Opioids in the perifornical lateral hypothalamus suppress ethanol drinking

Abstract

The opioid system is known to enhance motivated behaviors, including ethanol drinking and food ingestion, by acting in various reward-related brain regions, such as the nucleus accumbens, ventral tegmental area and medial hypothalamus. There is indirect evidence, however, suggesting that opioid peptides may act differently in the perifornical lateral hypothalamus (PF/LH), causing a suppression of consummatory behavior. Using brain-cannulated Sprague-Dawley rats trained to voluntarily drink 7% ethanol, the present study tested the hypothesis that opioids in the PF/LH can reduce the consumption of ethanol, with animals receiving PF/LH injections of the δ-opioid receptor agonist D-Ala2-met-enkephalinamide (DALA), the μ-receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), the κ-receptor agonist (±)-trans-U-50,488 methanesulfonate (U-50,488H), or the general opioid antagonist methylated naloxone (m-naloxone). The consumption of ethanol, lab chow, and water was monitored for 4 h after injection. The results showed that the three opioid receptor agonists injected into the PF/LH specifically and significantly reduced ethanol intake, while causing little change in chow or water intake, and the opposite effect, enhanced ethanol intake, was observed with the opioid antagonist. Of the three opioid agonists, the δ-agonist appears to produce the most consistent and long-lasting suppression of consumption. This effect was not observed with injections 2 mm dorsal to this area, focusing attention on the PF/LH as the main site of action. These results suggest that the opioid peptides have a specific role in the PF/LH of reducing ethanol drinking, which is distinct from their more commonly observed appetitive actions in other brain areas. The additional finding, that m-naloxone in the PF/LH stimulates ethanol intake in contrast to its generally suppressive effect in other regions, focuses attention on this hypothalamic area and its distinctive role in contributing to the variable effects sometimes observed with opioid antagonist therapy for alcoholism.

Figure 1

Injection sites of animals included in the analysis. (A) Sites for PF/LH injections, as indicated by black dots. (B) Sites for anatomical control injections. Adapted from The Rat Brain, compact 6th edition, G. Paxinos and C. Watson, Copyright 2007.

Figure 2

DALA injected in the PF/LH significantly decreased ethanol intake for up to 4 h after injection, but it had no effect on food intake and increased water intake at 2 h and 4 h after injection of the higher dose (7.1 nmol: n = 11/group; 3.6 nmol: n = 10/group). Values are mean ± S.E.M.. The vehicle intake presented is the average from the 2 sets of injections. *p < 0.017, #p < 0.050 vs. individual paired vehicle injection at specific time points.

Figure 3

DAMGO injected in the PF/LH significantly suppressed ethanol intake for 1 h post-injection, while having no effect on food or water intake (2.9 nmol: n = 11/group; 1.5 nmol: n = 6/group). Values are mean ± S.E.M.. The vehicle intake presented is the average from the 2 sets of injections. *p < 0.017, vs. individual paired vehicle injection at specific time points.

Figure 4

U-50,488H injected in the PF/LH dose-dependently and significantly decreased ethanol intake for 1 h post-injection, without affecting food or water intake (5.4 nmol: n = 7/group; 2.7 nmol: n = 5/group). Values are mean ± S.E.M.. The vehicle intake presented is the average from the 2 sets of injections. *p < 0.017, #p < 0.050 vs. individual paired vehicle injection at specific time points.

Figure 5

Injection of the general opioid receptor antagonist, m-naloxone, in the PF/LH significantly increased ethanol intake for 1 h post-injection, but left food and water intake unaffected (n = 9/group). Values are mean ± S.E.M.. #p < 0.050, vs. vehicle injection at specific time points.