivity in the striatum. Neuropharmacology 79:626-33
Wu, Haiyin; O'Neill, Brian; Han, Dawn D et al. (2014) Restoration of cocaine stimulation and reward by reintroducing wild type dopamine transporter in adult knock-in mice with a cocaine-insensitive dopamine transporter. Neuropharmacology 86:31-7
O'Neill, B; Tilley, M R; Gu, H H (2013) Cocaine produces conditioned place aversion in mice with a cocaine-insensitive dopamine transporter. Genes Brain Behav 12:34-8
O'Neill, Brian; Gu, Howard H (2013) Amphetamine-induced locomotion in a hyperdopaminergic ADHD mouse model depends on genetic background. Pharmacol Biochem Behav 103:455-9
Thirtamara Rajamani, Keerthi; Doherty-Lyons, Shannon; Bolden, Crystal et al. (2013) Prenatal and early-life exposure to high-level diesel exhaust particles leads to increased locomotor activity and repetitive behaviors in mice. Autism Res 6:248-57
Naughton, Bart J; Thirtamara-Rajamani, Keerthi; Wang, Chuansong et al. (2012) Specific knockdown of the D2 long dopamine receptor variant. Neuroreport 23:1-5
Martin, Bradley J; Naughton, Bartholomew J; Thirtamara-Rajamani, Keerthi et al. (2011) Dopamine transporter inhibition is necessary for cocaine-induced increases in dendritic spine density in the nucleus accumbens. Synapse 65:490-6
Hill, Erik R; Huang, Xiaoqin; Zhan, Chang-Guo et al. (2011) Interaction of tyrosine 151 in norepinephrine transporter with the 2? group of cocaine analog RTI-113. Neuropharmacology 61:112-20
Naughton, B J; Han, Dawn D; Gu, Howard H (2011) Fluorescence-based evaluation of shRNA efficacy. Anal Biochem 417:162-4

Showing the most recent 10 out of 15 publications