Elsevier

Alcohol

Volume 48, Issue 6, September 2014, Pages 543-549
Alcohol

The α2-adrenergic receptor agonist, clonidine, reduces alcohol drinking in alcohol-preferring (P) rats

https://doi.org/10.1016/j.alcohol.2014.07.002Get rights and content

Abstract

Evidence suggests that noradrenergic signaling may play a role in mediating alcohol-drinking behavior in both rodents and humans. We have investigated this possibility by administering clonidine to alcohol-drinking rats selectively bred for alcohol preference (P line). Clonidine is an α2-adrenergic receptor agonist which, at low doses, inhibits noradrenergic signaling by decreasing norepinephrine release from presynaptic noradrenergic neurons. Adult male P rats were given 24 h access to food and water and scheduled access to a 15% (v/v) alcohol solution for 2 h daily. Rats received intra-peritoneal (IP) injections with clonidine (0, 10, 20, 40, or 80 μg/kg body weight [BW], 10–11 rats/treatment group) once/day at 30 min prior to onset of the daily 2 h alcohol access period for 2 consecutive days. Clonidine, in doses of 40 or 80 μg/kg BW, significantly reduced alcohol intake on both days of treatment (p < 0.001). Two weeks later, rats were treated with clonidine for 5 consecutive days and clonidine, in doses of 40 or 80 μg/kg BW, reduced alcohol intake on all 5 treatment days (p < 0.001). Clonidine did not alter water consumption during the daily 2 h free-choice between alcohol and water. In a separate group of male P rats, clonidine (40 μg/kg BW) suppressed intake of a saccharin solution (0.04 g/L). These results are consistent with and complement our previous findings that the α1-adrenergic receptor antagonist, prazosin, decreases voluntary alcohol drinking in alcohol-preferring rats, but suggests that effects of clonidine may not be specific for alcohol. The results suggest that although activation of the noradrenergic system plays an important role in mediating voluntary alcohol drinking, care is needed in selecting which drugs to use to suppress central noradrenergic signaling in order to maximize the selectivity of the drugs for treating alcohol-use disorders.

Introduction

It has been suggested that excessive noradrenergic activation which accompanies anxiety and hyperarousal may contribute to increased alcohol drinking in an effort to self-medicate, since alcohol is sympatho-suppressive, anxiolytic, and sedating (Edwards et al., 1972, Koob and LeMoal, 1997, Kushner et al., 1990, Kushner et al., 1999, Shirao et al., 1988). Numerous lines of evidence support this view: a) anxiety is associated with increased brain noradrenergic and associated sympathoadrenal activation (Kopin, 1984, Sullivan et al., 1999), b) “anxious” rats consume more alcohol than “non-anxious” rats (Spanagel et al., 1995), c) blocking norepinephrine biosynthesis decreases alcohol self-administration by rodents (Amit et al., 1977, Brown et al., 1977, Davis et al., 1978), d) alcoholics commonly state that relief of anxiety is an important reason for drinking (e.g., Edwards et al., 1972), e) alcoholism co-occurs at high rates with anxiety disorders (Kushner et al., 1990), suggesting that the two disorders represent manifestations of similar underlying mechanisms (Merikangas et al., 1994, Merikangas et al., 1998, Sinha et al., 1998), f) patients with co-morbid anxiety and alcoholism more frequently report that they use alcohol to control anxiety and panic symptoms as compared to other reasons for alcohol use (Kushner et al., 1990), g) increased sympathetic activation is seen during periods of increased anxiety and during prolonged alcohol abstinence (Ehrenreich et al., 1997, Sullivan et al., 1999), and h) increased sympathoadrenal activation and anxiety-like behavior is observed for long periods following termination of chronic alcohol consumption in rats (Rasmussen et al., 2001, Rasmussen et al., 2006). Taken together, these findings suggest that excessive sympathetic activation may contribute not only to maintenance of alcohol drinking and alcohol abuse but may also be one of the aversive physiological events that occur during alcohol withdrawal and abstinence that increases risk of relapse to alcohol drinking (Koob & LeMoal, 1997).

We previously tested the hypothesis that noradrenergic activation promotes and maintains alcohol drinking by assessing whether alcohol drinking in rats is decreased by prazosin treatment. Prazosin is a drug that is centrally active when administered peripherally and that decreases brain noradrenergic signaling by blocking postsynaptic α1-adrenergic receptors. Prazosin dose-dependently reduced withdrawal-induced operant self-administration of alcohol in alcohol-dependent Wistar rats (Walker, Rasmussen, Raskind, & Koob, 2008). Prazosin also suppressed voluntary alcohol drinking by rats selectively bred for alcohol preference (P line) when administered either acutely (Rasmussen, Alexander, Raskind, & Froehlich, 2009) or chronically (Froehlich et al., 2013, Froehlich et al., 2013). The ability of prazosin to reduce alcohol drinking has been confirmed in humans; Simpson et al. (2009) reported that prazosin decreased relapse alcohol drinking in treatment-seeking alcohol-dependent men. These results from both rodents and humans provide compelling evidence that noradrenergic activation plays an important role in mediating alcohol drinking and alcohol relapse.

If alcohol drinking is due in part to activation of the noradrenergic system, any drug that decreases noradrenergic signaling might be expected to decrease alcohol drinking. We recently determined that combined treatment of P rats with both prazosin and propranolol (which block α1- and β-adrenergic receptors, respectively) decreased alcohol drinking more effectively than treatment with either drug alone (Rasmussen, Beckwith, Kincaid, & Froehlich, 2014), suggesting that α1- and β-adrenergic receptors may have complementary roles in facilitating alcohol drinking. This suggests that administration of an α2-adrenergic receptor agonist such as clonidine, which can decrease noradrenergic signaling by decreasing norepinephrine release from presynaptic terminals (Aghajanian and VanderMaelen, 1982, Starke et al., 1974) and thus decrease the amount of norepinephrine available for binding to either α1- or β-adrenergic post-synaptic receptors, may be especially effective in decreasing alcohol drinking. Accordingly, in the present study we evaluated the effect of clonidine on voluntary alcohol drinking in selectively bred alcohol-preferring (P) rats.

Section snippets

Animals

Male P rats (n = 51 in Study 1; n = 20 in Study 2) from the 60th generation of selective breeding for alcohol preference served as subjects. The rats were individually housed in stainless-steel hanging cages in an isolated vivarium with controlled temperature (21 ± 1 °C) and a 12 h light/dark cycle (lights off at 1000 h). Standard rodent chow (Laboratory Rodent Diet #7001, Harlan Teklad, Madison, WI) and water were available ad libitum at all times throughout the study. All experimental

Results

Daily alcohol intake during the 2 h alcohol-access period prior to onset of drug treatment in Study 1 averaged 1.3 ± 0.2 g/kg BW/2 h, which is lower than the intake seen in some of our previous studies using 2 h alcohol access in P rats. This is likely because the rats in the current study were older and larger than those we have previously used (which have averaged only about 350–400 g BW and have consumed approximately 2.0 g alcohol/kg BW during 2 h of alcohol access). Weight gain above 400 g

Discussion

Clonidine, the α2-adrenergic receptor agonist which in moderate doses decreases noradrenergic signaling by stimulating inhibitory pre-synaptic α2-adrenergic receptors (Aghajanian and VanderMaelen, 1982, Starke et al., 1974), decreased voluntary alcohol drinking in a dose-dependent manner when administered to P rats for either 2 or 5 consecutive days. These results are consistent with our reports that prazosin, which decreases noradrenergic signaling by blocking post-synaptic α1-adrenergic

Acknowledgments

This material is based upon work supported in part by resources from the VA Puget Sound Health Care System, Seattle, Washington, and by National Institutes of Health Grants AA017839, AA10567, and AA13881 (DDR); AA10709 and AA007611 (JCF); and AA018604 (JCF and DDR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Alcohol Abuse and Alcoholism or the National Institutes of Health.

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