Subtypes of alpha1- and alpha2-adrenoceptors mediating noradrenergic modulation of spontaneous inhibitory postsynaptic currents in the hypothalamic paraventricular nucleus.

Noradrenergic inputs to the hypothalamic paraventricular nucleus (PVN) play important roles in the regulation of neuroendocrine and autonomic functions. Previous reports show that noradrenaline increases the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in a subpopulation of type II neurones, acting via alpha(1)-adrenoceptors (ARs), but reduces this frequency in most type I and another subpopulation of type II neurones, via alpha(2)-ARs on presynaptic GABA neurones. Here, we identified the subtypes of alpha-ARs mediating noradrenaline-induced increases and decreases in the sIPSC frequency of PVN neurones, by using slice patch recordings from PVN neurones. In both type I and II neurones, the noradrenaline-induced decrease in sIPSC frequency was completely blocked by BRL44408 (alpha(2A)-AR antagonist) at 1-3 micro M, which is approximately 1/100 of its equilibrium dissociation constant (pA(2) = 8.0), but not by prazosin (20-100 micro M, alpha(2B/C)-AR antagonist; pA(2) = 7.5). The effect of noradrenaline was mimicked by guanfacine (alpha(2A)-AR agonist) with an EC(50) of 0.1 micro M. In type II neurones, the noradrenaline-induced increase in sIPSC frequency was not blocked by any of the following antagonists: RS17053 (10 micro M, alpha(1A)-AR antagonist), BMY7378 (2 micro M, alpha(1D)-AR antagonist), prazosin (0.1 micro M, alpha(1)-AR antagonist; pA(2) = 10.5), or chloroethylclonidine (10 micro M, alpha(1B/D)-AR antagonist). However, the effect of noradrenaline was blocked by higher concentrations of prazosin (1 micro M) or RS17053 (100 micro M), suggesting the involvement of alpha(1L)-subtype, a low affinity form of alpha(1A)-ARs. Collectively, our results indicate that the alpha(2A)-, or alpha(1L)-ARs on the GABA neurones mediate the noradrenaline-induced decreases, or increases in the frequencies of the sIPSCs of PVN neurones, respectively.