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 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.

Keywords: Alcohol; Clonidine; Ethanol; Noradrenergic; Norepinephrine; P rat.

Figure 1. INITIAL 2-DAY TREATMENT

Effects of clonidine (10, 20, 40, 80 µg/kg BW, IP) on 2-h alcohol intake by adult male P rats. Clonidine was injected on each of 2 consecutive days (Days 1 and 2) at 30 min prior to onset of a 2-h free-choice between alcohol (15% v/v) and water. ***p < 0.001 vs. saline control treatment, independent of drug treatment day; *p < 0.05 vs. previous saline control treatment, independent of post-drug day.

Figure 2. INITIAL 2-DAY TREATMENT

Effects of clonidine (10, 20, 40, 80 µg/kg BW, IP) on 2-h water intake by adult male P rats. Clonidine was injected on each of 2 consecutive days (Days 1 and 2) at 30 min prior to onset of a 2-h free-choice between alcohol (15% v/v) and water.

Figure 3. SUBSEQUENT 5-DAY TREATMENT

Effects of clonidine (10, 20, 40, 80 µg/kg BW, IP) on 2-h alcohol intake by adult male P rats. Clonidine was injected on each of 5 consecutive days (Days 1–5) at 30 min prior to onset of a 2-h free-choice between alcohol (15% v/v) and water. Alcohol was not available on weekends. The Pre-Drug Day was a Friday preceding Drug Days 1–5 (Monday–Friday of the following week) and Post-Drug Days 3 and 4 were on Monday and Tuesday of the week following termination of clonidine treatment. ***p < 0.001 vs. saline control treatment, independent of drug treatment day.

Figure 4. SUBSEQUENT 5-DAY TREATMENT

Effects of clonidine (10, 20, 40, 80 µg/kg BW, IP) on 2-h water intake by adult male P rats. Clonidine was injected on each of 5 consecutive days (Days 1–5) at 30 min prior to onset of a 2-h free-choice between alcohol (15% v/v) and water. Alcohol was not available on weekends. The Pre-Drug Day was a Friday preceding Drug Days 1–5 (Monday–Friday of the following week) and Post-Drug Days 3 and 4 were on Monday and Tuesday of the week following termination of clonidine treatment.

Figure 5. EFFECTS OF CLONIDINE ON SACCHARIN INTAKE

Clonidine (40 µg/kg BW, IP) was injected on each of 3 consecutive days at 30 min prior to onset of a 2-h free-choice between water and saccharin solution (0.04 g/L). **p < 0.01 vs. saline control treatment, independent of treatment day.