Stimulation of locus coeruleus neurons by non‐I1/I2‐type imidazoline receptors: an in vivo and in vitro electrophysiological study

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Abstract
Imidazoline binding sites have been reported to be present in the locus coeruleus (LC). To investigate the role of these sites in the control of LC neuron activity, we studied the effect of imidazolines using in vivo and in vitro single‐unit extracellular recording techniques. In anaesthetized rats, local (27 pmoles) and systemic (1 mg kg−1, i.v.) administrations of 2‐(2‐benzofuranyl)‐2‐imidazoline (2‐BFI), a selective I‐imidazoline receptor ligand, increased the firing rate of LC cells (maximal increase: 22 ± 5%, PP−1, i.p., every 12 h for 14 days) abolished this effect. In rat midpontine brain slices containing the LC, bath application (1 mM) of the imidazolines 2‐BFI, 2‐(4,5‐dihydroimidaz‐2‐yl)‐quinoline (BU224), idazoxan, efaroxan, phentolamine and (2‐2‐methoxy‐1,4‐benzodioxan‐2‐yl)‐2‐imidazoline (RX821002) reversibly stimulated LC cells. The maximal effect was ∼90% except for RX821002 and efaroxan which induced smaller maximal effects (∼58% and ∼35% respectively). Simultaneous application of idazoxan and 2BFI did not lead to additive effects. Bath application of the α2‐adrenoceptor antagonists, yohimbine (1–10 μM) and N‐ethoxycarbonyl‐1,2‐dihydroquinoline (EEDQ) (10 μM), failed to modify LC activity. The irreversible blockade of α2‐adrenoceptors with EEDQ (10 μM) did not alter the effect of idazoxan or that of efaroxan. Previous application of clorgyline (10 μM) did not modify the excitatory effect of 2‐BFI or efaroxan. Changes in the pH of the bathing solution (6.84–7.84) did not influence the effect caused by idazoxan. Bath application of 2‐BFI (1 mM) reversed the inhibition induced by diazoxide (300 μM), an ATP‐sensitive K+ channel opener, whereas application of glibenclamide (3 μM), an ATP‐sensitive K+ channel blocker, partially blocked the effect of 2‐BFI. This study shows that imidazoline compounds stimulate the firing rate of LC neurons. This effect is not mediated by α2‐adrenoceptors nor by I1 or I2‐imidazoline receptors but involves a different subtype of imidazoline receptor. Our results indicate that this receptor is located extracellularly and modulates ATP‐sensitive K+ channels.