A Novel Delta Opioid Receptor Antagonist, SoRI-9409, Produces a Selective and Long-Lasting Decrease in Ethanol Consumption in Heavy-Drinking Rats

Nielsen, Carsten K.; Simms, Jeffrey A.; Pierson, Haley B.; Li, Rui; Saini, Surendra K.; Ananthan, Subramaniam; Bartlett, Selena E.

doi:10.1016/j.biopsych.2008.07.018

« Previous Next »Biological Psychiatry
Volume 64, Issue 11 , Pages 974-981, 1 December 2008

A Novel Delta Opioid Receptor Antagonist, SoRI-9409, Produces a Selective and Long-Lasting Decrease in Ethanol Consumption in Heavy-Drinking Rats

Carsten K. Nielsen
- Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California
Jeffrey A. Simms
- Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California
Haley B. Pierson
- Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California
Rui Li
- Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California
Surendra K. Saini
- Organic Chemistry Department, Southern Research Institute, Birmingham, Alabama
Subramaniam Ananthan
- Organic Chemistry Department, Southern Research Institute, Birmingham, Alabama
Selena E. Bartlett
- Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California
- Address reprint requests to Selena E. Bartlett, Ph.D., Ernest Gallo Clinic and Research Center, University of California San Francisco, 5858 Horton Street, Suite 200, Emeryville, CA, 94608

Received 5 March 2008; received in revised form 12 July 2008; accepted 18 July 2008. published online 09 September 2008.

Background

Naltrexone, a compound with high affinity for the μ opioid receptor (MOP-R) reduces alcohol consumption. SoRI-9409 is a derivative of naltrexone that has highest affinity at δ 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 was measured in high- and low-ethanol–consuming rats with two different drinking paradigms. SoRI-9409-, naltrexone-, and naltrindole-mediated inhibition of DOP-R–stimulated [³⁵S]GTPγS binding was 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 [³⁵S]GTPγS 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.

Key Words: Alcoholism, ethanol, naltrexone, opioid receptor antagonist, rats, SoRI-9409