ArticleThe neuropeptide-Y Y5 receptor antagonist L-152,804 decreases alcohol self-administration in inbred alcohol-preferring (iP) rats
Introduction
Neuropeptide-Y (NPY) has been implicated in a variety of neurobiological functions (Wettstein et al., 1995) and is the most abundant and widely distributed peptide in the mammalian central nervous system (CNS) (Allen et al., 1983, Heilig and Widerlov, 1990). The actions of NPY are mediated by a family of G-protein-coupled receptors (Balasubramaniam, 1997, Dumont et al., 1993), which includes at least five subtypes: Y1, Y2, Y4, Y5, and Y6 (Blomqvist & Herzog, 1997). The Y1 (Larsen et al., 1993, Mikkelsen and Larsen, 1992), Y2 (Gustafson et al., 1997), and Y5 (Gerald et al., 1996) receptor subtypes are located in the brain tissue of rodents as demonstrated by hybridization. NPY Y5 receptors are present at significant levels in the paraventricular nucleus of the hypothalamus (PVN), arcuate nucleus, thalamus, and amygdala, which suggests the presence of functional hypothalamic–limbic neural circuits (Gerald et al., 1996), and the highly conserved expression of the Y5 receptor between human and rat hypothalamus and limbic brain regions (Nichol et al., 1999) indicates a major neurobiological role for this receptor.
Evidence has accumulated implicating the NPY Y5 receptor in feeding behavior. Research using NPY Y5 agonists (Gerald et al., 1996, Haynes et al., 1998, Hu et al., 1996, Kirby et al., 1995, Wyss et al., 1998), antagonists (Criscione et al., 1998), and antisense nucleotides (Flynn et al., 1999, Tang-Christensen et al., 1998) indicates that ingestive behavior appears to be at least partially mediated by NPY activity at the Y5 receptor. The role of NPY activity at the Y5 receptor in feeding behavior suggests that NPY function at this receptor may also modulate ethanol intake, because addictive behaviors may usurp homeostatic mechanisms, which evolved to regulate food intake (Samson & Hodge, 1996). Consistent with this hypothesis, we have shown that blockade of NPY Y5 receptors with the selective antagonist L-152,804 modulates the onset and maintenance of operant ethanol self-administration in C57BL/6J mice (Schroeder et al., 2003a).
Additional research indicates that genetically selected alcohol-preferring (P) ratlines exhibit different levels of NPY expression in the brain and different levels of ethanol intake following NPY administration. The increased drinking of P rats may be related to NPYergic activity in this selectively bred ratline. A genetic linkage analysis on the F2 intercross progenies of P and nonpreferring (NP) rats revealed a chromosomal region containing a NPY precursor gene (Bice et al., 1998, Carr et al., 1998). In addition, P rats and high-alcohol-drinking rats have lower levels of NPY in the amygdala when compared to their low-drinking counterparts (Ehlers et al., 1998a, Hwang et al., 1999). Moreover, P rats demonstrate greater NPY expression in the arcuate nucleus and PVN than NP rats (Hwang et al., 1999). Finally, pharmacological data have shown that intracerebral ventricular infusion of NPY decreases ethanol intake in P but not in NP rats (Badia-Elder et al., 2001, Gilpin et al., 2003) or unselected Wistar rats (Badia-Elder et al., 2001, Slawecki et al., 2000).
To further examine the role of NPY Y5 receptors in the mediation of ethanol self-administration, the present set of experiments was designed to test the influence of the Y5 antagonist L-152,804 on voluntary ethanol intake and on ethanol-reinforced responding using a genetic model of high alcohol intake, which is the P rat. The P ratline has been found to fulfill the requirements of an animal model of alcoholism (Lester & Freed, 1973). P rats voluntarily consume ethanol in quantities that produce significant blood alcohol concentrations (50–200 mg%), respond for the pharmacological rather than the sensory effects of ethanol, and develop tolerance and dependence through voluntary drinking (Kampov-Polevoy et al., 2000, Li et al., 1987, Murphy et al., 2002). Two separate groups of inbred alcohol-preferring rats (iP) were allowed to self-administer 10% (vol/vol) ethanol in either the 24-h two-bottle choice test or 1-h operant sessions. Following the establishment of baseline intake or ethanol-reinforced responding, rats were injected with the novel and selective nonpeptide NPY Y5 antagonist L-152,804 (Kanatani et al., 2000) to determine the role of this receptor subtype in the maintenance of operant ethanol self-administration experiments in a rodent genetic model of alcoholism.
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Animals
Twenty-four male iP rats weighing 350–500 g at the beginning of training were used in the studies. This stock of iP rats was derived from breeders of the selected line of P rats originally provided in 1999 by Indiana University (courtesy of Dr. T.K. Li) and has been bred for an additional 10 generations (6–10 breeders per generation) at the University of North Carolina at Chapel Hill. The rats were housed individually in Plexiglas cages at the University of North Carolina at Chapel Hill
Effects of L-152,804 on two-bottle drinking behavior
Fig. 1a illustrates the effects of L-152,804 on g/kg two-bottle ethanol intake. A two-way repeated measures ANOVA (injection × time) on cumulative g/kg ethanol intake revealed a significant interaction [F(4, 28) = 5.44, p = .002] indicating that L-152,804 altered the dose of ethanol self-administered in a time-dependent manner. Student–Newman–Keuls analysis indicated that injection of the 3 and 10 mg/kg doses of L-152,804 significantly decreased ethanol intake as compared to vehicle levels at 4 and 6 h
Discussion
The present results suggest that NPY activity at Y5 receptors is required for full expression of ethanol's reinforcing effects in selectively bred iP rats. This is consistent with a growing literature that implicates NPY receptors in regulating ethanol self-administration (Kelley et al., 2001, Schroeder et al., 2003a, Schroeder et al., 2003b, Thiele et al., 1998, Thiele et al., 2000, Thiele et al., 2002). More specifically, reductions in ethanol intake in iP rats produced by L-152,804 are
Acknowledgments
This work was supported by grants AA09981 and AA011605 from the National Institute on Alcohol Abuse and Alcoholism to CWH and by The Bowles Center for Alcohol Studies at The University of North Carolina Chapel Hill.
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