Opposite effects of N,N-dimethyltryptamine (DMT) and 5-methoxy-n,n-dimethyltryptamine (5-MeODMT) on acoustic startle: spinal vs brain sites of action.

The present studies examined the role of the spinal cord and the brain in mediating the effects of the hallucinogens N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) on the acoustic startle response in the rat. Systemic administration of these agents, which distributes to both the brain and spinal cord, produced opposite effects, as DMT depressed and 5-MeODMT increased acoustic startle. However, when administered directly into the lateral ventricle in the forebrain (intraventricular administration) 5-hydroxytryptamine (5-HT), DMT and 5-MeODMT all depressed acoustic startle, DMT and 5-MeODMT being about equipotent in this regard. In contrast, when administered directly into the spinal cord subarachnoid space (intrathecal administration), 5-HT and 5-MeODMT increased startle, whereas DMT was without effect. In another series of studies, the effects of systemically-administered DMT and 5-MeODMT on the "startle" elicited by electrical stimulation of the nucleus reticularis pontis caudalis (RPC) were determined. Since the RPC is the last nucleus of the primary startle circuit before the spinal cord, agents which act downstream from the RPC (i.e., in the lower brainstem and spinal cord) would be expected to alter RPC-elicited "startle," while agents which act upstream from the RPC would be without effect. Given systemically, 5-MeODMT markedly increased RPC-elicited "startle" while DMT was without effect. These data indicate that DMT and 5-MeODMT are equipotent in depressing startle through actions in the brain. In contrast, the difference in the effects of DMT and 5-MeODMT on acoustic startle is related to the spinal excitatory effects of 5-MeODMT which DMT does not possess. From the present results it is suggested that the relative potencies of DMT and 5-MeODMT in other behavioral measures may relate to the role of brain (equipotent) or spinal (5-MeODMT more potent than DMT) sites of action for the various behaviors.