Opioids in the Hypothalamic Paraventricular Nucleus Stimulate Ethanol Intake

Abstract

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 two doses each of morphine or m-naloxone. To test for receptor specificity, two 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 k-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 k-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 k-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 k-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 k-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.

The Role of Delta Opioid Receptors in Ethanol Consumption and Seeking: Implications for New Treatments for Alcohol Use Disorders

“…In support of the earlier studies, systemic administration of the DOP-R agonist, SNC80, in mice and microinjections of the DOP-R agonist, DALA (7-14 nM), into the NAc and hypothalamic paraventricular nucleus (HPN) of rats lead to increased ethanol consumption (Barson et al, 2009;Barson et al, 2010;van Rijn et al, 2010). In mice trained using the 10% ethanol 4 hr limited access paradigm, SNC80 increased ethanol consumption (van Rijn et al, 2010).…”

“…An increase in the rewarding actions of ethanol by TAN67 may subsequently lead to reduced consumption (van Rijn & Whistler, 2009) as less ethanol may be required to produce ethanol's effects. Conversely, activation of DOP-Rs and the subsequent increased rewarding effects of ethanol may have contributed to further increased levels of ethanol consumption following treatment with DOP-R agonists (Barson et al, 2009;Barson et al, 2010;van Rijn et al, 2010). Collectively, these studies suggest that activation and inhibition of DOP-R activity may modulate ethanol consumption via different mechanisms in the central nervous system.…”

“…In rats trained to consume up to 7% ethanol for 12 h each day with incremental increases in the concentration of ethanol every four days, the administration of DALA into the NAc selectively increased ethanol consumption over food and water (Barson et al, 2009). Similarly, the effects of DALA administered into the HPN were selective for ethanol over food and water consumption (Barson et al, 2010). DOP-R agonists have also been shown to reduce ethanol consumption in rats (Margolis et al, 2008) and mice (van Rijn & Whistler, 2009).…”

“…The different effects on ethanol consumption by cerebral injections of the DOP-R agonists, DPDPE and DALA, (Barson et al, 2009;Barson et al, 2010;Margolis et al, 2008) suggest that www.intechopen.com…”

“…Recently, further studies have examined the effects of activation of the DOP-R on ethanol consumption using various DOP-R agonists (Barson et al, 2009;Barson et al, 2010;van Rijn et al, 2010) (Table 1). In support of the earlier studies, systemic administration of the DOP-R agonist, SNC80, in mice and microinjections of the DOP-R agonist, DALA (7-14 nM), into the NAc and hypothalamic paraventricular nucleus (HPN) of rats lead to increased ethanol consumption (Barson et al, 2009;Barson et al, 2010;van Rijn et al, 2010).…”