Alterations of postsynaptic density proteins in the hippocampus of rat offspring from the morphine-addicted mother: Beneficial effect of dextromethorphan.
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.
Yang
San Nan
SN
Department of Pediatrics, Chang-Gung Memorial Hospital, Kaohsiung, Taiwan.
Liu
Chieh-An
CA
Chung
Mei-Yung
MY
Huang
Hsin-Chun
HC
Yeh
Geng-Chang
GC
Wong
Chih-Shung
CS
Lin
Wei-Wen
WW
Yang
Chun-Hua
CH
Tao
Pao-Luh
PL
D000818:Animals; D000831:Animals, Newborn; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D003915:Dextromethorphan / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects* / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism; D009020:Morphine / Q000009:adverse effects*; D009021:Morphine Dependence / Q000150:complications*; D009294:Narcotics / Q000009:adverse effects; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D018691:Excitatory Amino Acid Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009294:Narcotics; D016194:Receptors, N-Methyl-D-Aspartate; D003915:Dextromethorphan; D009020:Morphine; D052248:Nitric Oxide Synthase Type I