The Kappa Partial Agonist PPL-103 as a Potential Cocaine Abuse Pharmacotherapy

Abstract
Currentlyclinically used drug abuse medications exist for treatment of addiction to opiatesalcoholand
nicotinebut not cocaineThe objective of the proposed project is to test the hypothesis that the partial
kappa agonist PPLcan be effective as a pharmacotherapy for treatment of cocaine abuseBecause
of chronic drug induced changes in the kappa opioid receptor systemkappa receptor directed compounds
have been proposed as potential drug abuse medicationsThe kappa receptor antagonist JDTic has been
shown to be effective in some models of cocaine abuse and a brief clinical trial was initiatedAnother
approach would be to use a kappa partial agonistwhich would be expected to diminish the dysphoric
properties of the upregulated dynorphin systemNalmefenea kappa partial agonist that is approved for
alcohol abuse in Europeaccomplishes thishowever mu antagonism in this compound can be aversive in
itselfPhoenix PharmaLabsPPLhas developed a novel family of opioid receptor ligandsincluding PPLwhich displays a unique combination of high binding affinity and novel activities at the three opioid receptorskappamuand deltaIt is a potentmoderate efficacy kappa agonistit is potent but has very low efficacy as
mu agonistand it is a moderate efficacy delta agonistPPLis not dysphoric like most kappa agonistsbut
is also not self administered in ratsDespite low mu efficacyit does not precipitate withdrawaland even
substitutes for morphine in morphine dependent animalsIn additionPPLexerts minimal effects on motor
coordination and gastrointestinal transit in animalsThereforewe hypothesize that this compound offers
substantial potential as a superior cocaine addiction therapyThereforethe aim of the project is to test
that hypothesis using the cocaine self administration assay in ratsSpecific Aimwill determine whether
systemically administered PPLmg kgi pcan attenuate cocaine self administration in both
short accessShAhand long accessLgAhself administration sessions in both male and female ratsSpecific Aimwill determine whether PPLblocks relapse of cocaine self administration using the
reinstatement paradigmIn these experiments PPLwill be tested for its ability to block reinstatement
induced by the three primary mediators of relapsea cocaine primedrug associated cuesand stressas
induced by the chemical stressor yohimbineThese straightforward experiments will determine whether a
kappa partial agonist can effectively attenuate cocaine taking and seeking behavior and whether PPLhas
appropriate characteristics to act as a potential cocaine abuse pharmacotherapy Narrative
Cocaine abuse is a major public health problem thatunlike abuse of opiatesnicotine or alcoholhas no
pharmcotherapeutic optionsThe objective of the proposed project is to verify the efficacy of our kappa opioid
receptor partial agonistknown as PPLfor its ability to reduce cocaine self administration and relapse in
rats