Kv7 channel modulators reduce the stress-induced hyperthermia response and cause locomotor sedation in rats

摘要

Rationale: Kv7 channels (KCNQ) are potassium ion channels that are important in controlling neuronal excitability, which have been implicated in psychiatric disorders. Specifically, a role for Kv7 channels in anxiety processes has been proposed. Objectives: The main aim of this study was to investigate possible anxiolytic effects of Kv7 channel modulators in rats applying the stress-induced hyperthermia (SIN) paradigm, a preclinical paradigm, which uses the autonomic stress-induced rise in body temperature as a readout parameter of stress. Results: The non-selective Kv7.2-5 channel positive allosteric modulators (PAMs) flupirtine and retigabine reduced the SIH response and basal body temperature with concomitant locomotor sedation. Administration of the Kv7.4/Kv7.5 channel negative allosteric modulator R-BMS204352 prior to injection with flupirtine did not antagonize the effects on body temperature and locomotor activity. Administration of the Kv7.4/Kv7.5 preferential PAM S-BMS204352 only modestly affected basal body temperature but did not affect the SIN response or locomotor activity levels. Conclusions: The present study supports a role of Kv7.2/Kv7.3 channels in anxiety reduction, hypothermia and sedation, whereas preferential activation of Kv7.4/Kv7.5 channels only modestly affected body temperature and locomotor activity. Thus, the effects of Kv7 channel openers may be dissociated with regard to the contribution of different Kv7 subunits and Kv7 channel isoforms