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Clonidine‐ethanol synergistic behavioral impairment requires activation of central α2A adrenergic receptors

Clonidine‐ethanol combination induces synergistic behavioral impairment in rats as measured by rotorod performance and loss of righting reflex (LORR). We tested the hypothesis that the neurochemical effects of ethanol are substantially enhanced by prior activation of central α2A‐adrenergic receptors (AR). Increasing levels of α2‐AR activation (30, 60, and 90 μg/kg clonidine, i.v.) caused proportionate increases in behavioral impairment elicited by ethanol (1 g/kg, i.v.). Possible involvement of the imidazoline (I1) receptor, which is also activated by clonidine, was ruled out by demonstrating the inability of the selective I1 agonist rilmenidine (300 μg/kg, i.v.) to cause behavioral impairment alone or with ethanol. Pharmacological blockade of central α2A‐AR’s (RX821002, 0.3 mg i.c.) abolished the clonidine component of the behavioral response, leaving only the ethanol response, which was similar to ethanol single drug treatment in aCSF controls. By contrast, blockade of central α2B‐AR’s (ARC‐239) independently evoked a strong sedative effect. We conclude that activation of central α2A‐AR’s is required to elicit synergistic behavioral impairment by clonidine‐ethanol combination. Furthermore, I1 and α2B‐adrenergic receptors, which are also activated by clonidine, do not play a role in this synergistic interaction.