Development of serotonergic and adrenergic receptors in the rat spinal cord: effects of neonatal chemical lesions and hyperthyroidism.

The sympathetic preganglionic neurons in the spinal cord receive dense serotonergic (5-HT) and catecholaminergic (CA) afferent inputs from the descending supraspinal pathways. In the rat spinal cord, the levels of these biogenic amines and their receptors are low at birth, but undergo rapid ontogenetic increases in the ensuing 2-3 postnatal weeks until the adult levels are reached. In many systems it has been shown that denervation of presynaptic neurons leads to an up-regulation of the number of postsynaptic receptors. To determine whether the 5-HT and CA receptors in the developing spinal cord are also subject to such transsynaptic regulation, we examined the ontogeny of serotonergic receptors and alpha- and beta-adrenergic receptors in thoracolumbar spinal cord of rats given neurotoxins which destroy serotonergic (5,7-dihydroxytryptamine (5,7-DHT)) or noradrenergic (6-hydroxydopamine (6-OHDA)) nerve terminals. Intracisternal administration of 5,7-DHT or 6-OHDA at 1 and 6 days of age prevented, respectively, the development of 5-HT and CA levels in the spinal cord. Rats lesioned with 5,7-DHT displayed a marked elevation of 5-HT receptors with a binding of 50% greater than controls at 1 week and a continuing increase to twice normal by 4 weeks. A similar pattern of up-regulation was also detected with the alpha-adrenergic receptor, as rats lesioned with 6-OHDA exhibited persistent increases in receptor concentration. However, in these same animals ontogeny of the beta-adrenergic receptor in the spinal cord remained virtually unaffected by the chemical lesion. In several other parts of the nervous system, it has been demonstrated that the beta-adrenergic sensitivity can be modulated by hormonal signals, particularly that of the thyroid hormones. This phenomenon was examined in the spinal cord and in confirmation with previous studies neonatal treatment of triiodothyronine (0.1 mg/kg, s.c. daily) was capable of evoking persistent increases in beta-adrenergic receptor binding. These results suggest that: (a) development of the postjunctional serotonergic and alpha-adrenergic receptors in the rat spinal cord can occur in the absence of the prejunctional nerve terminals and are subject to transsynaptic modulation; (b) beta-adrenergic receptors in the spinal cord also can develop after prejunctional lesions but are regulated by hormonal rather than neuronal factors.

Development of beta-adrenergic receptors and the in vitro accumulation of cyclic AMP in the chick spinal cord.

To clarify the functional development of the descending monoaminergic input to the chick spinal cord we have studied the ontogeny of beta-adrenergic receptors by measuring the specific binding the tritiated dihydroalprenolol (DHA). In addition, we examined the ability of isoproterenol to stimulate the accumulation of cyclic AMP in slices of developing chick spinal cord. Results show that the chick spinal cord contains a high density of beta-adrenergic receptors that are apparently linked to adenylate cyclase. During development, both the density of beta-receptors, as determined by the specific binding of DHA, and the response of tissue slices to isoproterenol underwent marked changes. beta-Adrenergic receptors (approximately 4 fmol/mg tissue) were first detected on the fourteenth day in ovo. Receptor density increased to approximately 20 fmol/mg by day 20. Between day 20 and the time of hatching, a sharp increase in receptor density, to approximately 50 fmol/mg, was seen. The density of receptors remained high until the second day after hatching, fell off to approximately 30 fmol/mg by the fourth day, and remained relatively unchanged through day 30. The response of spinal cord slices to isoproterenol showed a similar pattern of development with the peak response (7-fold increase in levels of cyclic AMP) occurring at or near the time of hatching. During the period between day 18 in ovo and the time of hatching, when both the response of tissue slices to isoproterenol and the density of beta-receptors increased markedly, the activity of phosphodiesterase did not change. Therefore, the pronounced changes in adrenergic responsiveness that occurred near the time of hatching appear to be related primarily to changes in the density of beta-adrenergic receptors coupled to adenylate cyclase. Such developmental changes in the density of beta-adrenergic receptors and adrenergic responsiveness may play an important role in determining the functional state of the descending monoaminergic systems in the chick spinal cord.

Central adrenergic receptor changes in the inherited noradrenergic hyperinnervated mutant mouse tottering.

Adrenergic receptor binding characteristics were analyzed in the mutant mouse tottering (tg/tg), a single gene locus autosomal recessive mutation causing hyperinnervation by locus coeruleus neurons of their target regions, which results in epilepsy. Instead of the expected down-regulation of receptors due to the hyperinnervation, both [3H]prazosin (alpha 1-receptor) and [125I]iodopindolol (beta-receptor) binding were normal in the tg/tg hippocampus, spinal cord and slightly increased in the cerebellum. This lack of postsynaptic receptor modulation in the target cells, combined with increased levels of norepinephrine due to the aberrant axon growth, may the critical factors in the expression of the abnormal spike-wave absence seizures in the tg/tg mouse.

Thyroid hormone control of preganglionic innervation of the adrenal medulla and chromaffin cell development in the rat. An ultrastructural, morphometric and biochemical evaluation.

In the rat, functional connections between the splanchnic nerve and the adrenal medulla are immature at birth and do not become fully competent until the first postnatal week. Neonatal administration of triiodothyronine (T3) accelerates this process, and the present study was undertaken to elucidate the underlying mechanisms. Rats were given T3 (0.1 mg/kg, s.c.) daily for 9 days beginning 1 day after birth. Preganglionic innervation of the adrenal medulla was examined by retrograde axonal transport of horseradish peroxidase (HRP). At 10 days of age, there was an increased number of labeled perikarya in the spinal cord of the hyperthyroid pups. Ultrastructural examination revealed a corresponding increase in synaptic density in the adrenal medulla and in the activity of choline acetyltransferase, a marker for preganglionic cholinergic nerve terminals. These effects were attenuated by 25 days of age, whereupon deficits in HRP-labeled neurons and adrenomedullary synapses were noted. Similarly, replication of chromaffin cells was enhanced transiently in the T3 group during the initial stage of hyperthyroidism, but subsequent long-lasting deficits in cell numbers were noted, along with a corresponding retardation of ontogeny of adrenal catecholamine biosynthesis and storage. Thus, neonatal hyperthyroidism accelerates synaptic development in the sympatho-adrenal axis but suppresses maturation of the target chromaffin cells, ultimately leading to impaired adrenomedullary function.