Calmodulin Inhibitors Produce Phase Shifts of Circadian Rhythms In Vivo and In Vitro

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Abstract
The effect of calmodulin inibitors on the circadian rhythm of locomotor activity and on the rhythm of suprachiasmatic nuclear (SCN) neuron firing rate recorded in vitro from hypothalamic slices was examined. Trifluoperazine produces changes in a dose-dependent manner in the phase of the activity rhythm, with phase advances throughout most of the subjective day extending into the subjec tive night. These phase changes in the activity rhythm occur rapidly and without induction of locomotor activity at the time of treatment. Similarly, trifluoperazine and the naphthalenesulfonamide W-7 produce changes in phase delays in the subjective night extending into early subjective day. The effects are greater with respect to amplitude when measured acutely after treatment than in the next cycle, and both the acute and next-day effects are greater than those observed in vivo, indicating that data from in vitro studies need to be interpreted with caution. These observations indicate that calmodulin inhibitors affect rhythms directly in vivo by altering SCN neuron pacemaker function, as this reflects involvement of calcium-calmodulin binding with activation of a calmodulin-dependent kinase, either to alter intracellular cAMP levels or to alter gene expression directly to modulate the phase of the SCN clock.