Effects of alpha-2 adrenergic agonism on excessive alcohol drinking and associated mechanical allodynia
Rohl, Christian Dieter
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RATIONALE: Alcohol use disorder (AUD) is a devastating neurologic condition that affects millions of people every year. Despite its prevalence, there is still a lack of knowledge and effective treatment options available to alleviate aversive withdrawal symptoms. One such symptom is mechanical allodynia which is the development of a pain response following innocuous tactile stimuli and is found in many chronic pain disorders. The adrenergic system has been previously shown to play a role in modulating ethanol drinking behavior and withdrawal symptoms, but has also been demonstrated to impact nociception. The alpha2-adrenoceptor, in particular, exerts an inhibitory effect on adrenergic and non-adrenergic neurons, and systemically administered agonists have produced reductions in drinking behavior and antinociception. Though this receptor system has been extensively studied, there has yet to be an investigation of the role of alpha2-adrenoceptor agonsim in regards to alcohol withdrawal-induced mechanical allodynia. OBJECTIVES: The objectives of this study were to determine the extent that the alpha2-adrenoceptor agonist, clonidine, could reduce drinking behavior and withdrawal associated mechanical allodynia in C57B1/6J mice chronically exposed to ethanol. METHODS: We employed a series of behavioral tests to examine ethanol actions in adult male and female mice following the administration of varying doses of clonidine (0-160 µg/kg). To investigate the effect on ethanol drinking behavior, we subjected mice to a two-bottle choice, intermittent access paradigm with 24hr access to 20% (v/v) ethanol solutions every other day (Monday, Wednesday and Friday)(MWF group). After stabilization of intake, mice were intraperitoneally administered with vehicle or clonidine, and their actions on the intake of food water and ethanol were determined. Nociceptive threshold was determined following 72hrs of alcohol abstinence using an electronic von Frey device. MWF mice were compared to water drinking control animals following vehicle treatment and again after a 30 minute pretreatment with clonidine. In a separate experiment, alcohol-naïve mice were subjected to the same two-bottle choice schedule, except the ethanol was replaced with 1.15% (w/v) sucrose solutions. Mice were then treated with clonidine and its actions on sucrose, water and food intake were determined. RESULTS: Systemic injection of clonidine decreased ethanol intake during both short and long periods of ethanol intake, decreased allodynia following prolonged abstinence from alcohol and had no effect on the consumption of naturally-reinforcing substances such as sucrose. CONCLUSION: Our results indicate that alpha2-adrenoceptor agonsim leads to a reduction in ethanol drinking behaviors in mice and is sufficient in reversing the changes to pain threshold following prolonged alcohol withdrawal.