Lesion of the serotoninergic system in neonate rats is an ideal model for assessing the activity of chemical substances capable of affecting neuronal plasticity and regeneration (Jonsson et al., Dev Brain Res 16: 171-180, 1984). Treatment of newborn rats within 6 hr from birth with the selective neurotoxin 5,7-dihydroxytryptamine causes degeneration of the most distal serotoninergic axons. In our experimental conditions we have observed that after such neurotoxic treatment there is spinal cord denervation, which is particularly remarkable in the lumbar segment. This degenerative event is followed by gradual regeneration of the lesioned axons, with good reinnervation of the entire cord within 8 weeks. The degeneration-regeneration process is correlated with a transient hyperinnervation of the pons-medulla and hypothalamus by the short collaterals (pruning effect), as evidenced by increased serotonin content. Perinatal morphine exposure markedly impairs serotonin regeneration in the spinal cord. In addition, opiate treated rats are more susceptible to lesions, as shown by the neurotoxin induced denervation of the cortex, pons-medulla, and hypothalamus, which does not occur in lesioned controls. Therefore, our observations suggest that perinatal exposure to morphine affects the plasticity and regeneration of the developing serotoninergic system by increasing its susceptibility to neurotoxic lesions and reducing its regenerative capacity.
Peripheral nerve lesions cause retrograde changes in the spinal cord, involving initially the descending serotoninergic pathways and later the substance P sensory input and methionine-enkephalin interneurons. Within 48 h after sciatic nerve resection there is a significant increase of 5-hydroxyindoleacetic acid in the lumbar spinal cord with no changes of serotonin metabolism in the cell body areas. The immunocytochemical analysis of the spinal cord shows that 20 days after nerve lesion there is a loss of substance P-positive boutons in the laminae I and II of the dorsal horn in the lumbar segment. Such a morphological change is correlated by radioimmunoassay for substance P and methionine-enkephalin, that reveals a significant loss of both peptides. Treatment with acetyl-L-carnitine prevents the early 5-hydroxyindoleacetic acid increase and the reduction of peptide content observed 20 days after lesioning the sciatic nerve. These data suggest that treatment with acetyl-L-carnitine exerts a neuroprotective activity preventing the retrograde changes triggered by peripheral nerve lesions.
It has been reported that chronic ethanol exposure during intrauterine life may cause severe adverse effects in early infancy that have been termed fetal alcohol syndrome. These alterations may perturb the normal brain development as though alcohol exposure might have altered the basic cellular interrelationship underlying neuronal plasticity. The neonatal lesion of the serotoninergic pathways in the central nervous system with the selective neurotoxin 5,7-DHT supplies an ideal model for studying the effects of substances of abuse on degenerative and regenerative events. The authors' data indicate that perinatal exposure to ethanol (3% in drinking water) causes a more rapid degeneration of the serotoninergic pathways affected by 5,7-DHT; conversely, regeneration and reinnervation of the lumbar spinal cord are markedly improved by ethanol exposure. These results suggest that perinatal ethanol exposure promotes cellular changes that at later stages are capable of improving neural repair in the brain.
