The Novel Short-Acting Kappa Opioid Receptor Antagonist LY2444296 Blocks Neuroendocrine and Behavioral Effects of Chronic but not Acute Mild Stress in Rats.

Background: Considerable evidence supports the hypothesis that psychiatric co-morbidity (including depression) in the context of addictive diseases triggers relapse, and is an underlying factor of failure of treatment-seeking patients to remain abstinent. Stress is one major trigger of relapse to specific addictive diseases, which results in upregulation of Kappa opioid receptor (KOPr) signaling tone, largely through increased mRNA transcription and activity of its endogenous agonists, the dynorphins, leading to depressive- like and relapse-like behaviors. Synthetic KOPr agonists induce dysphoria in humans, as well as depressant-like effects in preclinical models. Therefore, KOPr antagonism has received considerable attention as a novel antidepressant and anti-relapse pharmacotherapeutic approach. However, most of the current knowledge on the pharmacotherapeutic potential of KOPr antagonism is based on antagonists (e.g. nor-BNI, JDTic) with unusual pharmacokinetic and pharmacodynamic properties, including delayed onset of KOPr selectivity, very slow onset and extended durations of action. These features have limited experimental designs, interpretation and translation of results into the clinic. Therefore, novel compounds with typical medication-like durations of action (i.e. o24 h) are needed to further the understanding of KOPr/dynorphin involvement in the neurobiology of stress and relapse. In the light of these premises, we characterized in vivo the pharmacotherapeutic- like effectiveness of systemic administration of LY 2444296 (also known as FP3FBZ; kind gift of Eli Lilly Co.), a novel shorter-acting KOPr antagonist, which is a close structural analog of LY 2456302 that has reached the clinical investigation stage. Methods: First, we verified the specificity of the novel KOPr antagonist by testing the efficacy of systemic administration of LY2444296 (0, 1, 3 mg/kg; i.p.; pre-treatment time 30 minutes) in blocking KOPr-agonist induced behavioral and neuroendocrine effects, using U69,593-induced conditioned place aversion, U69,593-reduced locomotor activity and U69,593-induced rise in serum corticosterone. Next, we tested the efficacy of systemic administration of LY2444296 (0, 1, 3 mg/kg; i.p.; pre-treatment time 30 minutes) in reducing signs of depressive-like behavior (measured as immobility time during a Porsolt’s forced swim test, FST). We also tested stress levels (measuring the stress-responsive hormone corticosterone 30 minutes after the FST) in rats with three different stress exposure, including a) 2-day forced swimming (acute stress); b) repeated saline injections 3/day for 14 consecutive days (chronic stress), followed by a FST; protracted (8 weeks) social isolation (chronic stress), followed by a FST. A non-stressed group of rats was also included for comparison. Data were analyzed with factorial or repeated measures twoway ANOVA, followed by the Student Neumann Keul’s test for multiple comparisons. Significance was set at po0.05. Results: Acute LY2444296 administration decreased KOPr agonist-induced conditioned place aversion and KOPrinduced hypolocomotion. LY2444296 alone did not alter locomotor activity, and did not induce place preference or aversion. Pretreatment with LY2444296 prevented the KOPr agonist-induced rise in serum corticosterone. In rats never exposed to stress, acute LY2444296 administration did not alter basal serum corticosterone levels. In rats exposed to an acute stress, acute LY2444296 administration did not reduce immobility time during the FST or affect serum corticosterone level measured 30 min after the FST. However, acute pre-treatment with LY2444296 reduced both immobility time in the FST and the serum corticosterone level in animals exposed to repeated injections over 14 days. Preliminary results suggest that acute pre-treatment with LY2444296 also reduces immobility time in the FST for animals exposed to protracted social isolation. Conclusions: Taken together, these results suggest that a KOPr antagonist with medication-like duration of action can acutely prevent KOPr-mediated behavioral and neuroendocrine effects. Also, the KOPr antagonist decreased behavioral and neuroendocrine effects occurring after chronic, but not acute stress conditions. Further studies are needed to determine its efficacy in preventing relapse like behaviors in specific addictive diseases because this and similar compounds have potential in the translational investigation of stress responsiveness and depression-like co-morbidity in addictive states.