Impact of Cocaine History on Pharmacotherapy Effectiveness

点击翻译按钮获取中文摘要

PROJECT SUMMARY With cocaine-related overdose deaths increasing every year, cocaine abuse is a serious public health concern. Despite decades of basic research, there are still no Food and Drug-approved pharmacotherapies for cocaine use disorder (CUD). A growing body of evidence suggests that prior cocaine use history may alter the development and screening of new CUD pharmacotherapies. We propose to leverage the translational utility of preclinical drug-vs-nondrug choice procedures to determine how different cocaine self-administration histories impact the effectiveness of the muscarinic acetylcholine receptor (mAChR)1 positive allosteric modulator VU0364572 to attenuate cocaine-vs-food choice and cocaine-induced increases in nucleus accumbens (NAc) dopamine (DA) release using fiber photometry (i.e., dLight). The scientific premise of this project is that candidate medications that are effective in decreasing drug choice across a broader range of experimental conditions, including cocaine history, would be hypothesized to be more effective clinically. Aim 1 will determine the effects of behavioral history (i.e., short- vs extended-access cocaine self-administration) on VU0364572 effectiveness to attenuate cocaine-vs-food choice behavior. In a 2 x 4 experimental design, each group will undergo either short-access (ShA) or extended-access (EA) cocaine self-administration conditions. Under these two access conditions, effects of 4 treatments (vehicle, 0.32, 1.0, and 1.8 mg/kg VU0364572) will be assessed. Aim 2 will determine the effects of cocaine history on effectiveness of VU0364572 to attenuate cocaine-elevated NAc DA release using dLight technology. In a 3 x 2 experimental design, each group will be exposed to one of three cocaine access conditions (ShA, EA, or cocaine naïve) and either vehicle or VU0364572 treatment. Using dLight fiber photometry, NAc DA response to cocaine infusions will be assessed. These neurochemical endpoints will be compared across groups and collected in conjunction with cocaine-vs- food choice data, allowing for within-subjects comparison of neurochemical and behavioral data. Completion of these studies will test innovative and translationally relevant hypotheses regarding the effects of cocaine history on mAChR1 PAM efficacy to decrease cocaine self-administration and cocaine-induced enhancement of mesolimbic DA signaling.