Project Grant R44DA055443

IN VIVO CHARACTERIZATION OF 5-HT7 MODULATORS IN RAT MODELS OF COCAINE USE DISORDER - COCAINE IS ONE OF THE MOST COMMONLY ABUSED ILLICIT DRUGS, AND THE NEGATIVE IMPACT OF THIS DRUG IS APPARENT IN THE 2011 DRUG ABUSE WARNING NETWORK (DAWN) REPORT WHICH REVEALED THAT >500,000 PATIENTS REQUIRED HOSPITAL EMERGENCY DEPARTMENT SERVICES AS A RESULT OF COCAINE USE. DESPITE THE CLEAR AND COMPELLING NEED, THERE ARE NO FDA APPROVED MEDICATIONS FOR THE TREATMENT OF COCAINE USE DISORDER (CUD). COCAINE PRODUCES EUPHORIA VIA THE MESOCORTICOLIMBIC DOPAMINE (MCL-DA) SYSTEM, ALSO KNOWN AS THE REWARD SYSTEM. DOPAMINE RELEASE AND TRANSPORT SYSTEMS WITHIN THE MCL-DA ARE ALTERED BY BOTH ACUTE AND CHRONIC EXPOSURE TO COCAINE. OVER TIME AND CONTINUED USE, COCAINE WILL PRODUCE ADAPTATIONS IN ADDITIONAL NEURAL CIRCUITS RESULTING IN IMPAIRED EXECUTIVE FUNCTION AND DECISION-MAKING PROCESSES AND CAUSING NEGATIVE EMOTIONAL AFFECT FOR USERS. IT HAS BEEN PREVIOUSLY DEMONSTRATED THAT THERE IS SUBSTANTIAL INTERPLAY BETWEEN MCL-DA ACTIVITY AND SEROTONERGIC NEURONS THAT EXTEND INTO THIS REGION OF THE BRAIN. IN ADDITION, SEVERAL STUDIES HAVE DEMONSTRATED THAT SEROTONIN (5-HT) RELEASING SEROTONERGIC NEURONS REGULATE THE ACTIVITY OF DOPAMINERGIC NEURONS IN THESE REGIONS OF THE MCL-DA SYSTEM UNDER BOTH NORMAL CONDITIONS AND IN THE PRESENCE OF COCAINE. A LINK BETWEEN DA AND 5-HT7 SIGNALING SUGGESTS THAT MODULATING 5-HT7 SIGNALING MAY BE A VIABLE AND NOVEL APPROACH TO CUD. IN ADDITION TO THE POTENTIAL OF 5-HT7 ANTAGONISM TO REGULATE THE MCL-DA SYSTEM, OUR STRATEGY IN THIS PROGRAM STEMS FROM EXTENSIVE LITERATURE DEMONSTRATING THE ROLE OF 5-HT7 RECEPTORS IN IMPROVING ATTENTIONAL SET SHIFTING, REVERSAL LEARNING, AND EXTINCTION IN PRECLINICAL ASSAYS. BY IMPROVING COGNITIVE FLEXIBILITY AND FACILITATING EXTINCTION LEARNING IN ADDITION TO MODULATING REWARD IN THE MCL-DA, WE PROPOSE THAT SELECTIVE 5-HT7 RECEPTOR ANTAGONISTS ARE THE PHARMACOTHERAPY STRATEGY NEEDED IN THE TREATMENT OF CUD. WE HAVE IDENTIFIED A SERIES OF NOVEL, DRUG- LIKE 5-HT7 RECEPTOR ANTAGONISTS WHICH REDUCED COCAINE REINSTATEMENT IN A WELL-ESTABLISHED RAT MODEL OF RELAPSE IN OUR PRELIMINARY STUDIES. WE PROPOSE TO TEST ESCALATING DOSES OF OUR FIRST-GENERATION LEAD IN THIS COCAINE REINSTATEMENT MODEL TO ACHIEVE A FULL DOSE-RESPONSE. ONCE ACHIEVED, WE WILL BUILD ON OUR UNDERSTANDING OF THE SAR FOR OUR 5-HT7 ANTAGONISTS TO IDENTIFY NOVEL, ORALLY BIOAVAILABLE, BBB PENETRANT LEAD COMPOUNDS OPTIMIZED FOR ADVANCED IN VIVO EFFICACY STUDIES. WE WILL TEST THE EFFECTIVENESS OF OUR COMPOUNDS TO REDUCE ONGOING COCAINE RESPONDING AS A POTENTIAL MAINTENANCE THERAPEUTIC AND TO IDENTIFY BEHAVIORALLY ACTIVE DOSES TO BE ADVANCED FOR EVALUATION IN A PANEL OF COCAINE REINSTATEMENT MODELS INCLUDING COCAINE-, CUE- AND STRESS-INDUCED REINSTATEMENT. WE HYPOTHESIZE THAT OUR COMPOUNDS WILL ACCELERATE OR AUGMENT EXTINCTION LEARNING AND REDUCE REINSTATEMENT OF COCAINE RESPONDING WHETHER PRODUCED BY A NONCONTINGENT INJECTION OF COCAINE, ASSOCIATED CUES, OR STRESS- INDUCED BY INJECTION OF YOHIMBINE. LEADS IDENTIFIED IN THESE IN VIVO SCREENS WILL MOVE FORWARD AS PRECLINICAL CANDIDATES TO USE AS MEDICATIONS TO REDUCE THE POTENTIAL FOR RELAPSE AND IMPROVE TREATMENT OUTCOMES FOR CUD.