Perinatal exposure to methadone affects central cholinergic activity in the weanling rat

doi:10.1016/0376-8716(96)01238-0

Drug and Alcohol Dependence

Volume 41, Issue 2, June 1996, Pages 119-126

https://doi.org/10.1016/0376-8716(96)01238-0 Get rights and content

Abstract

Pregnant rats were implanted with osmotic minipumps containing either methadone hydrochloride (initial dose, 9 mg/kg/day) or sterile water. Their offspring were cross-fostered so that they were exposed to methadone prenatally and/or postnatally. Perinatal methadone exposure disrupted cholinergic activity on postnatal day 21 as measured by the turnover rate of acetylcholine (TR_ACh) in both female and male rats, although there were some sexually-dimorphic responses. The most profoundly affected brain region was the striatum, where prenatal exposure to methadone increased ACh turnover, whether or not the rats continued to be exposed to methadone postnatally. It appears unlikely that neonatal withdrawal contributes to brain regional changes in ACh turnover, as continued postnatal exposure to methadone did not prevent the prenatal methadone induced changes.

References (29)

D.L. Cheney et al.
Effects of acute and chronic morphine on regional rat brain acetylcholine turnover rate
Life Sci.
(1974)
J.T. Coyle et al.
Neurochemical aspects of the ontogenesis of cholinergic neurons in the rat brain
Brain Res.
(1976)
D.D. Davis et al.
Neurobehavioral functioning in children exposed to narcotics in utero
Addict. Behav.
(1988)
E.K. Enters et al.
The effect of prenatal methadone exposure on development and nociception during the early postnatal period of the rat
Neurotoxicol. Teratol.
(1991)
H. Guo et al.
The effect of prenatal exposure to methadone on neurotransmitters in neonatal rats
Dev. Brain Res.
(1990)
I. Izquierdo
Acetylcholine release is modulated by different opioid receptor types in different brain regions and species
Trends Pharmacol. Sci.
(1990)
P.A. Lapchak et al.
Regulation of endogenous acetylcholine release from mammalian brain slices by opiate receptors: hippocampus, striatum and cerebral cortex of guinea-pig and rat
Neuroscience
(1989)
O.H. Lowry et al.
Protein measurement with the Folin phenol reagent
J. Biol. Chem.
(1951)
E.G. McGeer et al.
Differential development of caudate enzymes in the neonatal rat
Brain Res.
(1971)
F. Moroni et al.
Modulation of ACh turnover rate in the septal-hippocampal pathway by electrical stimulation and lesioning
Brain Res.
(1978)

S.E. Robinson et al.

Prenatal exposure to methadone affects central cholinergic neuronal activity in the weanling rat

Dev. Brain Res.

(1991)

S.E. Robinson et al.

Prenatal exposure to methadone delays the development of striatal cholinergic neurons

Dev. Brain Res.

(1993)

T.A. Slotkin

Perinatal exposure to methadone: how do early biochemical alterations cause neurofunctional disturbances?

A. Tempel et al.

Morphine- induced downregulation of mu-opioid receptors in neonatal rat brain

Brain Res.

(1988)

Cited by (20)

Trans-generational effects of parental exposure to drugs of abuse on offspring memory functions
2024, Neuroscience and Biobehavioral Reviews
Recent evidence reported that parental-derived phenotypes can be passed on to the next generations. Within the inheritance of epigenetic characteristics allowing the transmission of information related to the ancestral environment to the offspring, the specific case of the trans-generational effects of parental drug addiction has been extensively studied. Drug addiction is a chronic disorder resulting from complex interactions among environmental, genetic, and drug-related factors. Repeated exposures to drugs induce epigenetic changes in the reward circuitry that in turn mediate enduring changes in brain function. Addictive drugs can exert their effects trans-generally and influence the offspring of addicted parents. Although there is growing evidence that shows a wide range of behavioral, physiological, and molecular phenotypes in inter-, multi-, and trans-generational studies, transmitted phenotypes often vary widely even within similar protocols. Given the breadth of literature findings, in the present review, we restricted our investigation to learning and memory performances, as examples of the offspring’s complex behavioral outcomes following parental exposure to drugs of abuse, including morphine, cocaine, cannabinoids, nicotine, heroin, and alcohol.
Endogenous and exogenous opioid effects on oligodendrocyte biology and developmental brain myelination
2021, Neurotoxicology and Teratology
Citation Excerpt :
Developing oligodendrocytes express neurotransmitter receptors and are responsive to different neurotransmitter signals (Sato-Bigbee et al., 1999; Yuan et al., 1998), therefore opioid addiction treatments could affect cell maturation and myelination through the disruption of oligodendroglial-neuronal signaling. Pioneer studies demonstrated that perinatal exposure to methadone delays the expression of the cholinergic phenotype in the striatum (Guo et al., 1990; Robinson et al., 1993; Robinson et al., 1996a; Robinson et al., 1996b), reducing striatal acetylcholine (Ach) levels in neonatal rats regardless of whether or not drug exposure continues into the early postnatal period (Robinson et al., 1996b). Perinatal methadone exposure also alters the function of dopaminergic, noradrenergic and serotonergic neurons in the neonatal and early postnatal period with some of these changes even persisting into adulthood (Rech et al., 1980).
The elevated presence of opioid receptors and their ligands throughout the developing brain points to the existence of maturational functions of the endogenous opioid system that still remain poorly understood. The alarmingly increasing rates of opioid use and abuse underscore the urgent need for clear identification of those functions and the cellular bases and molecular mechanisms underlying their physiological roles under normal and pathological conditions. This review is focused on current knowledge on the direct and indirect regulatory roles that opioids may have on oligodendrocyte development and their generation of myelin, a complex insulating membrane that not only facilitates rapid impulse conduction but also participates in mechanisms of brain plasticity and adaptation. Information is examined in relation to the importance of endogenous opioid function, as well as direct and indirect effects of opioid analogues, which like methadone and buprenorphine are used in medication-assisted therapies for opioid addiction during pregnancy and pharmacotherapy in neonatal abstinence syndrome. Potential opioid effects are also discussed regarding late myelination of the brain prefrontal cortex in adolescents and young adults. Such knowledge is fundamental for the design of safer pharmacological interventions for opioid abuse, minimizing deleterious effects in the developing nervous system.
The cellular basis of fetal endoplasmic reticulum stress and oxidative stress in drug-induced neurodevelopmental deficits
2019, Neurobiology of Stress
Citation Excerpt :
In humans, prenatal opioid exposure can lead to various adverse health problems in infants, longer hospital stays, and a higher rate of admission to intensive care units (Kivisto et al., 2015; Tolia et al., 2018). In animal models, prenatal exposure to opioid is associated with abnormal CNS function including dysregulated cholinergic activity, delayed neural tube defects, decreased myelination, impaired memory performance, impaired fear memory extinction and hippocampal CA1 synaptic plasticity, enhanced activity of blood-brain barrier transport system of opiate peptides, delayed development of monoamine oxidase isoforms, decreased brain volume, and altered neurochemistry (Banks et al., 1996; Nasiraei-Moghadam et al., 2005; Robinson et al., 1996; Sanchez et al., 2008; Tan et al., 2015; Tsang et al., 1986; Zagon and McLaughlin, 1977). Human neuroimaging studies examining early cerebral connective tract development showed that methadone-exposed infants demonstrated higher mean diffusivity in the superior longitudinal fasciculus regionally (Walhovd et al., 2012) and reduced fractional anisotropy and altered microstructure in major white matter tracts (Monnelly et al., 2018).
Prenatal substance exposure is a growing public health concern worldwide. Although the opioid crisis remains one of the most prevalent addiction problems in our society, abuse of cocaine, methamphetamines, and other illicit drugs, particularly amongst pregnant women, are nonetheless significant and widespread. Evidence demonstrates prenatal drug exposure can affect fetal brain development and thus can have long-lasting impact on neurobehavioral and cognitive performance later in life. In this review, we highlight research examining the most prevalent drugs of abuse and their effects on brain development with a focus on endoplasmic reticulum stress and oxidative stress signaling pathways. A thorough exploration of drug-induced cellular stress mechanisms during prenatal brain development may provide insight into therapeutic interventions to combat effects of prenatal drug exposure.
Modeling prenatal opioid exposure in animals: Current findings and future directions
2018, Frontiers in Neuroendocrinology
The past decade has seen a drastic rise in the number of infants exposed to opioids in utero. It is unclear what lasting effect this exposure may have on these children. Animal models of prenatal opioid exposure may provide insight into potential areas of vulnerability. The present review summarizes the findings across animal models of prenatal opioid exposure, including exposure to morphine, methadone, buprenorphine, and oxycodone. Details regarding the drug, doses, and duration of treatment, as well as key findings, are summarized in tables with associated references. Finally, significant gaps in the current preclinical literature and future directions are discussed.
Oligodendrocyte Responses, Myelination, and Opioid Addiction Treatments
2016, Neuropathology of Drug Addictions and Substance Misuse Volume 3: General Processes and Mechanisms, Prescription Medications, Caffeine and Areca, Polydrug Misuse, Emerging Addictions and Non-Drug Addictions
Buprenorphine and methadone are effectively used for the management of pregnant opioid-dependent addicts. However, little is known regarding potential effects of these long-lasting opioids on brain maturation. This chapter is focused on understanding the consequences of perinatal exposure to these drugs on developmental myelination. Recent findings indicated that perinatal exposure to therapeutic doses of either methadone or buprenorphine alter the timing and extent of myelin deposition in the developing rat brain. Parallel in vitro studies demonstrated that methadone and buprenorphine indeed exert drug and dose-specific direct effects on cells of the oligodendroglial lineage, altering their schedule of differentiation into mature oligodendrocytes capable of myelin formation. These findings support the idea of a crucial function of the endogenous opioid system in controlling the timing of oligodendrocyte maturation. Interfering with these regulatory systems by opioid use or opioid maintenance treatments could disrupt the normal process of myelin formation at critical stages of myelination and plasticity, in both the developing infant and adolescent brain.
Effects of perinatal buprenorphine and methadone exposures on striatal cholinergic ontogeny
2002, Neurotoxicology and Teratology
The effects of exposure to various doses of buprenorphine, methadone or water during the perinatal period were studied on striatal cholinergic development in the rat. Rats were exposed to buprenorphine (0.3 or 3.0 mg/kg/day), methadone (9 mg/kg/day) and/or water prenatally, postnatally or both pre- and postnatally via maternally implanted osmotic minipumps. The effects of buprenorphine varied with the dose used. There were some similarities between the effects of perinatal buprenorphine and perinatal methadone, such as a reduction in striatal acetylcholine (ACh) content in 4-day-old pups exposed prenatally to methadone or buprenorphine (0.3 mg/kg/day). However, differences were also observed between the effects of the two drugs. Unlike methadone, the 0.3-mg/kg/day dose of buprenorphine produced a sex-related increase in striatal ACh in male postnatal day (PND) 21 pups. The 3-mg/kg/day dose of buprenorphine produced a completely different range of results, such as decreased striatal ACh content in 4-day-old pups exposed to the drug postnatally and in 21-day-old pups exposed both pre- and postnatally. Differences in the effects of the two drugs may be related to the different affinities and efficacies of the drugs at different opioid receptor subtypes.

View all citing articles on Scopus

¹: Present address: Division of Intramural Research, NIDA, Baltimore, MD 21224.

View full text

Perinatal exposure to methadone affects central cholinergic activity in the weanling rat

Abstract

Life Sci.

Brain Res.

Addict. Behav.

Neurotoxicol. Teratol.

Dev. Brain Res.

Trends Pharmacol. Sci.

Neuroscience

J. Biol. Chem.

Brain Res.

Brain Res.

Dev. Brain Res.

Dev. Brain Res.

Brain Res.