There is an urgent need for treatments for cocaine dependence, which is a chronic relapsing disorder. Factors contributing to relapse include sampling cocaine and exposure to environmental cues that are associated with cocaine. Our grant has allowed us to advance knowledge on the mechanisms of motivation for cocaine that can be elicited by cocaine priming and/or exposure to cocaine-associated cues. This new 3rd competing renewal application proposes to investigate two important leads from our work. First, we discovered that although manipulations that increase serotonin (5-HT) 1B receptor (R) stimulation increase cocaine's reinforcing value during maintenance of self-administration, these same manipulations decrease cocaine's reinforcing value and reinstatement of cocaine-seeking behavior by cocaine cues and cocaine priming during abstinence. These findings suggest that 5-HT1BRs play a role in the brain pathology that uderlies withdrawal-induced increases in drug seeking and that 5-HT1BR agonists may be effective anti-relapse medications. We aim to investigate whether the FDA approved 5-HT1BR agonist sumatriptan produces similar effects and whether 5-HT1BR agonist effects persist during longer abstinence periods and with chronic administration. Second, we found that a 5-HT2AR antagonist and 5-HT2CR agonist decrease cue and cocaine-primed reinstatement of cocaine-seeking behavior and that these drugs may interact to attenuate cocaine-induced behavior. These findings suggest that combinations of low doses of each drug may be therapuetic while also reducing side-effects that occur with higher doses of either given alone. We aim to test this hypothesis by investigating low dose combinations of FDA approved and more highly selective 5-HT2AR antagonists and 5-HT2CR agonists for their effects on cocaine self-administration and cocaine-primed and cue reinstatement. We will also investigate the mechanisms involved in the effects of these 5-HT drugs using both electrophysiology and neurochemistry measures. Our aims have the exciting potential to rapidly translate to new treatments for cocaine dependence and will provide new knowledge regarding the mechanisms of cocaine addiction and treatment.
|Effective start/end date||4/1/14 → 3/31/20|
- HHS: National Institutes of Health (NIH): $1,892,527.00