Potentiation of barbiturate-induced alterations in presynaptic noradrenergic function in rat frontal cortex by imidazol(in)e alpha2-adrenoceptor agonists.
1. In order to resolve the extent to which presynaptic noradrenergic mechanisms contribute to the anaesthetic-sparing effects of alpha2-adrenoceptor agonists in vivo microdialysis was used to investigate the combined effects of sodium pentobarbitone and imidazol(in)e alpha2-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 microM) 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) alpha2-adrenoceptor agonists. The dose rate employed for each compound was 2 microg kg(-1) h(-1) over 2 h. 5. The co-administration of intravenous clonidine or mivazerol, each at 2 microg 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 [3H]-mivazerol administration than after [3H]-clonidine administration. Sodium pentobarbitone did not alter the accumulation of tritium in brain tissue after the administration of either alpha2-adrenoceptor agonist. 7. These data demonstrate that alpha2-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 alpha2-adrenoceptor agonists.
Dalley
J W
JW
Department of Experimental Psychology, University of Cambridge.
Parker
C A
CA
Wülfert
E
E
Hudson
A L
AL
Nutt
D J
DJ
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001463:Barbiturates / Q000494:pharmacology; D002540:Cerebral Cortex / Q000502:physiology; D004357:Drug Synergism; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D017661:Receptors, Presynaptic / Q000187:drug effects*
D000316:Adrenergic alpha-Agonists; D001463:Barbiturates; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; D017661:Receptors, Presynaptic; D010424:Pentobarbital