Mechanisms of regrowth of the bulbospinal serotonin system following 5,6-dihydroxytryptamine induced axotomy. I. Biochemical correlates

Abstract

The regrowth of the bulbospinal serotonin neurons after 5,6-dihydroxytryptamine (5,6-DHT)-induced axotomy has been followed between 1–2 weeks and 8 months after neurotoxin injection, using determinations of endogenous serotonin (5-HT) and [ 3H]5-HT uptake, and measurements of the conversion of [ 3H]tryptophan ([ 3H]TP) into [ 3H]5-HT and [ 3H]5-HIAA in vitro. In the spinal cord there was, at 2 weeks after the 5,6-DHT treatment (75 μg), a drastic reduction in all three parameters throughout the cord signifying that the 5,6-DHT-induced axotomy causes an almost complete denervation of the spinal cord from the lumbar up to the most cranial cervical segments. With time there was a gradual recovery in the [ 3H]5-HT uptake, which appeared to progress in a cranio-caudal direction. By 2 months the recovery was noted mainly in the upper cervical segments; by 4 months it was evident also in the lower cervical segments, and by 8 months it had reached the thoracic and lumbar segments. By 7–8 months, when the [ 3H]5-HT uptake had recovered to 60% of normal in the upper cervical segments and to 25% of normal in the lumbar cord, endogenous 5-HT had recovered to 34% of the age-matched vehicle-treated controls in the cervical cord and to 13% in the lumbar cord, while the [ 3H]5-HT synthesis from [ 3H]TP had recovered to about 40–50%. The [ 3H]5-HIAA/[ 3H]5-HT ratio (reflecting the rate of metabolism of the newly synthesized transmitter) and the medium/tissue ratio (reflecting the rate of spontaneous release under the in vitro conditions) had undergone a more than two-fold increase in the long-term 5,6-DHT-treated rats, indicating an increased turnover of the transmitter in the partially reinnervated spinal cord. In medulla oblongata, where the cell bodies of origin of the bulbospinal serotonin neurons, as well as proximal terminal areas are located, there was acutely a partial (40–50%) reduction in [ 3H]5-HT uptake and [ 3H]5-HT synthesis capacity, whereas the endogenous 5-HT content was increased by 30% (due to accumulation of the transmitter in the lesioned axon stumps). There was a rapid and extensive recovery, resulting in supranormal values in all three parameters by 7–8 months. This was accompanied by a marked retardation of the in vitro turnover of newly-synthesized [ 3H]5-HT (reflected in marked reductions in the [ 3H]5-HIAA/[ 3H]5-HT and the medium/tissue ratios). The results demonstrate an extensive recovery of the neurotransmitter biosynthetic machinery during regeneration of the chemically axotomized serotonin neurons. Moreover, the observations of increased transmitter turnover in the incompletely reinnervated areas in the spinal cord and decreased turnover in the hyperinnervated brain stem areas suggest that regional compensatory mechanisms may alleviate the functional consequences of the abnormal distribution of the regenerated terminals. It is proposed that with a combination of axonal regeneration, increased utilization of the transmitter, and development of receptor supersensitivity also an incomplete regeneration, resulting in a partial reinnervation of an area, can become efficient in restoring normal function in the CNS.