The role of excitatory amino acids in the expression of precipitated acute and chronic clonidine withdrawal: an in vivo voltammetric study in the rat locus coeruleus

It has been previously shown that activation of excitatory amino acid (EAA) pathways contributes to hyperactivity of the locus coeruleus (LC) in antagonist precipitated opioid withdrawal. In this study, using differential normal pulse voltammetry to monitor catechol oxidation as an index of the activity of the LC, the role of EAA pathways in antagonist precipitated withdrawal after acute and chronic clonidine treatment was examined. Intracerebroventricular clonidine (10 μg i.c.v.) significantly reduced LC activity to 54.4 ± 3.1% of baseline 45 minutes following the injection. Subsequent systemic injection of the selective α₂ receptor antagonist atipamezole (0.2 mg/kg i.v.) or vohimbine (0.5 mg/kg i.v.) resulted in a rapid reversal of the depressant effects and a significant increase in LC activity above baseline. Pretreatment with the non-selective EAA receptor antagonist γ-d-glutamylglycine (DGG) (50 μg i.c.v.) attenuated the atipamezole-induced rebound response of the LC but not the reversal of clonidine action. However, both the yohimbine-induced rebound and reversal of clonidine effects were attenuated by DGG treated animals. In chronic clonidine treated animals (2, 5, 7, 10 μg/h i.c.v., 5 days), a challenge with atipamezole (0.2 mg/kg i.v.) produced an immediate increase in LC activity, blood pressure and heart rate. The magnitude of these responses was dependent on the dose of clonidine. The atipamezole-induced increase in LC activity and blood pressure was significantly attenuated by pretreatment with DGG (200 μg i.c.v.). These findings suggest that LC hyperactivity and blood pressure increases elicited during clonidine withdrawal are mediated in part by activation of EAA receptors. In this regard, the mechanisms underlying clonidine withdrawal closely resembles those underlying opioid withdrawal.