INHIBITORY-ACTION OF MUSCARINIC AGONISTS ON NEURONS IN THE RAT LATERODORSAL TEGMENTAL NUCLEUS IN-VITRO

1. The effects of the mixed cholinergic agonist carbachol and the musc arinic agonist methacholine (MCh) on neurons of the laterodorsal tegme ntal nucleus (LDT) were studied with the use of intracellular and whol e-cell patch-clamp recordings in a rat brain stem slice preparation. 2 . Neurons were classified into one of two categories on the basis of t heir intrinsic membrane properties: those that displayed a prominent l ow-threshold calcium burst (LTB, 60%) and those that did not exhibit s uch a burst (non-LTB, 40%). 3. Neurons from which recordings were obta ined were filled with biocytin, visualized with Texas-red avidin, and identified as cholinergic or noncholinergic with NADPH-diaphorase hist ochemistry. Eighty percent of the LTB neurons that were processed in t his manner were cholinergic, and 60% of the non-LTB neurons were choli nergic. 4. Carbachol elicited a membrane hyperpolarization associated with a decrease in input resistance in 95% of the cells tested. Under voltage clamp this response was shown to be due to an outward current that reversed near the equilibrium potential for potassium and display ed marked inward rectification. The conductance/voltage relationship w as fit to the Boltzmann equation with a mean V1/2 = -73 +/- 4 (SD) mV and a mean k value of 10 +/- 4. The carbachol-evoked current was fully blocked by extracellular barium. 5. There was no significant effect o f carbachol on the transient currents I(A) or I(T). 6. The carbachol-e voked current was mimicked by the specific muscarinic agonist methacho line and blocked by high concentrations of the muscarinic receptor ant agonist pirenzepine (IC50 = 580 nM). 7. These data indicate that the m uscarinic agonist-evoked inhibition of LDT neurons is due to the activ ation of an inwardly rectifying potassium current mediated by a non-M1 muscarinic receptor. 8. These findings suggest an important role for acetylcholine in feedback inhibition of LDT neurons that play a promin ent role in the generation of rapid eye movement (REM) sleep phenomeno logy. There is little or no activity in monoaminergic neurons during R EM sleep, suggesting an absence of their inhibitory influence on highl y active LDT neurons in this state. Hyperpolarization of bursting LDT neurons is needed to remove inactivation of the low-threshold calcium current so that bursting observed during REM sleep in association with pontogeniculooccipital (PGO) waves can occur. Evidence from this stud y suggests that a likely source of the requisite hyperpolarizing input on LDT neurons during REM sleep arises from a strong inhibitory feedb ack originating from cholinergic LDT neurons.