The locus coeruleus noradrenergic system in the rat brain studied by dual-probe microdialysis

A dual-probe microdialysis technique was applied to the locus coeruleus (LC) and prefrontal cortex (PFC) of the brain of conscious rats. One probe was implanted close to the LC and was used to apply receptor-specific compounds by retrograde microdialysis. The effects of the LC infusions were recorded by a sampling noradrenaline by a second probe that was implanted in the ipsilateral prefrontal cortex. Infusion of sodium channel blocker tetrodotoxin (1 microM; 90 min) into the LC decreased extracellular noradrenaline in the PFC to approximately 20% of control values. Infusion of alpha2-adrenoceptor agonist clonidine (100 microM, infused during 15 or 45 min) near to the LC, decreased extracellular noradrenaline in the PFC to 35 and 20% of controls, respectively. These results indicate that > 80% of the extracellular levels of noradrenaline in the PFC is derived from LC innervation, and confirms the importance of alpha2-autoreceptors on noradrenergic neurons in the LC. Infusion of the cholinergic receptor agonist, carbachol (100 microM, 45 min) near to the LC increased extracellular noradrenaline in the PFC to approximately 150% of controls. Infusions of the excitatory amino-acid agonists NMDA and kainate into the LC caused marked increases in extracellular noradrenaline in the PFC to 240 and 200% of controls, respectively. The experiments with clonidine, carbachol, NMDA and kainate were repeated in anesthetized rats. Clonidine and carbachol were similarly effective as in conscious animals but the effects of NMDA and kainate on extracellular noradrenaline in the PFC were clearly suppressed: 145 and 130% of controls, respectively. These results suggest that increased arousal or behavioural activation might have contributed to the increases in extracellular noradrenaline that was seen after infusion of the glutamate agonists. These results also provide evidence for localization of cholinergic-, NMDA-, non-NMDA-receptor on noradrenergic neurons in the LC. Finally it is concluded that dual-probe microdialysis is a useful method to further investigate the pharmacology of LC-noradrenergic neurons. Carbachol and clonidine are suitable tools for a rapid and reversible stimulation or inhibition, respectively, of noradrenergic LC neurons.