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. 2012 Jan;17(1):76-85.
doi: 10.1111/j.1369-1600.2010.00291.x. Epub 2011 Feb 11.

Evidence that vasopressin V1b receptors mediate the transition to excessive drinking in ethanol-dependent rats

Scott Edwards  1 , Miguel Guerrero, Ola M Ghoneim, Edward Roberts, George F Koob
Affiliations

Evidence that vasopressin V1b receptors mediate the transition to excessive drinking in ethanol-dependent rats

Scott Edwards et al. Addict Biol. 2012 Jan.

Abstract

Alcoholism is a devastating condition that represents a progression from initial alcohol use to dependence. Although most individuals are capable of consuming alcohol in a limited fashion, the development of alcohol dependence in a subset of individuals is often associated with negative emotional states (including anxiety and depression). Since the alleviation of this negative motivational state via excessive alcohol consumption often becomes a central goal of alcoholics, the transition from initial use to dependence is postulated to be associated with a transition from positive to negative reinforcement mechanisms. Vasopressin is a neuropeptide known to potentiate the effects of CRF on the HPA axis, and emerging evidence also suggests a role for centrally located vasopressin acting on V(1b) receptors in the regulation of stress- and anxiety-like behaviors in rodents. The present study determined state-dependent alterations in vasopressin/V(1b) R signaling in an animal model of ethanol dependence. The V(1b) R antagonist SSR149415 dose-dependently reduced excessive levels of ethanol self-administration observed in dependent animals without affecting the limited levels of ethanol drinking in non-dependent animals. Ethanol self-administration reduced V(1b) receptor levels in the basolateral amygdala of non-dependent animals, a neuroadaptation that could theoretically facilitate the positive reinforcing effects of alcohol. In contrast, V(1b) R levels were seemingly restored in ethanol-dependent rats, a switch that may in part underlie a transition from positive to negative reinforcement mechanisms with dependence. Together, our data suggest a key role for vasopressin/V(1b) R signaling in the transition to ethanol dependence.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Experimental timeline and blood alcohol level cycling. (A) Pharmacological testing and time points for tissue collection for Western analysis occurred after approximately 8–10 weeks of chronic intermittent ethanol vapor exposure. (B) All analyses were conducted when ethanol-dependent animals were in acute (6hr) withdrawal, a time point coinciding with diminished blood alcohol levels (BALs) and increased ethanol self-administration behavior. Asterisks indicate ***p<0.001 significant effect of withdrawal time point.
Figure 2
Figure 2
Ethanol self-administration in ethanol-dependent and non-dependent animals. (A) Induction of ethanol dependence and correlation of limited ethanol self-administration before and excessive drinking after dependence induction following chronic intermittent ethanol vapor exposure. (B) Effects of vasopressin V1bR antagonism on ethanol self-administration, showing a dose-dependent reduction in ethanol drinking in dependent, but not non-dependent, animals. Responses are graphed as mean ± SEM, with correlative data points representing individual averages of the five sessions before vs. five sessions after dependence induction. Asterisks indicate ***p<0.001 significant effect of group × test session (A) or ***p<0.001, **p<0.01 significant effect of group (B). Pound signs indicate ## p<0.01 significant effect of dose in ethanol-dependent group.
Figure 3
Figure 3
Regulation of vasopressin V1bR levels by ethanol self-administration. (A) In the basolateral amygdala, V1bR immunoreactivity is significantly reduced in the non-dependent ethanol self-administering group (versus naïve control animals) and seemingly restored in ethanol-dependent animals. (B) Representative immunoblot showing changes in V1bR immunoreactivity with no change in beta-tubulin levels. (C) Diagram of regions collected by the slice/punch technique and analyzed by Western blot. MEA (medial nucleus of the amygdala), CEA (central nucleus of the amygdala), BLA (basolateral nucleus of the amygdala), LS (lateral septum), DH (dorsal hippocampus). Immunoreactivity (% change from naïve control group) is graphed as mean ± SEM. Asterisks indicate **p<0.01 significant decrease in V1bR immunoreactivity in non-dependent group vs. naïve controls. Pound sign indicates p<0.05 significant increase in V1bR immunoreactivity in ethanol-dependent vs. non-dependent group.
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