The role of beta- and alpha-adrenergic receptors on alcohol drinking

Abstract

Alcohol Use Disorders (AUD) is characterized by compulsion-like alcohol drinking (CLAD), where intake despite negative consequences can be a major clinical obstacle. With few treatment options available for AUD, there is a significant need for novel therapies. The noradrenergic system is an important hub for regulating stress responses and maladaptive drives for alcohol. Studies have shown that drugs targeting α1 adrenenergic receptors (ARs) may represent a pharmacological treatment for pathological drinking. However, the involvement of β ARs for treating human drinking has received scant investigation, and thus we sought to provide pre-clinical validation for possible AR utility for CLAD by analyzing whether β AR antagonists propranolol (β1/2), betaxolol (β1), and ICI, 118,551 (β2) impacted CLAD and alcohol-only drinking (AOD) in male Wistar rats. We found that the highest dose of propranolol tested systemically (10 mg/kg) reduced alcohol drinking, while 5 mg/kg propranolol reduced drinking with a trend to impact CLAD more than AOD, and with no effects of 2.5 mg/kg. Betaxolol (2.5 mg/kg) also decreased drinking, while ICI 118.551 had no effects. Also, while AR compounds might have utility for AUD, they can also lead to undesirable side effects. Here, a combination of ineffective doses of propranolol and prazosin reduced both CLAD and AOD. Finally, we investigated the effect of propranolol and betaxolol in two brain areas related to pathological drinking, the anterior insula (aINS) and medial prefrontal cortex (mPFC). Surprisingly, propranolol (1-10 μg) in aINS or mPFC did not affect CLAD or AOD. Together, our findings provide new pharmacological insights into noradrenergic regulation of alcohol consumption, which may inform AUD therapy.

Figure 1.. Dose dependent effects of inhibiting β ARs and β1 ARs with propranolol and betaxolol on alcohol drinking.

(A-C) Systemic administration of propranolol at (A) 2.5mg/kg, (B) 5mg/kg, and (C) 10mg/kg. (D) Systemic administration of β1 AR antagonist betaxolol at (D) 2.5mg/kg. (E) Systemic administration of betaxolol 5mg/kg or β2 ARs antagonist ICI 118,551. (F) Percentage change in drinking (relative to vehicle) for propranolol at 2.5, 5 and 10mg/kg. (G) Percentage of vehicle change for betaxolol 2.5, 5mg/kg and ICI 118,551. *,** p<0.05, p<0.01 for treatment or drinking condition effects, from two-way ANOVA.

Figure 2.. Correlations related to propranolol and betaxolol effects on drinking.

(A-C) Drug-related changes in AOD and changes in CLAD were not correlated for 5 mg/kg propranolol (A), 10 mg/kg propranolol (B), or 2.5 mg/kg betaxolol (C). (D,E) Relation between changes in drinking with 5 mg/kg propranolol (y-axis) and basal intake levels (x-axis) for AOD (D) and CLAD (E). (F,G) Relation between change in drinking with 10 mg/kg propranolol and basal intake levels for AOD (F) and CLAD (G). (H,I) Relation between change in drinking with 2.5 mg/kg betaxolol and basal intake levels for AOD (H) and CLAD (I). (J) Drug-related changes in AOD and changes in CLAD were not correlated for 5 mg/kg betaxolol. (K,L) Relation between change in drinking with 5 mg/kg betaxolol and basal intake levels for AOD (K) and CLAD (L). A dashed line indicates where drug intake was not different from vehicle, and values below the dashed line indicate that alcohol drinking under drug exposure was reduced relative to vehicle treatment. @, @@ p<0.05, p<0.01 correlation.

Figure 3.. Co-administration of ineffective doses of prazosin and propranolol reduced AOD and CLAD.

(A) Schematic experimental timeline for co-administration of ineffective doses of prazosin and propranolol. Prazosin (0.25mg/kg) or vehicle was first injected, and 10 minutes animals were injected with propranolol (2.5mg/kg) or vehicle and then 20 minutes later were exposed to AOD or CLAD drinking. (B) Systemic administration of prazosin or propranolol alone did not affect AOD or CLAD. However, co-administration of these drugs together decreased both drinking conditions. (C) Prazosin+propranolol changes in AOD and CLAD were not correlated. (D) Changes in AOD were not correlated with the basal AOD. (E) Changes on CLAD were negatively correlated with basal quinine-alcohol drinking. (F) Co-administration of prazosin and propranolol did not change the concurrent water intake. A dashed line in (C-E) indicates where drug intake was not different from vehicle, and values below the dashed line indicate that alcohol drinking under drug exposure was reduced relative to vehicle treatment. *,** p<0.05, p<0.01 for treatment or drinking condition effects, from two-way ANOVA. @ p<0.05 correlation.

Figure 4.. Inhibition of β ARs in aINS did not affect AOD or CLAD.

(A,B) Intra-aINS administration of propranolol (0.5, 2, 5, or 10μg) had no impact on alcohol intake. (C) Administration of β1 ARs antagonist betaxolol (307ng) into aINS had limited effects on CLAD (see Results). *,** p<0.05, p<0.01 for treatment or drinking condition effects, from two-way ANOVA.

Figure 5.. Inhibition of β and α1 ARs in mPFC did not affect AOD or CLAD.

Intra-mPFC injection of propranolol 0.5 or 5μg (A), propranolol 10μg or betaxolol 307ng (B), or prazosin 0.3μg (C), had no impact on AOD or CLAD.