Muscarine reduces inwardly rectifying potassium conductance in rat nucleus accumbens neurones.

1. Intracellular recordings were made from neurones in the nucleus accumbens in slices from the rat brain maintained in vitro. 2. Muscarine (1-100 microM) depolarized 101 of 107 neurones; this was associated with an increase in the input resistance. The potential change reversed polarity with conditioning hyperpolarization and the reversal potential was linearly related to the logarithm of the extracellular potassium concentration. 3. The depolarization caused by muscarine was not changed by tetrodotoxin (1 microM) or by a solution that contained lower levels of calcium (0.24 instead of 2.4 mM), higher levels of magnesium (5 instead of 1.2 mM) and cobalt (2 mM). 4. Muscarine caused an inward current and a decrease in slope conductance when applied to neurones voltage clamped near their resting potential (-82 mV). The current caused by muscarine reversed polarity at the potassium equilibrium potential. The current-voltage relation of the neurones between -60 and -120 mV was well fitted by assuming a voltage-independent potassium conductance and an inward rectifier potassium conductance; muscarine reduced predominantly the inward rectifier conductance. 5. Phorbol-12,13-diacetate (3 microM) and 5-hydroxytryptamine mimicked the action of muscarine. The inward currents caused by muscarine or 5-hydroxytryptamine were occluded by the inward current evoked by the phorbol ester. 6. The depolarization caused by muscarine was competitively antagonized by pirenzepine; the dissociation constant of 11 nM suggested involvement of the M1 receptor. 7. It is concluded that muscarine acts at M1 receptors to reduce the membrane potassium conductance and that activation of protein kinase C may be an intermediate step.