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

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 intraperitoneal (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.

Role of cortical alpha-2 adrenoceptors in alcohol withdrawal-induced depression and tricyclic antidepressants

“…Hence, yohimbine, which also contains alpha-2 ARs antagonism may reinstates alcohol seeking after extinction (Marinelli et al, 2007). On the other hand, alpha-2 AR agonists may reduce alcohol consumption or alcohol-withdrawal symptoms (Opitz, 1990; Muzyk et al, 2011; Rasmussen et al, 2014; Fredriksson et al, 2015; Giovanitti et al, 2015). However, it has also been reported that specific agonists or antagonists of alpha-2 ARs may produce only minor changes in the voluntary alcohol drinking in alcohol-preferring rats (Korpi 1990).…”

“…Hence, yohimbine, an alpha-2 AR antagonist can reinstate alcohol seeking after extinction (Funk et al, 2016; Marinelli et al, 2007). On the other hand, alpha-2 A AR agonists that may decrease availability of NE reduce alcohol consumption (Fredriksson et al, 2015; Opitz, 1990; Rasmussen et al, 2014). However, very few studies have investigated direct effects of alcohol on apha-2 ARs, particularly in relation to depressive-like characteristics.…”

Endophenotypes for Alcohol Use Disorder: An Update on the Field

“…This suggests that ethanol and saccharin consumption may have overlapping effects on (genetically-influenced) neurobiological systems involved in reward, such as the opioid, serotonin, and dopamine systems [110]. Consistent with this idea, P rats who were administered clonidine (a noradrenergic signaling inhibitor) reduced alcohol consumption and saccharin consumption, but not water consumption [111]. In another example, P rats who were administered TP-10 (a dual-specificity cyclic adenosine monophosphate/cyclic guanosine monophosphate-inhibiting enzyme inhibitor) reduced their alcohol and saccharin self administration [112].…”

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

“…Additonally, tolerance did not appear to develop following repeated daily treatments (Rasmussen, Kincaid, & Froehlich, 2015). Another study found that clonidine, an α2-adrenergic receptor agonist, can also reduce ethanol drinking by P rats (Rasmussen, Alexander, Malone, Federoff, & Froehlich, 2014; Rasmussen, Beckwith, Kincaid, & Froehlich, 2014). In addition, the triple monoamine uptake inhibitor (i.e., DAT, NET and SERT) DOV 102,677 reduced ethanol intake by P rats (Yang et al, 2012).…”