The delta opioid receptor antagonist, SoRI-9409, decreases yohimbine stress-induced reinstatement of ethanol-seeking.

Abstract
A major problem in treating alcohol use disorders (AUDs) is the high rate of relapse due to stress and re-exposure to cues, or an environment previously associated with alcohol use. Stressors can induce relapse to alcohol-seeking in humans or reinstatement in rodents. Delta opioid peptide receptors (DOP-Rs) play a role in cue-induced reinstatement of ethanol-seeking; however, their role in stress-induced reinstatement of ethanol-seeking is not known. The objective of this study was to determine the role of DOP-Rs in yohimbine-stress-induced reinstatement of ethanol-seeking. Male, Long-Evans rats were trained to self-administer 10% ethanol in daily 30-minute operant, self-administration sessions using a FR3 schedule of reinforcement, followed by extinction training. Once extinction criteria were met, we examined the effects of the DOP-R antagonist, SoRI-9409 (0-5 mg/kg, i.p.) on yohimbine (2 mg/kg, i.p.) stress-induced reinstatement. Additionally, DOP-R-stimulated [(35) S]GTPγS binding was measured in brain membranes, and plasma levels of corticosterone (CORT) were determined. Pre-treatment with SoRI-9409 decreased yohimbine stress-induced reinstatement of ethanol-seeking, but did not affect yohimbine-induced increases in plasma CORT levels. Additionally, yohimbine increased DOP-R-stimulated (35) [S]GTPγS binding in brain membranes of ethanol-trained rats, an effect that was inhibited by SoRI-9409. This suggests that the DOP-R plays an important role in yohimbine-stress-induced reinstatement of ethanol-seeking behavior, and DOP-R antagonists may be promising candidates for further development as a treatment for AUDs.

The neurokinin 1 receptor antagonist, ezlopitant, reduces appetitive responding for sucrose and ethanol.

Published: PLoS One. 2010 Sep 1;5(9). pii: e12527.
Authors: Steensland P, Simms JA, Nielsen CK, Holgate J, Bito-Onon JJ, Bartlett SE. Ernest Gallo Clinic and Research Center, UCSF.

Abstract
BACKGROUND: The current obesity epidemic is thought to be partly driven by over-consumption of sugar-sweetened diets and soft drinks. Loss-of-control over eating and addiction to drugs of abuse share overlapping brain mechanisms, including changes in motivational drive, such that stimuli that are often no longer 'liked' are still intensely 'wanted' [7]. The neurokinin 1 (NK1) receptor system has been implicated in both learned appetitive behaviors and addiction to alcohol and opioids; however, its role in natural reward seeking remains unknown.

METHODOLOGY/PRINCIPAL FINDINGS: We sought to determine whether the NK1-receptor system plays a role in the reinforcing properties of sucrose using a novel selective and clinically safe NK1-receptor antagonist, ezlopitant (CJ-11,974), in three animal models of sucrose consumption and seeking. Furthermore, we compared the effect of ezlopitant on ethanol consumption and seeking in rodents. The NK1-receptor antagonist, ezlopitant, decreased appetitive responding for sucrose more potently than for ethanol using an operant self-administration protocol, without affecting general locomotor activity. To further evaluate the selectivity of the NK1-receptor antagonist in decreasing consumption of sweetened solutions, we compared the effects of ezlopitant on water, saccharin-, and sodium chloride (NaCl) solution consumption. Ezlopitant decreased intake of saccharin, but had no effect on water or salty solution consumption.

CONCLUSIONS/SIGNIFICANCE: The present study indicates that the NK1-receptor may be a part of a common pathway regulating the self-administration, motivational, and reinforcing aspects of sweetened solutions, regardless of caloric value, and those of substances of abuse. Additionally, these results indicate that the NK1-receptor system may serve as a therapeutic target for obesity, induced by over-consumption of natural reinforcers.

A novel delta opioid receptor antagonist, SoRI-9409, produces a selective and long-lasting decrease in ethanol consumption in heavy-drinking rats.

Published: Biol Psychiatry. 2008 Dec 1;64(11):974-81. Epub 2008 Sep 6.
Authors: Nielsen CK, Simms JA, Pierson HB, Li R, Saini SK, Ananthan S, Bartlett SE. Ernest Gallo Clinic and Research Center, UCSF.

Abstract
BACKGROUND: Naltrexone, a compound with high affinity for the mu opioid receptor (MOP-R), reduces alcohol consumption. SoRI-9409 is a derivative of naltrexone that has highest affinity at delta opioid receptors (DOP-Rs). We have investigated the effects of SoRI-9409 on ethanol consumption to determine the consequences of altering the naltrexone compound to a form with increased efficacy at DOP-Rs.

METHODS: Effects of the opioid receptor antagonists, SoRI-9409 (0-30 mg/kg, IP), naltrexone (0-30 mg/kg, IP), or naltrindole (0-10 mg/kg, IP) on ethanol consumption were measured in high- and low-ethanol-consuming rats with two different drinking paradigms. SoRI-9409-, naltrexone-, and naltrindole-mediated inhibition of DOP-R-stimulated [(35)S]GTP gamma S binding were measured in brain membranes prepared from high-ethanol-consuming rats. The effects of SoRI-9409 on morphine-mediated analgesia, conditioned place preference, and anxiety were also examined.

RESULTS: In high, but not low-ethanol-consuming animals, SoRI-9409 is threefold more effective and selective at reducing ethanol consumption, when compared with naltrexone or naltrindole for up to 24 hours. SoRI-9409 administered daily for 28 days continuously reduced ethanol consumption, and when the administration of SoRI-9409 was terminated, the amount of ethanol consumed remained lower compared with vehicle-treated animals. Furthermore, SoRI-9409 inhibits DOP-R-stimulated [(35)S]GTP gamma S binding in brain membranes of high-ethanol-consuming rats.

CONCLUSIONS: SoRI-9409 causes selective and long-lasting reductions of ethanol consumption. This suggests that compounds that have high affinity for DOP-Rs, such as SoRI-9409, might be promising candidates for development as a novel therapeutic for the treatment of alcoholism.

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