Opioids in the Hypothalamic Paraventricular Nucleus Stimulate Ethanol Intake
Article first published online: 24 NOV 2009
Copyright © 2009 by the Research Society on Alcoholism
Alcoholism: Clinical and Experimental Research
Volume 34, Issue 2, pages 214–222, February 2010
How to Cite
Barson, J. R., Carr, A. J., Soun, J. E., Sobhani, N. C., Rada, P., Leibowitz, S. F. and Hoebel, B. G. (2010), Opioids in the Hypothalamic Paraventricular Nucleus Stimulate Ethanol Intake. Alcoholism: Clinical and Experimental Research, 34: 214–222. doi: 10.1111/j.1530-0277.2009.01084.x
- Issue published online: 13 JAN 2010
- Article first published online: 24 NOV 2009
- Received for publication April 10, 2009; accepted September 4, 2009.
- Paraventricular Nucleus;
Background: Specialized hypothalamic systems that increase food intake might also increase ethanol intake. To test this possibility, morphine and receptor-specific opioid agonists were microinjected in the paraventricular nucleus (PVN) of rats that had learned to drink ethanol. To cross-validate the results, naloxone methiodide (m-naloxone), an opioid antagonist, was microinjected with the expectation that it would have the opposite effect of morphine and the specific opioid agonists.
Methods: Sprague–Dawley rats were trained, without sugar, to drink 4 or 7% ethanol and were then implanted with chronic brain cannulas aimed at the PVN. After recovery, those drinking 7% ethanol, with food and water available, were injected with 2 doses each of morphine or m-naloxone. To test for receptor specificity, 2 doses each of the μ-receptor agonist [d-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin (DAMGO), δ-receptor agonist d-Ala-Gly-Phe-Met-NH2 (DALA), or κ-receptor agonist U-50,488H were injected. DAMGO was also tested in rats drinking 4% ethanol without food or water available. As an anatomical control for drug reflux, injections were made 2 mm dorsal to the PVN.
Results: A main result was a significant increase in ethanol intake induced by PVN injection of morphine. The opposite effect was produced by m-naloxone. The effects of morphine and m-naloxone were exclusively on intake of ethanol, even though food and water were freely available. In the analysis with specific receptor agonists, PVN injection of the δ-agonist DALA significantly increased 7% ethanol intake without affecting food or water intake. This is in contrast to the κ-agonist U-50,488H, which decreased ethanol intake, and the μ-agonist DAMGO, which had no effect on ethanol intake in the presence or absence of food and water. In the anatomical control location 2 mm dorsal to the PVN, no drug caused any significant changes in ethanol, food, or water intake, providing evidence that the active site was close to the cannula tip.
Conclusions: The δ-opioid receptor agonist in the PVN increased ethanol intake in strong preference over food and water, while the κ-opioid agonist suppressed ethanol intake. Prior studies show that learning to drink ethanol stimulates PVN expression and production of the peptides enkephalin and dynorphin, which are endogenous agonists for the δ- and κ-receptors, respectively. These results suggest that enkephalin via the δ-opioid system can function locally within a positive feedback circuit to cause ethanol intake to escalate and ultimately contribute to the abuse of ethanol. This is in contrast to dynorphin via the κ-opioid system, which may act to counter this escalation. Naltrexone therapy for alcoholism may act, in part, by blocking the enkephalin-triggered positive feedback cycle.