A118G polymorphism of OPRM1 gene is associated with schizophrenia.

Schizophrenia is ranked among multifactor diseases in whose pathogenesis, besides environmental factors, an interplay of functional polymorphisms of a larger number of candidate genes is involved. Neurodevelopmental abnormities are among the most accepted hypotheses in the etiology of schizophrenia. Recently, the role of oligodendrocytes in the development of the cortex has been cited repeatedly. During their various phases of differentiation oligodendrocytes present on their surfaces diverse receptors, among others the mu-opioid receptor (OPRM1). The study was focused on the relationship between the functional A118G polymorphism of the OPRM1 gene (rs1799971) and schizophrenia in groups of 130 male patients and 452 male controls. An association study revealed yet unpublished statistically significant difference of allelic and genotypic frequencies between the control and patient groups. According to our present knowledge, we assume that the OPRM1 gene polymorphism can influence the myelination of CNS neurons through regulations of expression of OPRM1 receptors on surfaces of oligodendrocytes. The neuronal myelination seems to be one of the important factors in the pathogenesis of schizophrenia.

Different transfer of nociceptive sensitivity from rats with postnatal hippocampal lesions to control rats.

Hippocampal lesions in newborn rats alter the development of mechanisms involved in the processing of nociception. The hippocampal lesion was induced by the bilateral infusion, into the lateral cerebral ventricles, of 0.25 microL of saline containing either 0.25 micromol quinolinic acid (QUIN) and/or 0.25 micromol N-acetyl-L-aspartyl-L-glutamate (NAAG) on postnatal day 12. The same amount of sterile saline was injected into the sham-operated animals (group SHAM). It was expected that the QUIN- and NAAG-lesioned rats would exhibit some differences in thermal pain perception; however, we wanted to know if the control rats would exhibit, at least in part, similar changes in pain perception as their chemically lesioned siblings with which they were housed. Young adult NAAG-injured rats exhibited increased withdrawal latencies in the tail-flick and plantar tests, whereas young adult QUIN-injured animals exhibited only marginally decreased latencies. Nociceptive responses in the SHAM rats paralleled the littermates that had been neonatally treated with QUIN or NAAG, i.e. the responses in the SHAM(QUIN) group decreased, whereas the responses in the SHAM(NAAG) group increased. No significant changes in nociception were observed in intact animals, regardless of which group they were housed with. Our results show that social factors, which were originally demonstrated only for the pain behavior, may also influence basal nociceptive sensitivity in rats. We concluded that the "sham operation" may have had a long-term, nonspecific impact on nociceptive behavior by inducing behavioral mimicry of other animals.

Neonatal administration of N-acetyl-L-aspartyl-L-glutamate induces early neurodegeneration in hippocampus and alters behaviour in young adult rats.

N-acetyl-L-aspartyl-L-glutamate (NAAG) is a dipeptide that could be considered a sequestered form of L-glutamate. As much as 25% of L-glutamate in brain may be present in the form of NAAG. NAAG is also one of the most abundant neuroactive small molecules in the CNS: it is an agonist at Group II metabotropic glutamate receptors (mGluR II) and, at higher concentrations, at the N-methyl-D-aspartate (NMDA) type of ionotropic glutamate receptors. As such, NAAG can be either neuroprotective or neurotoxic and, in fact, both characteristics have been discussed and described in the literature. In the present studies, 250 nmol NAAG was infused into each lateral cerebral ventricle of 12-day-old rat pups and, using Nissl-stained sections, neurodegeneration in the hippocampus was evaluated 24 or 96 h after the infusion. In several experiments, the neuronal death was also visualised by Fluoro-Jade B staining and studied by TUNEL technique. Some of the NAAG-treated animals were allowed to survive until 50 days post partum and subjected to behavioural (open field) tests. The administration of NAAG to 12-day-old rats resulted in extensive death of neurons particularly in the dentate gyrus of the hippocampus. The neurodegeneration was, in part, prevented by administration of an NMDA receptor antagonist MK-801 (0.1 mg/kg). The nuclear DNA-fragmentation demonstrated by TUNEL technique pointed to the presence of non-specific single-strand DNA cleavage. The NAAG-associated neonatal neuronal damage may have perturbed development of synaptic circuitry during adolescence as indicated by an altered performance of the experimental animals in the open field testing (changes in grooming activity) at postnatal day 50. The results underscore the potential neurotoxicity of NAAG in neonatal rat brain and implicate neonatally induced, NMDA receptor-mediated neuronal loss in the development of abnormal behaviour in young adult rats.

Glutamatergic hypothesis of schizophrenia: involvement of Na+/K+-dependent glutamate transport.

Hypothetical model based on deficient glutamatergic neurotransmission caused by hyperactive glutamate transport in astrocytes surrounding excitatory synapses in the prefrontal cortex is examined in relation to the aetiology of schizophrenia. The model is consistent with actions of neuroleptics, such as clozapine, in animal experiments and it is strongly supported by recent findings of increased expression of glutamate transporter GLT in prefrontal cortex of patients with schizophrenia. It is proposed that mechanisms regulating glutamate transport be investigated as potential targets for novel classes of neuroactive compounds with neuroleptic characteristics. Development of new efficient techniques designed specifically for the purpose of studying rapid activity-dependent translocation of glutamate transporters and associated molecules such as Na+, K+-ATPase is essential and should be encouraged.

Quinolinic acid induces NMDA receptor-mediated lipid peroxidation in rat brain microvessels.

Quinolinic acid increased the generation of lipid peroxidation products by isolated rat brain microvessels in vitro. The effect was inhibited both by a specific NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid and by reduced glutathione (GSH). Furthermore, quinolinic acid displaced specific binding of [(3)H]-L-glutamate by cerebral microvessel membranes, particularly in the presence of NMDA receptor co-agonist (glycine) and modulator (spermidine). We conclude that quinolinic acid can cause potentially cytotoxic lipid peroxidation in brain microvessels via an NMDA receptor mediated mechanism.

N-Acetyl-L-aspartyl-L-glutamate changes functional and structural properties of rat blood-brain barrier.

Intracerebroventricular administration of N-acetyl-L-aspartyl-L-glutamate (NAAG), an agonist at group II metabotropic and NR1/NR2D-containing N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors, increased the permeability of the blood-brain barrier (BBB) to serum albumin in the striatum, but produced no similar effects in the entorhinal cortex or in the hippocampal formation. Electron microscopy showed that NAAG, but not its hydrolytic products L-glutamate and N-acetyl-L-aspartate, increased the number of transport vesicles in the hippocampal endothelial cells. Furthermore, immunocytochemistry detected NR2D subunits on hippocampal capillaries. Consequently, NAAG may have influenced the vesicular transport via NMDA receptors. There was, however, no correlation with the regional pattern of BBB changes (increased permeability in the striatum) that, in turn, could not be directly related to the NAAG-induced neurodegeneration described previously in the hippocampus where no significant changes in BBB permeability were detected.

Main subunits of ionotropic glutamate receptors are expressed in isolated rat brain microvessels.

Excitatory amino acids are known to modulate blood-brain barrier (BBB) permeability, however, the information on glutamate receptors in cerebral capillaries is inconsistent. In the present study, freshly isolated microvessels obtained from saline-perfused rat brains were used. Gene expression of the main N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor subunits NMDAR1 and GLUR1, respectively, were investigated by reverse transcription-polymerase chain reaction (RT-PCR). The results confirmed the presence of both NMDAR1 and GLUR1 mRNAs in microvessels of seven brain regions studied. Moreover, specific binding of [3H]glutamate to capillary membranes and its displacement by AMPA, NMDA and metabotropic, but not kainate receptor agonists were observed. These results suggest that rat brain capillaries and/or albuminally adhering astrocyte processes possess functional glutamate receptors. Thus, the effects of glutamate agonists and antagonists in modulation of BBB function might be mediated directly by cerebral microvessels.