A1 noradrenergic action on medial preoptic-medial septal neurons: a neuropharmacological study

In an attempt to determine whether the excitatory and inhibitory orthodromic responses of single medial preoptic-medial septal (MPO-S) neurons to discrete electrical stimulation of the A1 noradrenergic region were mediated specifically by norepinephrine (NE) and involved different types of adrenoreceptors, a series of electrophysiological and neuropharmacological experiments was conducted. Extracellular single unit recording and local drug application techniques were used in female rats under urethane anesthesia. Chemical lesion of the catecholaminergic nerve terminal plexus in the medial preoptic area with 6-hydroxydopamine abolished both excitatory and inhibitory orthodromic effects of A1 region stimulation on MPO-S neurons, suggesting the noradrenergic nature of the effects. This conclusion was corroborated by the observation that the orthodromic effects were mimicked by locally applied exogenous NE. The excitatory effects were reliably mimicked by a low concentration of NE (0.5 mM; in-barrel concentration) and methoxamine (1.0 mM, an alpha-1 agonist), but not by either low or high concentrations (1 and 100 mM) of clonidine (an alpha-2 agonist) and isoproterenol (a beta agonist). The inhibitory orthodromic effects of A1 region stimulation were reliably mimicked by a high concentration of NE (50 mM), clonidine (100 mM) and isoproterenol (100 mM), but not by a low concentration of NE (0.5 mM), methoxamine (1 mM), clonidine (1 mM) or isoproterenol (1 mM). A high concentration (100 mM) of methoxamine mimicked the inhibitory effects less than 40% of the time. The low concentration (0.5 mM) NE-induced excitation that matched the excitatory orthodromic effect of A1 region stimulation was blocked by phentolamine (100 mM), an alpha blocker, but not by timolol (100 mM), a beta blocker. On the other hand, the high concentration (50 mM) NE-induced inhibition that matched the inhibitory orthodromic effect of A1 region stimulation was blocked by timolol, but not by phentolamine. Taken together, the present results are consistent with the hypotheses that the ascending noradrenergic projections from the A1 region affect the excitability of MPO-S neurons directly through NE and that the excitatory and inhibitory orthodromic effects involve different types of adrenoreceptors, i.e., alpha-1 and beta receptors, respectively.