Modulation of multiple ethanol withdrawal-induced anxiety-like behavior by CRF and CRF1 receptors
Introduction
Repeated ethanol exposures and withdrawals induce long-lasting adaptive changes in the brain that are reflected by behavioral consequences (e.g., Holter et al., 1998, Malcolm et al., 2000, McCown and Breese, 1990). In this respect, a recent investigation showed that anxiety-like behavior, as indexed by the social interaction test, increased in rats repeatedly withdrawn from exposure to ethanol (Overstreet et al., 2002). Rats exposed continuously for 15 days to a diet containing 4.5% ethanol exhibited a normal level of social interaction upon withdrawal, indicative that the ethanol alone was not responsible for the sensitization of the anxiety-like behavior associated with the repeated withdrawals (Overstreet et al., 2002).
Several investigators have reported alterations in the hypothalamo–pituitary–adrenal (HPA) axis after chronic ethanol treatment (e.g., Rasmussen et al., 2000, Rivier and Lee, 2001). Antagonists of corticotropin-releasing factor (CRF) have been reported to reduce anxiety-like behavior observed in ethanol-withdrawn rats Koob et al., 1998, Rassnick et al., 1993 and attenuate foot shock-induced reinstatement of ethanol-seeking behavior (Le et al., 2000). While CRF, by driving the HPA axis, could be a key factor in the adaptive changes associated with chronic ethanol, a recent study demonstrated that adrenalectomy does not modulate foot shock-induced reinstatement of ethanol-seeking behavior (Le et al., 2000). Based upon this background, it is hypothesized that CRF contributes to the sensitized anxiety-like behavior observed in rats repeatedly withdrawn from chronic ethanol diet (ED).
To examine the role of CRF in the multiple-withdrawal-induced sensitization, it was tested whether central administration of CRF would substitute for the initial two withdrawals at 6 and 11 days of the multiple withdrawal protocol to induce anxiety-like behavior. Subsequently, it was determined if selective antagonists for CRF1 and CRF2 receptors would prevent the anxiety-like behavior seen with repeated withdrawals. These studies will support the proposed hypothesis that CRF acting on CRF1 receptors contributes to the anxiety-like behavior observed during repeated ethanol withdrawals.
Section snippets
Animals
Male Sprague–Dawley rats (Charles-River, Raleigh) were purchased at 40 days of age (160–180 g). After giving 5 days to adapt to local conditions (22 °C, 50% humidity, 12:12-h light–dark cycle with lights on between 0900 and 2100 h), they were placed on a nutritionally complete diet used previously in our laboratory (e.g., Frye et al., 1983, Moy et al., 2000, Overstreet et al., 2002). Intakes of the liquid diet were recorded daily, and body weights were measured weekly. These experiments were
Effect of intraventricular CRF administration on withdrawal-induced anxiety-like behavior
Rats that were initially treated with a single dose of CRF intraventricularly exhibited lower social interaction behavior than the rats given artificial cerebrospinal fluid, confirming the anxiogenic properties of CRF [Fig. 1; F(3,45)=13.32, P<.001]. Interestingly, the control rats that were used as partners for the CRF- and vehicle-treated rats (PART-C and PART-V, respectively) spent as much time in social interaction as the vehicle-treated rats, although their partners differed greatly in the
Discussion
Previous studies have demonstrated that restraint stress applied at weekly intervals prior to 5 days of 4.5% ED resulted in sensitization of a withdrawal-induced reduction in social interaction behavior (Breese et al., 2003). Inasmuch as the present findings confirm that a single withdrawal from 7% ED does not induce anxiety-like behavior (Overstreet et al., 2002), we were able to examine whether CRF would substitute for multiple stresses to sensitize anxiety.
It was initially demonstrated that
Acknowledgments
This research was supported by funding from NIAAA (2 P60 AA-011605-06, AA-014073, AA-014284). We wish to thank Taisho Pharmaceutical (Saitama, Japan) for the generous supply of CRA1000 and Pfizer (Groton, CN) for CP-154,526. We thank Dhritiman Muckerjee, Qi Yu, and Mili Senapati for expert technical assistance.
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