Reduction of Motion Sickness Through Targeting Histamine N-Methyltransferase in the Dorsal Vagal Complex of the Brain.

Abstract

To investigate the role of histamine N-methyltransferase (HNMT) activity in the development of motion sickness (MS) in the dorsal vagal complex (DVC) to inform the development of new drugs for MS, Beagle dogs and Sprague-Dawley rats were rotated to simulate MS. HNMT expression in the brain stem and DVC was measured. The effects of systemic application of tacrine, an HNMT inhibitor, on the development of MS were observed. Moreover, we microinjected a histamine receptor H1 inhibitor, promethazine, into the DVC to verify the involvement of histaminergic neurotransmission in MS. Finally, lentiviral vectors were microinjected into the DVC to determine the effects of altered HNMT expression on MS. We found the following: 1) HNMT expression in the medulla oblongata of dogs and rats insusceptible to MS was higher than in susceptible animals; 2) tacrine dose-dependently promoted MS in both animals and raised histamine level in rat medulla oblongata; 3) blocking histaminergic neurotransmission in the DVC with promethazine inhibited MS; 4) rotatory stimulus induced an elevation in HNMT expression, and vestibular training elevated the basal level of HNMT in the DVC during habituation to MS; 5) in vivo transfection of a lentiviral vector packaged with the HNMT gene increased HNMT expression in the DVC and reduced MS; and 6) microinjection of a lentiviral vector driving the interference of HNMT gene expression in vivo significantly inhibited HNMT expression in the DVC and exacerbated MS. In conclusion, HNMT expression in the brain stem is inversely correlated with MS development. Increasing HNMT expression or stimulating its activity in the DVC could inhibit MS.