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α 2A ‐Adrenergic Receptor Signaling Underlies Synergistic Enhancement of Ethanol‐Induced Behavioral Impairment by Clonidine
Author(s) -
Bender Tara Summer,
AbdelRahman Abdel A.
Publication year - 2009
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2008.00860.x
Subject(s) - clonidine , imidazoline receptor , locus coeruleus , agonist , rilmenidine , endocrinology , medicine , alpha (finance) , pharmacology , righting reflex , blockade , receptor , chemistry , reflex , central nervous system , construct validity , nursing , patient satisfaction
Background: We tested the hypothesis that central α 2A ‐adrenergic receptor (α 2A AR) signaling plays a key role in clonidine‐ethanol evoked synergistic behavioral impairment. Methods: Male Sprague‐Dawley rats, with intracisternal and jugular vein cannulae implanted 6 days earlier, were tested for drug‐induced behavioral impairment. The latter was assessed as the duration of loss of righting reflex (LORR) and rotorod performance every 15 minutes until the rat recovered to the baseline walk criterion (180 seconds). In a separate cohort, c‐Fos expression in locus coeruleus (LC) and cerebellum was determined as a marker of neuronal activity following drug treatment. Results: Rats that received clonidine (60 μg/kg, i.v.) followed by ethanol (1 g/kg, i.v.) exhibited synergistic impairment of rotorod performance and LORR. The mixed α 2A AR and I 1 ‐imidazoline receptor agonist clonidine (30, 60, and 90 μg/kg) synergistically and dose‐dependently enhanced behavioral impairment elicited by ethanol (1 g/kg). Possible involvement of I 1 ‐imidazoline receptors was ruled out because selective I 1 ‐agonist rilmenidine (300 μg/kg, i.v.) did not cause behavioral impairment alone or enhance ethanol‐evoked behavioral impairment. Pharmacological blockade of central α 2A AR (RX821002, 0.3 mg i.c.) abolished the synergy between clonidine and ethanol; the behavioral response caused by the drug combination was similar to that caused by ethanol alone. Conversely, involvement of central α 2B AR in the interaction was ruled out because blockade of central α 2B AR (ARC‐239) independently evoked a strong sedative effect. Clonidine (60 μg/kg) or ethanol (1 g/kg) alone increased, but their combination decreased, c‐Fos levels in LC, while inconsistent c‐Fos responses were observed in cerebellum. Conclusions: Central α 2A AR, but not I 1 ‐imidazoline or α 2B AR, signaling is implicated in the synergistic enhancement of ethanol‐evoked behavioral impairment by clonidine. Although the mechanism of c‐Fos response remains to be investigated, this neurochemical response highlights the LC as a neuroanatomical target for clonidine‐ethanol behavioral interaction.