THE ROLE OF EXCITATORY AMINO-ACIDS IN THE EXPRESSION OF PRECIPITATED ACUTE AND CHRONIC CLONIDINE WITHDRAWAL - AN IN-VIVO VOLTAMMETRIC STUDYIN 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 d ifferential normal pulse voltammetry to monitor catechol oxidation as an index of the activity of the LC, the role of EAA pathways in antago nist precipitated withdrawal after acute and chronic clonidine treatme nt was examined. Intracerebroventricular clonidine (10 mu g i.c.v.) si gnificantly reduced LC activity to 54.4 +/- 3.1% of baseline 45 minute s following the injection. Subsequent systemic injection of the select ive alpha(2) receptor antagonist atipamezole (0.2 mg/kg i.v.) or yohim bine (0.5 mg/kg i.v.) resulted in a rapid reversal of the depressant e ffects and a significant increase in LC activity above baseline. Pretr eatment with the non-selective EAA receptor antagonist gamma-D-glutamy lglycine (DGG) (50 mu g i.c.v.) attenuated the atipamezole-induced reb ound response of the LC but not the reversal of clonidine action. Howe ver, both the yohimbine-induced rebound and reversal of clonidine effe cts were attenuated by DGG treated animals. In chronic clonidine treat ed animals (2, 5, 7, 10 mu g/h i.c.v., 5 days), a challenge with atipa mezole (0.2 mg/kg i.v.) produced an immediate increase in LC activity, blood pressure and heart rate. The magnitude of these responses was d ependent on the dose of clonidine. The atipamezole-induced increase in LC activity and blood pressure was significantly attenuated by pretre atment with DGG (200 mu g i.c.v.). These findings suggest that LC hype ractivity and blood pressure increases elicited during clonidine withd rawal are mediated in part by activation of EAA receptors. In this reg ard, the mechanisms underlying clonidine withdrawal closely resembles those underlying opioid withdrawal.