dizocilpine-maleate and Birth-Injuries

Birth complications involving fetal hypoxia and stress at adulthood, which are risk factors for schizophrenia, can produce alterations in subcortical dopamine (DA) function in rat models. As adults, rats born either by cesarean section (C-section) or by C-section with added global anoxia show increased stress-induced DA release from nucleus accumbens and increased amphetamine-induced locomotion, compared to vaginally born controls. Moreover, stress at adulthood interacts with these birth insults to modulate DA receptor and transporter levels. Glutamatergic transmission at the level of the nucleus accumbens, prefrontal cortex, and hippocampus are known to modulate subcortical DA activity. Thus, altered excitatory amino acid (EAA) function might contribute to the dopaminergic changes observed in rats after birth insult and/or stress at adulthood. To test this possibility, rats born vaginally, by C-section, or by C-section with 15 min of anoxia, were either repeatedly stressed (15 min of tail pinch daily for 5 days) at adulthood or received no stress, and levels of EAA receptor binding were measured by ligand autoradiography in limbic brain regions. As adults, rats born by C-section showed increases in AMPA receptor binding in nucleus accumbens shell, NMDA receptor binding in cingulate cortex, and kainate receptor binding in the hippocampal CA1 region. Anoxic rats showed increases in CA1 kainate receptor and anterior olfactory NMDA receptor binding. Stress at adulthood increased AMPA receptor binding in several regions of prefrontal cortex and reduced NMDA receptor binding in infralimbic cortex and dentate gyrus, across all birth groups. Two instances of interactions between birth insult and stress at adulthood were observed. Stress reduced cingulate cortex NMDA receptor binding and increased olfactory tubercle kainate receptor binding only in C-sectioned animals, but not in controls. The possibility that the observed EAA receptor changes contribute to dopaminergic dysfunction in these animal models is discussed, in light of known glutamate-DA interactions.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Autoradiography; Binding Sites; Birth Injuries; Brain; Cesarean Section; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Hypoxia; Iodine Isotopes; Male; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Stress, Physiological; Tritium

Blocking of NMDA receptors during a critical stage of development reduces the effects of nerve injury at birth on muscles and motoneurones. Injury to the sciatic nerve at birth causes many motoneurones to soleus and extensor digitorum longus (EDL) muscles of rats to die. This is reflected in a reduction of motor units in these muscles. In the soleus only 4 (12.3%) motor units remain while 10 (24.3%) remain in the EDL, showing that soleus alpha motoneurones are more sensitive to nerve injury at birth. Treatment with MK-801, an NMDA receptor blocker, rescues a proportion of motor units in both muscles, so that in the soleus 11 (36%) and in the EDL 17 (42%) of motor units survive. This loss of motor units results in muscle weakness and a reduction in force of both muscles. Treatment with MK-801 reduces the effect of nerve injury, so that muscles of treated animals are stronger and weigh more. Cross-sectional area and muscle fibre number in EDL muscles were assessed and found to be dramatically reduced after nerve injury at birth, so that the area was 20% of control, with only 13% of fibres remaining. Moreover the majority of the remaining EDL muscle fibres which are normally fast are converted into slow type I fibres, with 68% of fibres expressing slow myosin compared with 3% in control EDL muscles. In animals treated with MK-801 only 47% of muscle fibres are lost after nerve injury at birth, hence the area of the muscle is greater (51% of control). The change of muscle phenotype induced by nerve injury is prevented and the muscle fibre composition resembles that of normal EDL muscles in that 4% of muscle fibres express slow myosin compared with 3.5% in control EDL muscles. Thus, blocking NMDA receptors with MK-801 shortly after nerve injury at birth reduces the loss of motor units and this is directly reflected in an improved performance of the affected muscles.

Topics: Animals; Animals, Newborn; Birth Injuries; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hindlimb; Immunohistochemistry; Motor Neurons; Muscle Contraction; Muscle Fibers, Skeletal; Muscle, Skeletal; Organ Size; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sciatic Nerve