Alterations in the development of catecholamine turnover induced by perinatal methadone: Differences in central vs. peripheral sympathetic nervous systems

doi:10.1016/0024-3205(81)90707-4

Life Sciences

Volume 29, Issue 24, 14 December 1981, Pages 2519-2525

https://doi.org/10.1016/0024-3205(81)90707-4 Get rights and content

Abstract

Administration of methadone to pregnant and nursing rats slows synaptogenesis of central cathcholaminergic systems in the offspring but accelerates the onset of synaptic function in peripheral sympathetic pathways. Norepinephrine turnover, assessed by inhibiting catecholamine biosynthesis with alpha-methyl-p-tyrosine, was elevated in cardiac sympathetic nerve terminals in rats exposed perinatally to methadone. In contrast, turnover was unchanged in noradrenergic and dopaminergic systems in the brain. Similar results were obtained when methadone was given directly to the pups during postnatal life. These data suggest that opiate-induced alterations of impulse flow and transmitter turnover in a given neuron population may determine whether the effects of perinatal methadone exposure result in facilitation or inhibition of synaptic development.

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Cited by (9)

Heroin neuroteratogenicity: Delayed-onset deficits in catecholaminergic synaptic activity
2003, Brain Research
Citation Excerpt :
Our results also provide an interesting comparison with previous work on the effects of prenatal methadone exposure. Unlike heroin, methadone does not produce lasting alterations in norepinephrine or dopamine turnover [18], despite the fact that it elicits shortfalls in indices of presynaptic terminals of monoamine systems [19]. This again emphasizes the importance of effects on synaptic function as opposed to synaptic integrity as a predominating feature of heroin-induced neuroteratogenicity.
Prenatal heroin exposure evokes neurochemical and behavioral deficits that, in part, reflect disruption of septohippocampal cholinergic function. In earlier studies, we found that cholinergic synaptic defects involve primary changes in cell signaling proteins that are shared by other transmitter systems. In the current study, we determined whether heroin also targets noradrenergic and dopaminergic inputs that operate through the same signaling cascades. Mice exposed to prenatal heroin showed significant deficits in norepinephrine and dopamine levels and much more pronounced effects on neurotransmitter turnover, an index of synaptic activity. Adverse effects were not present in the immediate postnatal period but rather emerged just before weaning and worsened subsequently. By young adulthood, the most highly-affected regions (hippocampus, cerebral cortex) displayed almost complete inactivation of noradrenergic and dopaminergic tonic activity. These effects arise after prior deficits in cell signaling are discernible, suggesting that the presynaptic effects are secondary to actions on signal transduction cascades shared by numerous neurotransmitter inputs and targeted by other neuroteratogens. These results may explain why apparently unrelated developmental neurotoxicants may ultimately produce a common set of neurochemical and behavioral anomalies.
Maternal cocaine addiction and fetal behavioral state. I: A human model for the study of Sudden Infant Death Syndrome
1990, Medical Hypotheses
Abnormalities of respiratory regulation, such as apnea and abnormal hypoxic arousal during sleep, are mechanistic in the pathophysiology of SIDS. In utero cocaine exposure is associated with poor head growth, abnormal neurodevelopment, and an increased incidence of sudden, unexplained death, suggesting that in utero cocaine exposure disrupts the central regulation of breathing. It is likely that this disruption is due to altered CNS maturation. Indeed, cocaine alters norepinephrine metabolism within the locus coeruleus, important in arousal from sleep, suggesting that the increased incidence of SIDS in cocaine exposed infants may be secondary to sleep-related deficits in arousal. Since components of fetal behavioural state organization reflect the successful integration of the Central Nervous System, have a specific developmental timetable, and can be studied by fetal ultrasound techniques, we developed a strategy for assessing the state organization of the fetus by ultrasound techniques. We hypothesize that fetal evaluation of state will be a marker of abnormal CNS maturation and a predictor of risk, i.e. abnormal neurodevelopent and/or state related arousal deficits predisposing the cocaine exposed neonate to SIDS. We propose that the study of in utero cocaine exposed fetuses will provide a human model for examining the pathophysiology of SIDS.
In utero cocaine exposure: Observations of fetal behavioral state may predict neonatal outcome
1989, American Journal of Obstetrics and Gynecology
Components of fetal behavioral state organization reflect the successful integration of the central nervous system, have a specific developmental timetable, and can be studied with fetal ultrasonographic techniques. To test the hypothesis that evaluation of state organization is a marker of abnormal central nervous system maturation and a predictor of risk, we studied 20 fetuses and newborns exposed to cocaine in utero. Fetal assessments were accomplished by serial ultrasonographic examination, videotaped, and scored by a scheme developed by the authors to assess organization and regulation of behavioral states. Newborn neurobehavioral assessments also emphasized organization and regulation of behavioral state. Abnormal or delayed state behavior was identified in 13 of 20 fetuses. State organization was evaluated as suspect or abnormal for 16 of the 20 exposed newborns. Disorganized behavioral state in the fetus successfully predicted abnormal newborn behavior. These findings support the concepts that cocaine exposure disrupts central nervous system development and that fetal assessment of state is predictive of neonatal outcome.
Perinatal exposure to methadone: How do early biochemical alterations cause neurofunctional disturbances?
1988, Progress in Brain Research
This chapter summarizes the progress made toward identifying the sequence of events occurring in the perinatal opiate syndrome. Development of function of a noradrenergic synapse requires a coordinated maturation of nerve terminals, their ability to synthesize, store and release transmitter, and post-synaptic ontogeny of receptors and appropriate linkages of the receptors to cellular processes (adenylate cyclase, phosphoinositide turnover, ion channels). In the rat, the majority of these events occur postnatally synthesis. The final stage of presynaptic development appears to be the arrival in the nerve terminals of synaptic vesicles, which are necessary to convert dopamine to norepinephrine, to store the norepinephrine and to release it into the synapse upon appropriate stimulation. Catecholaminergic synapses, because of their ubiquity in both the central and the peripheral nervous system, have provided some of the most useful information concerning mechanisms of neurobehavioral teratology. Vesicle maturation can be evaluated through measurements of uptake of norepinephrine into isolated vesicle preparations and is a process separable from synaptosomal uptake.
Role of ornithine decarboxylase and the polyamines in nervous system development: Short-term postnatal administration of α-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase
1983, International Journal of Developmental Neuroscience
The role of ornithine decarboxylase (ODC) and the polyamines in development of central and peripheral catecholaminergic neurons was examined through the use of α-difluoromethylornithine (DFMO), a specific irreversible inhibitor of ODC. Short-term postnatal administration of DFMO (500 mg/kg daily on days 1–6) to neonatal rats resulted in effective inhibition of ODC and depletion of both putrescine and spermidine in brain, heart and kidney; after cessation of DFMO administration, polyamine levels returned to normal by 10–13 days of age. There were no signs of generalized toxicity of short-term DFMO treatment, as body weight gains were largely unaffected over the course of study (through weaning). However, development of peripheral sympathetic neurons was severely retarded by DFMO, with persistent and profound deficits of both cardiac and renal norepinephrine; the catecholamine deficiencies were unrelated to effects on end-organ growth, as cardiac weights were essentially normal whereas kidney weights were adversely affected by DFMO. Development of the adrenal medulla, a peripheral catecholaminergic tissue which displays approximately the same developmental profile as do sympathetic neurons but which does not develop axonal projections, was not slowed by DFMO treatment; similarly, central noradrenergic and dopaminergic neurons, which undergo the majority of axonal outgrowth and synaptogenesis during the second to third postnatal week (just after the period in which polyamines returned to control levels), developed normally as assessed by measurements of transmitter levels, tyrosine hydroxylase activity and synaptosomal uptake of [³H]norepinephrine or [³H]dopamine. Extension of the period of DFMO treatment and consequent depletion of polyamines into the period in which central synaptogenesis occurs does, however, produce slowing of development of brain catecholamine neuronal projections. Thus, the ODC/polyamine system appears to play a critical postnatal role in catecholamine systems specifically undergoing active synaptogenesis.
Norepinephrine content of the rat kidney during development: Alterations induced by perinatal methadone
1982, Life Sciences
The concentration and the total content of norepinephrine (NE) in the kidney were measured in Sprague-Dawley rats from 3 to 120 days after birth. Renal NE concentration was relatively low until the end of the second week, when it rose abruptly to adult levels; total NE content per kidney increased steadily throughout development. The effects of perinatal methadone treatment on renal NE development were examined by administering the drug either directly to the pups from 1 to 19 days after birth, or to the mother from 10 days of gestation to 20 days after birth. Both treatments resulted in significant deficits of body weight and kidney weight. Maternal methadone caused a significant deficit in renal NE which was most pronounced at two weeks of postnatal age; direct methadone had less effect on renal NE. These results suggest that renal sympathetic neurotransmission may become mature two weeks after birth and indicate further that maternal methadone interfares with this maturation.

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Alterations in the development of catecholamine turnover induced by perinatal methadone: Differences in central vs. peripheral sympathetic nervous systems

Abstract

Biochem. Pharmacol.

Neuropharmacol.

Devl. Neuroscience

J. Pharmacol. Exp. Ther.

Life Sci.

Life Sci.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

Life Sci.

J. Pharmacol. Exp. Ther.