Deehan GAJr, McKinzie DL, Carroll FI, McBride WJ, Rodd ZA. The long-lasting effects of JDTic, a kappa opioid receptor antagonist, on the expression of ethanol-seeking behavior and the relapse drinking of female alcohol-preferring (P) rats. Pharmacol Biochem Behav 101: 581-587

Department of Psychiatry, Institute of Psychiatric Research, Indiana School of Medicine, Indianapolis, IN 46202, USA.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 03/2012; 101(4):581-7. DOI: 10.1016/j.pbb.2012.03.006
Source: PubMed


The current study assessed the effects of the selective kappa opioid antagonist JDTic on alcohol (EtOH)-seeking behavior, EtOH relapse, and maintenance responding for EtOH. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) on a fixed-ratio 5 (FR-5) and water on a FR-1 schedule of reinforcement during 1-hr sessions. After 10 weeks, rats underwent extinction training for seven sessions. Rats were then maintained in their home cages for 3 weeks without EtOH access. All rats received an injection (s.c.) of 0, 1, 3, or 10 mg/kg JDTic (n=11-14/group) after the first week of the home cage period. Rats were then tested using the Pavlovian Spontaneous Recovery paradigm (PSR; an animal model of alcohol-seeking) for four sessions during which, responses on the EtOH and water levers were recorded but did not produce their respective reinforcer. Following PSR testing rats were returned to their home cages without access to EtOH for one week prior to the start of EtOH relapse testing. To examine EtOH relapse responding, rats were returned to the operant chambers and the EtOH (FR5) and water (FR1) levers were active. Finally, rats were then tested over 17 operant sessions to assess the effects of JDTic on maintenance responding for EtOH. Rats received 0, 1, 3, or 10 mg/kg JDTic (counterbalanced from the initial experiment) 30 minutes prior to the initial maintenance session. JDTic administered 14 and 25 days prior to testing dose-dependently reduced the expression of an EtOH PSR and relapse responding. In contrast, JDTic did not alter EtOH responding under maintenance conditions. Overall, the results of this study indicate that different mechanisms mediate EtOH self-administration under relapse and maintenance conditions and kappa opioid receptors are involved in mediating EtOH-seeking behavior and relapse responding but not on-going EtOH self-administration.

    • "A recent study (Walker and Koob, 2008) found that the selective kappa antagonist norbinaltorphimine selectively reduced ethanol intake in ethanol-dependent rats, suggesting that KOR antagonism could be a viable mechanism for the treatment of patients with a history of alcohol dependence. Additionally, the selective kappa antagonist JDTic, (3R)-7-hydroxy-N-[(2S)-1-[(3R,4R)-4-(3- hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinoline- carboxamide, decreased ethanol-seeking and relapse drinking in alcohol-preferring rats, but not maintenance responding (Deehan et al., 2012). LY2456302 1 is a high-affinity, selective KOR antagonist that is being developed for the treatment of alcohol dependence. "
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    ABSTRACT: The kappa opioid receptor (KOR) is thought to play an important therapeutic role in a wide range of neuropsychiatric and substance abuse disorders, including alcohol dependence. LY2456302 is a recently-developed KOR antagonist with high affinity and selectivity, and showed efficacy in suppression of ethanol consumption in rats. This study investigated brain penetration and KOR target engagement after single oral doses (from 0.5 mg up to 25 mg) of LY2456302 in 13 healthy human subjects. Three positron emission tomography (PET) scans with the KOR antagonist radiotracer (11)C-LY2795050 were conducted at baseline, 2.5 h post-dose, and 24 h post-dose. LY2456302 was well tolerated in all subjects without serious adverse events. Distribution volume was estimated using the multilinear analysis 1 (MA1) method for each scan. Receptor occupancy (RO) was derived from a graphical occupancy plot and related to LY2456302 plasma concentration to determine maximum occupancy (rmax) and IC50. LY2456302 dose-dependently blocked the binding of (11)C-LY2795050, and nearly saturated the receptors at 10 mg, 2.5 h postdose. Thus, a dose of 10 mg LY2456302 appears very well suited for further clinical testing. Based on the PK/RO model, the rmax and IC50 of LY2456302 were estimated as 93% and 0.58 to 0.65 ng/mL, respectively. Assuming that rmax is 100%, IC50 was estimated as 0.83 ng/mL.
    No preview · Article · Dec 2015 · Journal of Pharmacology and Experimental Therapeutics
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    • "Although the data from studies on basal alcohol consumption in DYN and KOR knock-out mice are mixed (Walker et al. 2012), pharmacological studies suggest that DYN and KOR can modulate alcohol consumption (Walker et al. 2011; Schank et al. 2012). KOR blockade also reduces spontaneous recovery of lever pressing for alcohol as well as cue-induced reinstatement of alcohol seeking (Deehan et al. 2012; Schank et al. 2012). Stress stimulates DYN release of in brain areas involved in motivation and reward (McLaughlin et al. 2003; Shirayama et al. 2004). "
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    ABSTRACT: Introduction Stress is related to heavy alcohol use and relapse in alcoholics. Using the reinstatement model, we have shown that corticotropin-releasing factor (CRF) underlies stress-induced relapse to alcohol seeking in laboratory rodents. Little is known about how other neurotransmitters interact with CRF in these effects. Dynorphin and its receptor (kappa opioid receptor, KOR) are involved in stress responses and in alcohol seeking. KOR and CRF receptors (CRF R) may interact in the production of stress-related behaviors but it is not known whether this interaction is involved in reinstatement of alcohol seeking. Methods Male Long Evans rats were trained to self-administer alcohol (12% w/v). After extinction of responding, we determined the effects of the KOR agonist, U50,488 (2.5, 5 mg/kg) on reinstatement of alcohol seeking, and their sensitivity to the selective KOR antagonist nor-binaltorphimine dihydrochloride (nor-BNI) (10 mg/kg) administered at different times before U50,488. We then examined the effects of nor-BNI on reinstatement induced by the stressor yohimbine (1.25 mg/kg) and on reinstatement induced by exposure to alcohol-associated cues. Finally, we determined whether CRF R1 blockade with antalarmin (10, 20 mg/kg) attenuates alcohol seeking induced by U50,488. Results U50,488 reinstated alcohol seeking. Prior treatment with nor-BNI 2, but not 24 h before administration of U50,488 or yohimbine blocked reinstatement induced by these drugs. Cue-induced reinstatement was blocked by nor-BNI administered 2 h prior to testing. Finally, U50,488-induced reinstatement was blocked by antalarmin. Conclusions These data further support a role for KOR in reinstatement of alcohol seeking under nonstress and stressful conditions and that KOR and CRF R interact in these effects.
    Full-text · Article · May 2014 · Brain and Behavior
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    ABSTRACT: Kappa opioid receptors (KORs) belong to the G-protein coupled class of receptors (GPCRs). They are activated by the endogenous opioid peptide dynorphin (DYN) and expressed at particularly high levels within brain areas implicated in modulation of motivation, emotion, and cognitive function. Chronic activation of KORs in animal models has maladaptive effects including increases in behaviors that reflect depression, the propensity to engage in drug-seeking behavior, and drug craving. The fact that KOR activation has such a profound influence on behaviors often triggered by stress has led to interest in selective KOR antagonists as potential therapeutic agents. This perspective provides a description of preclinical research conducted in the development of several different classes of selective KOR antagonists, a summary of the clinical studies conducted thus far, and recommendations for the type of work needed in the future to determine if these agents would be useful as pharmacotherapies for neuropsychiatric illness.
    No preview · Article · Jan 2013 · Journal of Medicinal Chemistry
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