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Modulation of the hyperpolarization-activated cation current, Ih, by noradrenaline (NA) and serotonin (5-HT) was examined in guinea-pig and cat medial and lateral geniculate relay neurones using the in vitro slice technique. 2. In the absence of pharmacological antagonists, local application of NA resulted in a slow depolarization and decrease in apparent input conductance, a response which was blocked by local or bath application of the alpha 1-adrenoceptor antagonist prazosin. Application of NA after pharmacological block of alpha 1- and alpha 2-adrenoceptors, or application of 5-HT in all conditions, induced a 1-3 mV slow depolarization which was associated with a pronounced increase in apparent input conductance. This response to NA and 5-HT persisted during blocked synaptic transmission and was present in both the guinea-pig and cat medial and lateral geniculate nuclei. 3. The increase in membrane conductance elicited by NA was mimicked by the beta-specific agonist isoprenaline and blocked by the beta-antagonists propranolol and atenolol, indicating that it is mediated by beta-adrenoceptors. The response to 5-HT was blocked by the 5-HT1 and 5-HT2 antagonist methysergide, but not by the 5-HT2 antagonist ritanserin. Applications of either the 5-HT1A agonist ipsapirone or the partial agonist 8-hydroxy-dipropylaminotetralin (8-OHDPAT) were without effect. 4. Current versus voltage relationships obtained under voltage clamp revealed NA and 5-HT to cause a voltage-dependent inward shift at membrane potentials negative to approximately -60 mV. This response appeared to be shared by NA and 5-HT since maximal application of 5-HT greatly reduced or abolished the response to NA. 5. Application of NA and/or 5-HT during hyperpolarizing voltage steps in voltage clamp resulted in a marked increase in amplitude of the hyperpolarization-activated cation current, Ih. In addition, the rate of activation of Ih was strongly increased during activation of beta-adrenoceptors. 6. The activation curve of the conductance underlying Ih (Gh) was shifted by 4-6 mV on the voltage axis with NA and/or 5-HT. The positive shift of Gh activation in the voltage domain resulted in an increase in the amplitude of Gh which is active at resting, and more hyperpolarized, membrane potentials. The subsequent increase in resting membrane conductance decreased the responsiveness of thalamic neurones to hyperpolarizations of all durations. 7. Local or bath application of caesium blocked both Ih and the increase in membrane conductance in response to NA and 5-HT. By contrast, barium blocked neither Ih nor the responses to NA and 5-HT.(ABSTRACT TRUNCATED AT 400 WORDS)
McCormick et al. (Sat,) studied this question.