Cocaine dependence is a chronic relapsing disorder for which there is currently no medication available. Due to the urgent need for anti-relapse medications, it is important to explore potential uses of FDA-approved drugs that would allow for rapid clinical translation. Minimally, potential treatments should reduce drug craving, since craving is often a precipitating factor in relapse. Another measure that is not often used, but has face validity for anti-relapse effects of treatment is resumption of cocaine self-administration after a period of abstinence. During previous funding periods, our research has made significant contributions toward understanding the neural mechanisms of motivation for cocaine that is elicited by cocaine priming injections or cocaine-associated cues, both of which elicit craving in cocaine abusers. In this new 3rd competing renewal, we propose to investigate an important lead from our work. Specifically, we discovered that although manipulations that increase serotonin (5-HT) 1B receptor (R) function enhance cocaine's reinforcing value during maintenance of self-administration in rats, these same manipulations given during protracted abstinence decrease cocaine's reinforcing value, as well as reinstatement of extinguished cocaine-seeking behavior induced by cocaine-associated cues or cocaine-priming injections. These findings suggest that 5-HT1BRs play a critical role in the pathological brain circuitry that underlies abstinence-induced increases in motivation for cocaine. More importantly, the findings suggest that 5-HT1BR agonists may be effective anti-relapse medications, which is exciting given that there are triptan-class 5-HT1BR agonists that are FDA-approved for the treatment of migraines. We have shown that the selective 5-HT1BR agonist CP94253 decreases resumption of cocaine self-administration and reinstatement of cocaine seeking behaviors after protracted abstinence and we have preliminary data suggesting that the FDA-approved, but less selective agonist zolmitriptan also decreases cocaine intake after a period of abstinence. In this proposal, we aim to compare the effects of CP94253 and zolmitriptan on cocaine self-administration and reinstatement of cocaine-seeking behavior during maintenance versus after a period of protracted abstinence. We also aim to examine whether inhibitory effects of the agonists are maintained after a lengthy abstinence period (60 days) and after 10 daily treatments. We plan to investigate whether the effects that we have observed with CP94253 in male rats that have self-administered cocaine generalize to female rats and generalize to male rats that have self- administered methamphetamine. Finally, we will investigate the neural mechanisms underlying the abstinence- induced switch in the direction of 5-HT1BR agonist effects using electrophysiological recording of dopamine neurons in the VTA.
Our aims have the exciting potential to rapidly translate to new medications for cocaine dependence and will provide new knowledge regarding the mechanisms of cocaine addiction.
We propose a preclinical investigation of 5-HT1B receptor agonists as potential treatments for cocaine abuse and dependence. Because some of these agonists are FDA approved for the treatment of migraine, positive findings could rapidly translate to new treatments for cocaine dependence. In addition, pharmacological and neurophysiological mechanisms of therapeutic effects will be explored that advance understanding of cocaine addiction and its treatment.
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|Pentkowski, Nathan S; Harder, Bryan G; Brunwasser, Samuel J et al. (2014) Pharmacological evidence for an abstinence-induced switch in 5-HT1B receptor modulation of cocaine self-administration and cocaine-seeking behavior. ACS Chem Neurosci 5:168-76|
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|Pockros, Lara A; Pentkowski, Nathan S; Swinford, Sarah E et al. (2011) Blockade of 5-HT2A receptors in the medial prefrontal cortex attenuates reinstatement of cue-elicited cocaine-seeking behavior in rats. Psychopharmacology (Berl) 213:307-20|
|Brackney, Ryan J; Cheung, Timothy H C; Neisewander, Janet L et al. (2011) The isolation of motivational, motoric, and schedule effects on operant performance: a modeling approach. J Exp Anal Behav 96:17-38|
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