Enhancement of photic shifts with the 5-HT1A mixed agonist/antagonist NAN-190: intra-suprachiasmatic nucleus pathway

Chronic desynchronization between the mammalian circadian pacemaker and its external environment, such as that observed from shift work or jet lag, can lead to various long-term health consequences. The circadian clock can be reset by exposure to light, although the magnitude of such adjustments is modest. 5-HT modulates the effects of light, and 5-HT_1A mixed agonist/antagonists, such as NAN-190, have been found to potentiate the phase resetting ability of light. The mechanism for this potentiation has yet to be uncovered, although it has been proposed that these drugs inhibit raphe output while simultaneously blocking post-synaptic 5-HT_1A receptors. The current study takes advantage of the heterogeneous network organization of the circadian clock to identify where in the circadian system NAN-190 exerts its influence. Retinorecipient cells in the ventrolateral suprachiasmatic nucleus (SCN) are activated by glutamate and release either gastrin-releasing peptide (GRP) or vasoactive intestinal polypeptide. Application of the glutamate agonist N-methyl-d-aspartic acid (NMDA) or either of these neuropeptides to the SCN mimics the effects of light. We hypothesized that NAN-190 would modify responses to treatments that activate the circadian system upstream, but not downstream, of where NAN-190 is acting. Hamsters were pretreated with NAN-190 or vehicle, followed by one of the neurochemicals 45 min later, during the early- and/or late-subjective night. NAN-190 potentiated NMDA-induced phase advances and delays as well as GRP-induced advances, but attenuated GRP-induced delays. NAN-190 did not potentiate NMDA-induced Fos expression, however greater GRP-induced Fos expression was found within the dorsolateral region of the SCN. These data suggest that NAN-190 acts, in part, by modifying the responsiveness of retinorecipient cells in the circadian clock. An understanding of the neural events that underlie the potentiation of photic phase shifts by NAN-190 could guide the development of novel chronobiotics which could be used to treat a variety of sleep and circadian disorders.