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

Abstract

1 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 eect of imidazolines using in vivo and in vitro single-unit extracellular recording techniques. 2 In anaesthetized rats, local (27 pmoles) and systemic (1 mg kg 71 , i.v.) administrations of 2-(2-benzofuranyl)-2-imidazoline (2-BFI), a selective I-imidazoline receptor ligand, increased the ®ring rate of LC cells (maximal increase: 22+5%, P50.001 and 16+7%, P50.001 respectively). Chronic pretreatment with the irreversible monoamine oxidase inhibitor clorgyline (3 mg kg 71 , i.p., every 12 h for 14 days) abolished this eect. 3 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 eect was *90% except for RX821002 and efaroxan which induced smaller maximal eects (*58% and *35% respectively). Simultaneous application of idazoxan and 2BFI did not lead to additive eects. 4 Bath application of the a 2 -adrenoceptor antagonists, yohimbine (1 ± 10 mM) and N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (10 mM), failed to modify LC activity. The irreversible blockade of a 2 -adrenoceptors with EEDQ (10 mM) did not alter the eect of idazoxan or that of efaroxan. Previous application of clorgyline (10 mM) did not modify the excitatory eect of 2-BFI or efaroxan. 5 Changes in the pH of the bathing solution (6.84 ± 7.84) did not in¯uence the eect caused by idazoxan. Bath application of 2-BFI (1 mM) reversed the inhibition induced by diazoxide (300 mM), an ATP-sensitive K + channel opener, whereas application of glibenclamide (3 mM), an ATP-sensitive K + channel blocker, partially blocked the eect of 2-BFI. 6 This study shows that imidazoline compounds stimulate the ®ring rate of LC neurons. This eect is not mediated by a 2 -adrenoceptors nor by I 1 or I 2 -imidazoline receptors but involves a dierent subtype of imidazoline receptor. Our results indicate that this receptor is located extracellularly and modulates ATP-sensitive K + channels.

Evidence for co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex

“…Conversely, the administration of the ␣ 2 -adrenoceptor antagonist idazoxan (1.5 mg kg −1 , i.p.) not only increased extracellular NA concentrations up to 170% of basal values, which is consistent with its ability to activate NA neurons, 23 but also increased extracellular DA to 165% of basal values ( Figure 4, right panel).…”

“…Instead, the ␣ 2 -adrenoceptor agonist clonidine not only profoundly reduced NA concentrations, consistent with its ability to suppress NA neuronal activity, 22 but also reduced to almost zero DA concentrations in the dialysates from PFC. Conversely, the ␣ 2 -adrenoceptor-antagonist idazoxan not only increased NA concentrations, in line with its ability to activate NA neurons, 23 but also markedly increased DA levels in dialysates from PFC.…”

In Vivo Effect of Venlafaxine on Locus Coeruleus Neurons: Role of Opioid, α2-Adrenergic, and 5-Hydroxytryptamine1A Receptors

“…Single-unit extracellular recordings of LC neurons were performed as described previously (Ugedo et al, 1998). The recording electrode was an Omegadot single-barrel glass micropipette filled with a 2% solution of Pontamine Sky Blue in 0.5% sodium acetate, and the electrode was broken back to a tip diameter of 1 to 2.5 m. The extracellular signal from the electrode was amplified, discriminated, and monitored on an oscilloscope and with an audio monitor.…”

Involvement of Supraspinal Imidazoline Receptors and Descending Monoaminergic Pathways in Tizanidine-Induced Inhibition of Rat Spinal Reflexes

“…I 1 receptors are located in the rostral ventrolateral medulla area of the brain stem (4,5) and regulate blood pressure (6) as well as food intake (7), while I 2 receptors are widely distributed in the brain. Non-I 1 / I 2 (subtype I 3 ) imidazoline binding sites mediate the insulinotropic effect of some imidazoline ligands (8 -10) by acting as blockers of ATP-sensitive K + channels (9,10), and more recently, they have been suggested to regulate neuronal activity in the locus coeruleus (11). So far, there have been no attempts to evaluate imidazoline-receptor subtypes involved in the depression of spinal reflexes by tizanidine.…”