Excitation of locus coeruleus neurons by an adenosine 3',5'-cyclic monophosphate-activated inward current: extracellular and intracellular studies in rat brain slices

The firing rate of locus coeruleus (LC) neurons in rat brain slices was increased reversibly by agents that either elevate intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) or mimic its actions (e.g., forskolin, and activator of adenylate cyclase, 8-Br-cAMP, a membrane permeable analog of cAMP, and Ro20-1724, a preferential inhibitor of cAMP-phosphodiesterase). Intracellular recordings showed that 8-Br-cAMP and forskolin induce a depolarization of LC neurons, accompanied by a decrease in input resistance. The 8-Br-cAMP- and forskolin-elicited depolarization persisted in the presence of cobalt, a calcium channel blocker. Steady-state current-voltage curves revealed that in the voltage range of -50 to -120 mV, 8-Br-cAMP and forskolin induced an inward current, which did not reverse at the potassium equilibrium potential and could not be blocked by tetrodotoxin. Partial replacement of sodium with Tris or choline markedly reduced the depolarization elicited by 8-Br-cAMP. We conclude that 8-Br-cAMP and forskolin act through a common mechanism to increase the firing rate of locus coeruleus neurons by inducing a cAMP-activated inward current, carried out at least in part by sodium ions.