Elevated spinal monoamine neurotransmitters after antenatal hypoxia-ischemia in rabbit cerebral palsy model

J Neurochem. 2015 Feb;132(4):394-402. doi: 10.1111/jnc.12997. Epub 2015 Jan 23.


We hypothesized that a deficiency in the descending serotonergic input to spinal cord may underlie postnatal muscle hypertonia after global antenatal hypoxic-ischemic injury in a rabbit model of cerebral palsy. Neurotransmitter content was determined by HPLC in the spinal cord of newborns with and without muscle hypertonia after fetal global hypoxic-ischemic brain injury and naïve controls. Contrary to our hypothesis, serotonin levels in both cervical and lumbar expansions and norepinephrine in cervical expansion were increased in hypertonic kits relative to non-hypertonic kits and controls, with unchanged number of serotonergic cells in caudal raphe by stereological count. Serotonergic fiber length per unit of volume was also increased in hypertonic kits' cervical and lumbar spinal cord, both in dorsal and ventral horns. Gene expression of serotonin transporter was increased and 5-HTR2 receptors were decreased in hypertonic kits relative to controls in cervical and lumbar cord. Intrathecal administration of non-selective serotonin receptor inhibitor methysergide decreased muscle tone in hypertonic kits only. Conversely, intrathecal administration of serotonin solution increased muscle tone only in non-hypertonic kits. We speculate that maturation of serotonergic system in spinal cord may be directly affected by decreased corticospinal connectivity after antenatal hypoxic-ischemic brain injury. Following prenatal hypoxia-ischemia, newborn rabbits exhibit elevated levels of serotonin in the spinal cord that were linked to muscle hypertonia. Serotonergic terminal density was also increased in hypertonic newborns' spinal cord. Intrathecal administration of the non-selective serotonin receptor inhibitor methysergide decreased muscle tone in hypertonic newborns only. Elevated spinal serotonin thus suggests a novel pathophysiological mechanism of hypertonia in cerebral palsy.

Keywords: hypoxia-ischemia; muscle hypertonia; perinatal brain injury; serotonin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Biomarkers / metabolism
  • Cerebral Palsy / etiology
  • Cerebral Palsy / metabolism*
  • Disease Models, Animal*
  • Female
  • Hypoxia-Ischemia, Brain / complications
  • Hypoxia-Ischemia, Brain / metabolism*
  • Molecular Sequence Data
  • Pregnancy
  • Rabbits
  • Receptors, Serotonin, 5-HT2 / metabolism*
  • Serotonin / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Spinal Cord / metabolism*


  • Biomarkers
  • Receptors, Serotonin, 5-HT2
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin

Associated data

  • GENBANK/NM000868
  • GENBANK/NM008312
  • GENBANK/NM012765