A novel delta opioid receptor antagonist, SoRI-9409, produces a selective and long-lasting decrease in ethanol consumption in heavy-drinking rats - PubMed (original) (raw)

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 et al. Biol Psychiatry. 2008.

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 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 [(35)S]GTP gamma S 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 [(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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Conflict of interest statement

The authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1

Figure 1

SoRI-9409 selectively reduces ethanol intake in high-ethanol–consuming rats. (A) SoRI-9409 (5, 15, and 30 mg/kg IP, n = 12) significantly and dose-dependently decreases ethanol consumption in rats, using the intermittent access to 20% ethanol drinking paradigm. (B) SoRI-9409 (5 and 15 mg/kg IP, n = 10) does not significantly affect sucrose consumption, using the two-bottle-choice 5% sucrose drinking paradigm. (C) Naltrexone (15 and 30 mg/kg IP, n = 12) significantly decreases ethanol consumption and (D). Naltrindole (1, 5, and 10 mg/kg IP, n = 12) does not significantly decrease ethanol consumption, using the intermittent access to 20% ethanol drinking paradigm. The values are expressed as mean ± SEM ethanol or sucrose consumed (g/kg/24 hours) (repeated measures analysis of variance followed by Newman-Keuls post hoc test *p < .05; **p < .01; ***p < .001; compared with vehicle).

Figure 2

Figure 2

SoRI-9409 reduces ethanol intake, using the continuous access 10% ethanol two-bottle-choice drinking paradigm. (A) SoRI-9409 (5, 15, and 30 mg/kg IP) significantly and dose-dependently decreases ethanol consumption in rats after 24 hours. (B) Naltrexone (5, 15, and 30 mg/kg IP) does not significantly decrease ethanol consumption. (C) Naltrindole (1, 5, and 10 mg/kg IP) significantly decreases ethanol consumption. The values are expressed as mean ± SEM ethanol consumed (g/kg/24 hours) (repeated measures analysis of variance followed by Newman-Keuls post hoc test). *p < .05; compared with vehicle, n = 12.

Figure 3

Figure 3

Multiple dosing of SoRI-9409 reduces ethanol intake in high-ethanol–consuming rats. Daily administration of SoRI-9409 (5 mg/kg IP) for 5 days (three drinking sessions) to long-term drinking rats significantly reduced ethanol intake in rats after 24 hours of ethanol access. Daily administration of vehicle to long-term drinking rats for 5 days did not affect ethanol intake (p > .05). When daily administrations of SoRI-9409 (or vehicle) were ceased, rats returned to baseline levels of ethanol intake. The values are expressed as mean ± SEM ethanol consumed (g/kg/24 hours) (Student t test). *p < .05; compared with baseline levels of ethanol intake, n = 8.

Figure 4

Figure 4

SoRI-9409 inhibits δ opioid receptor (DOP-R)-stimulated [35S]GTPγS binding in the striatum of long-term heavy drinking rats. (A) The DOP-R ligands SNC80, DPDPE, and TAN67 significantly stimulate [35S]GTPγS binding in the striatum of long-term heavy drinking rats. (B) SoRI-9409 and naltrindole but not naltrexone inhibit SNC80-stimulated [35S]GTPγS DOP-R striatal binding. (C) SoRI-9409, naltrindole, and naltrexone inhibit DPDPE-stimulated [35S]GTPγS striatal binding. (D) SoRI-9409 but not naltrindole or naltrexone inhibits TAN67-stimulated [35S]GTPγS DOP-R striatal binding. The values are expressed as mean ± SEM percentage increase in basal [35S]GTPγS binding.

Figure 5

Figure 5

Long-term treatment with SoRI-9409 reduces escalation of ethanol intake and induces a long-lasting reduction in ethanol intake when the drug is no longer present. Rats were administered either SoRI-9409 (5 mg/kg IP n = 16, closed circles) or vehicle (n = 15, closed squares) on each of 28 consecutive days, 30 min before the drinking session. SoRI-9409 significantly reduced ethanol consumption after 24 hours of ethanol access at each drinking session. The administration of either SoRI-9409 (open circles) or vehicle (open squares) was terminated after 28 days (12 ethanol exposures). Ethanol consumption in the SoRI-9409-treated but not the vehicle-treated group remained lower for a further 28 days. The values are expressed as mean ± SEM ethanol consumed (g/kg/24 hours) (Student t test). *p < .05; **p < .01; ***p < .001.

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