Potentiation of barbiturate‐induced alterations in presynaptic noradrenergic function in rat frontal cortex by imidazol(in)e α 2 ‐adrenoceptor agonists

1 In order to resolve the extent to which presynaptic noradrenergic mechanisms contribute to the anaesthetic‐sparing effects of α 2 ‐adrenoceptor agonists in vivo microdialysis was used to investigate the combined effects of sodium pentobarbitone and imidazol(in)e α 2 ‐adrenoceptor agonists on extracellular levels of noradrenaline (NA) in the rat frontal cortex. 2 Dialysate levels of NA were markedly reduced by the addition of TTX (2 μ M ) or by the removal of calcium in the perfusate. These data imply that dialysate NA levels are ultimately dependent on exocytotic release mechanisms from afferent coeruleo‐cortical neurones. 3 Systemic administration of sodium pentobarbitone (85 mg kg −1 , i.p.) induced general anaesthesia and reduced NA levels by 92% after 30 min. The restoration of basal levels 90 min later was closely associated with a return of the corneal blink reflex. 4 Basal NA levels in conscious animals were not affected by an intravenous infusion of equally radioactive solutions of either imidazoline (clonidine) or imidazole (mivazerol) α 2 ‐adrenoceptor agonists. The dose rate employed for each compound was 2 μg kg −1  h −1 over 2 h. 5 The co‐administration of intravenous clonidine or mivazerol, each at 2 μg kg −1  h −1 for 2 h, with sodium pentobarbitone (85 mg kg −1 , i.p.), produced a marked and prolonged reduction in NA efflux. After 2 h, NA levels remained suppressed by 95% (clonidine) and 80% (mivazerol) and animals remained deeply anaesthetized. 6 The accumulation of tritium in brain tissue was 42–73% lower across all brain regions examined after [ 3 H]‐mivazerol administration than after [ 3 H]‐clonidine administration. Sodium pentobarbitone did not alter the accumulation of tritium in brain tissue after the administration of either α 2 ‐adrenoceptor agonist. 7 These data demonstrate that α 2 ‐adrenoceptor agonists potentiate the inhibitory effects of sodium pentobarbitone on extracellular levels of NA in the frontal cortex. Further studies will be necessary to establish a causal role of noradrenergic mechanisms in the potentiation of anaesthesia by selective α 2 ‐adrenoceptor agonists.British Journal of Pharmacology (1998) 125 , 441–446; doi: 10.1038/sj.bjp.0702091