EXCITATORY ACTION OF N-METHYL-D-ASPARTATE ON THE RAT LOCUS-COERULEUS IS MEDIATED BY NITRIC-OXIDE - AN IN-VIVO VOLTAMMETRIC STUDY

Biochemical, electrophysiological and behavioural studies have provide d evidence that activation of N-methyl-D-aspartate (NMDA) receptors co ntributes to the hyperactivity of noradrenergic neurons of the locus c oeruleus (LC) in precipitated opioid withdrawal. Recently, it was demo nstrated that central administration of nitric oxide (NO) synthase inh ibitors suppresses this hyperactivity suggesting that NO mediates the NMDA receptor activation of LC in opioid withdrawal. Using a combinati on of microdialysis and in vivo voltammetry, this study examined wheth er local application of NMDA to the LC in opioid naive animals mimics the NO-dependent LC response seen in opioid withdrawal. In the urethan e anaesthetized rat, perfusion of the LC (2 mu l min(-1)) with a solut ion of NMDA (5 mmol) via a microdialysis probe for 9 min resulted in a rapid and robust increase (290.1 +/- 32.2% above baseline) in the cat echol oxidation current (CA . OC) recorded from the LC using different ial normal pulse voltammetry (DNPV). The NMDA microdialysis also produ ced a large increase in the blood pressure (150.4 +/- 6.9% above basel ine). An injection of the non-competitive NMDA receptor antagonist (+) MK-801 (0.5 mg kg(-1) i.v.), given 45 min after the start of NMDA appl ication, rapidly returned both the CA . OC signal and the blood pressu re response to baseline levels. Pretreatment of animals with intravent ricular nitric oxide synthase (NOS) inhibitor, N-omega-nitro-L-arginin e methyl ester (L-NAME) (100 mu g) significantly inhibited NOS activit y in the LC, PAC-PVC and cerebellum. This dose of L-NAME, administered prior to application of NMDA by microdialysis abolished the NMDA-indu ced rise in the CA OC recorded in the LC and the increase in systolic blood pressure. The results show that in voltammetry experiments, NMDA produces hyperactivity of LC and hypertension, responses that are dep endent upon the synthesis of NO. Thus, in opioid naive rats, regional NMDA application via microdialysis mimics characteristics of the LC re sponse that occur during the antagonist-precipitated opioid withdrawal . (C) 1998 Elsevier Science B.V. All rights reserved.