Alterations of postsynaptic density proteins in the hippocampus of rat offspring from the morphine‐addicted mother: Beneficial effect of dextromethorphan

Abstract

Infants passively exposed to morphine or heroin through their addicted mothers usually develop characteristic withdrawal syndrome of morphine after birth. In such early life, the central nervous system exhibits significant plasticity and can be altered by various prenatal influences, including prenatal morphine exposure. Here we studied the effects of prenatal morphine exposure on postsynaptic density protein 95 (PSD-95), an important cytoskeletal specialization involved in the anchoring of the NMDAR and neuronal nitric oxide synthase (nNOS), of the hippocampal CA1 subregion from young offspring at postnatal day 14 (P14). We also evaluated the therapeutic efficacy of dextromethorphan, a widely used antitussive drug with noncompetitive antagonistic effects on NMDARs, for such offspring. The results revealed that prenatal morphine exposure caused a maximal decrease in PSD-95 expression at P14 followed by an age-dependent improvement. In addition, prenatal morphine exposure reduced not only the expression of nNOS and the phosphorylation of cAMP responsive element-binding protein at serine 133 (CREB(Serine-133)), but also the magnitude of long-term depression (LTD) at P14. Subsequently, the morphine-treated offspring exhibited impaired performance in long-term learning and memory at later ages (P28-29). Prenatal coadministration of dextromethorphan with morphine during pregnancy and throughout lactation could significantly attenuate the adverse effects as described above. Collectively, the study demonstrates that maternal exposure to morphine decreases the magnitude of PSD-95, nNOS, the phosphorylation of CREB(Serine-133), and LTD expression in hippocampal CA1 subregion of young offspring (e.g., P14). Such alterations within the developing brain may play a role for subsequent neurological impairments (e.g., impaired performance of long-term learning and memory). The results raise a possibility that postsynaptic density proteins could serve an important role, at least in part, for the neurobiological pathogenesis in offspring from the morphine-addicted mother and provide tentative therapeutic strategy.

Carbohydrate Microarray

“…Strong Con A and SNA signals are shown in our binding assay, but the relative intensity of GlcNAc-binding lectins is not as good as those of Con A and SNA, which is the contribution of the interference by the terminal sialic acids [59]. All of the results are similar to the analyses from lectin microarray or dot blot analysis [55][56][57][58]. …”

“…Our results showed positive signals in the tests with the ECA, DBA, UEA-1 and WGA lectins, indicating that the mucin contains the determinants of Gal 1-4GlcNAc, GalNAc, Fuc 1-2Gal and GlcNAc/NeuAc, respectively. Man 1-3(Fuc 1-6)GlcNAc and NeuAc 2-6Gal 1-4GlcNAc containing biantennary or triantennary N-glycans have been reported as the major glyco-structures of human transferrin [55][56][57][58]. Strong Con A and SNA signals are shown in our binding assay, but the relative intensity of GlcNAc-binding lectins is not as good as those of Con A and SNA, which is the contribution of the interference by the terminal sialic acids [59].…”

Transgenerational modification of hippocampus TNF-α and S100B levels in the offspring of rats chronically exposed to morphine during adolescence

“…The hippocampus is an important part of the brain, especially for learning and memory (8). Due to the presence and distribution of opioid receptors in the hippocampus, chronic exposure to opiates has been reported to produce modifications in neural assignments, synaptic transmission, and behavioral tasks of the hippocampus (9)(10)(11). Despite these effects, no evidence exists to show that opiate consumption causes DNA alteration; however, recent studies have shown that chronic exposure to opiates affects chromatin-related proteins and therefore induces modifications in gene expression patterns.…”

“…Because chronic morphine consumption has shown epigenetic effects and causes durable abnormal activities in the hippocampus (9,16,31,32), epigenetic modifications are inheritable from parents to their offspring (12), and TNF-α and S100B are present in the hippocampus and involved in anomalous hippocampal functions (18,23). In the current research study, we investigate the consequences of chronic consumption of morphine by both male and female parents before mating and gestation on the hippocampus TNF-α and S100B levels of the parents themselves and their offspring.…”

Prenatal opiate exposure impairs radial arm maze performance and reduces levels of BDNF precursor following training

“…The rats were assessed while on morphine exposure or shortly after treatment ended. The detrimental effects of morphine could be attenuated by coadministration of dextromethorphan during pregnancy, suggesting that NMDA receptor changes were involved in the effect (Tao et al, 2001;Yang et al, 2006). The effects of prenatal heroin exposure on neural plasticity have also been noted.…”