Nitric oxide synthase (NOS), an enzyme involved in synthesis of nitric oxide (NO), has been localized in many diverse cell types. In the CNS and PNS, discrete neuron cell groups express NOS constitutively. Recent evidence indicates that NOS is inducible in neurons normally not expressing NOS. After transection of peripheral nerves, NOS expression was significantly up-regulated in the axotomized sensory ganglion cells, whereas in the corresponding motor neurons NOS was not induced unless axon regeneration was prevented and ensuing neuron death became massive. Studies on axotomy-induced NOS have been limited largely to spinal nerves, with only one reported in the vagus nerve. The aim of this study was to determine whether NOS induction in motor neurons of the brainstem after axotomy is regulated in a manner similar to that of the spinal cord. By NADPH-diaphorase histochemistry and NOS immunocytochemistry, the status of NOS in neurons of the hypoglossal nucleus, dorsal motor nucleus of the vagus, and motor nucleus of the facial nerve was examined 2 weeks after unilateral transection of the respective cranial nerves, and the results were compared with those of spinal motor neurons after transection of the sciatic nerve. NOS, undetectable in neurons of the three cranial motor nuclei of sham-operated animals, was observed in about 30-50% of neurons in the cranial motor nuclei ipsilateral to axotomy, but it was not detected in spinal motor neurons after axotomy. NOS localized in axotomized cranial motor neurons was unrelated to NOS of macrophages or endothelial cells. There was no appreciable cell loss from axotomy at this period except in the dorsal motor nucleus of the vagus, where some loss was observed. The results indicate that there is a fundamental difference in the regulation of NOS expression between motor neurons of the cranial and spinal nerves. The possible role of NOS/NO acting as cytoprotective or cytotoxic agent on injured motor neurons is discussed. Motor neurons of cranial and spinal nerves may serve as a useful model to further define the roles of NOS/NO in neurons, especially after traumatic injury.

Ketamine is an anesthetic and a popular abusive drug. As an anesthetic, effects of ketamine on glutamate and GABA transmission have been well documented but little is known about its long-term effects on the dopamine system. In the present study, the effects of ketamine on dopamine were studied in vitro and in vivo. In pheochromocytoma (PC 12) cells and NGF differentiated-PC 12 cells, ketamine decreased the cell viability while increasing dopamine (DA) concentrations in a dose-related manner. However, ketamine did not affect the expression of genes involved in DA synthesis. In the long-term (3 months) ketamine treated mice, significant increases of DA contents were found in the midbrain. Increased DA concentrations were further supported by up-regulation of tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis. Activation of midbrain dopaminergic neurons could be related to ketamine modulated cortical-subcortical glutamate connections. Using western blotting, significant increases in BDNF protein levels were found in the midbrain, suggesting that perhaps BDNF pathways in the cortical-subcortical connections might contribute to the long-term ketamine induced TH upregulation. These data suggest that long-term ketamine abuse caused a delayed and persistent upregulation of subcortical DA systems, which may contribute to the altered mental status in ketamine abusers.

This study was undertaken to elucidate whether (1) administration of testosterone to female rats attenuates axotomy-induced neuronal loss; (2) the efficacy of testosterone treatment is related to the age of animals, the dosage given, and the time and duration of the treatment; (3) neurons which project or terminate aberrantly can survive; and (4) the trophic actions of testosterone on neuronal survival and axonal outgrowth are operated under the same mechanisms. The hypoglossal and facial nerves were transected unilaterally at 3 and 6 weeks of age. In order to establish the dose-response curve, testosterone propionate (TP) at doses of 0.5, 1.0, 2.0, or 5.0 mg was injected subcutaneously twice weekly during the first 4 postaxotomy weeks, and once weekly thereafter for an additional 6 weeks. Neuronal numbers in the hypoglossal and facial motor nuclei were counted 10-12 weeks after axotomy in serial paraffin sections stained with cresyl violet. To determine the time course of TP effect, neuronal numbers were counted at 1, 4, 12, and 20 weeks after axotomy. In addition, neuronal loss 12 weeks after axotomy in rats treated with TP for the first 3 postaxotomy weeks only was compared with that in rats withheld TP treatment until the 5th postaxotomy week. To determine axonal projections and terminations of the surviving neurons, HRP retrograde tracing technique was used. Results indicated that TP treatment significantly attenuated neuronal loss in prepubertal and young adult female rats in a dose- and time-dependent manner. Only doses which elevated serum testosterone to levels comparable to or surpassing normal male levels were effective.(ABSTRACT TRUNCATED AT 250 WORDS)

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