Trace amines as novel modulators of spinal motor function
Gozal, Elizabeth A.
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Trace amines (TAs), tryptamine, tyramine, octopamine, and beta-phenylethylamine, named for their low endogenous concentrations in mammals, are related to the classical monoamine transmitters, but have been understudied and thought of as false transmitters. They share structural, physiological, pharmacological, and metabolic similarities with the monoamines, including synthesis by the aromatic-L-amino acid decarboxylase (AADC) enzyme. In 2001, a new class of receptors preferentially activated by the TAs, termed trace amine-associated receptors (TAARs), was discovered establishing a mechanism for TA actions independent of classic monoaminergic mechanisms. While the TAs and some of their receptors are present in the mammalian central nervous system (CNS), their physiologic role remains uncertain. I hypothesized that the TAs are found intrinsically in the spinal cord, and that they are able to modulate spinal neural networks. Using immunohistochemistry, numerous spinal neurons were identified that express AADC, TAs, and TAARs. Similar results were seen for AADC and TAAR1 with in situ hybridization. The most consistent observation was for labeling D cells associated with the central canal and in motoneurons. Overall, these results provided evidence for the presence of an anatomical substrate onto which the TAs could have intrinsic biological actions in the spinal cord. Using exogenous application of the TAs in the isolated spinal cord in vitro, and in vivo in the mid-thoracic chronically spinalized, I showed that the TAs could induce rhythmic locomotor-like activity. TA injection-induced hindlimb motor rhythms observed in chronic spinalized animals, supports TA spinal actions independent of the descending monoaminergic systems. In the presence of NMDA, TA applications recruited a variety of rhythmic motor patterns in the isolated spinal cord. This ranged from locomotor activity indistinguishable from 5-HT/NMDA induced locomotion to complex patterns including, an episodic form of locomotion where there were locomotor bouts with intervening quiescent periods. TA actions of pattern generating circuits had slower kinetics of activation than 5-HT and NA, were attenuated in the presence of monoamine transport inhibitors, and had increased intracellular labeling when incubated in a nominally Na+-free solution. Together these results suggest that the TAs require transport into neurons to exert their actions, and that transport occurs by Na+-dependent monoamine transporters as well as Na+-independent transporters. Finally, I used the in vitro isolated spinal cord with attached hindlimbs to record electromyographic (EMG) activity from various hindlimb muscles to compare the relationship between the TAs and serotonin (5-HT) evoked motor coordination and to examine the ability of the TAs to modulate ongoing 5-HT and NMDA locomotor-like activity. The TAs produced both the continuous and episodic patterns on muscles as observed in ventral root recordings, but EMG recordings provided more detailed insight into specific muscle actions. The TAs also generally increased both frequency and amplitude of ongoing 5-HT locomotor frequency, with tyramine and octopamine also particularly able to alter 5-HT motor coordination patterns.