Sexually dimorphic development and binding characteristics of NMDA receptors in the brain of the platyfish.

This study investigated age- and gender-specific variations in properties of the glutamate N-methyl-d-aspartate receptor (NMDAR) in a freshwater teleost, the platyfish (Xiphophorus maculatus). Prior localization of the immunoreactive (ir)-R1 subunit of the NMDAR protein (R1) in cells of the nucleus olfactoretinalis (NOR), a primary gonadotropin-releasing hormone (GnRH)-containing brain nucleus in the platyfish, suggests that NMDAR, as in mammals, is involved in modulation of the platyfish brain-pituitary-gonad (BPG) axis. The current study shows that the number of cells in the NOR displaying ir-R1 is significantly increased in pubescent and mature female platyfish when compared to immature and senescent animals. In males, there is no significant change in ir-R1 expression in the NOR at any time in their lifespan. The affinity of the noncompetitive antagonist ((3)H)MK-801 for the NMDAR is significantly increased in pubescent females while maximum binding of ((3)H)MK-801 to the receptor reaches a significant maximum in mature females. In males, both MK-801 affinity and maximum binding remain unchanged throughout development. This is the first report of gender differences in the association of NMDA receptors with neuroendocrine brain areas during development. It is also the first report to suggest NMDA receptor involvement in the development of the BPG axis in a nonmammalian vertebrate.

Cocaine adversely affects development of cortical embryonic neurons in vitro: immunocytochemical study of calcium-binding proteins.

Neurons of cerebral cortex from 15-16 day old embryos of white rats (Sprague-Dawley) were cultured in MEM enriched with 5% horse serum. On the 7th day after plating the cultures were divided into three experimental and one control groups (6-8 Petri dishes in each group). In group 1, cultures were grown without additives. In group 2, cocaine chloride was added at concentrations 0.3, 0.6 and 1 mg/ml of culture. In group 3, a monoclonal antibody against calcium-binding proteins, parvalbumin (APV) or calbindin (ACB) was added at a concentration 25 microl/ml. In group 4, a combination of cocaine +APV was added at a concentration 1 mg+25 microl/ml of culture media. On the 10th day cultures were immunostained using APV and ACB antibodies. In developing GABAergic neurons of group 2 cocaine produced cytotoxic effects that were expressed in drastic decrease in number of neurons and in degeneration of their processes. The lower concentrations of cocaine caused milder cytotoxity and their effects were reversible. The highest concentration of cocaine caused irreversible degeneration of neurons. Similar cytotoxity was caused by APV or ACB in group 3. The most severe cytotoxic effects were seen in group 4, where a mixture of cocaine and APV was used. Overall, it can be concluded that cocaine in higher concentrations directly affects development of GABAergic neurons in vitro.

Antipsychotic drug effects on glutamatergic activity.

Previous work from this laboratory indicated that some antipsychotic drugs possess unique action at N-methyl-D-aspartate (NMDA) receptors. A functional neurochemical assay showed that, at concentrations similar to those found in the cerebrospinal fluid (CSF) of schizophrenics, antipsychotic drugs augment NMDA activity while, at higher concentrations, NMDA activity is suppressed. Using similar analysis, the present paper reports that this pattern of response is also shown by the antipsychotic drugs thioridazine and chlorpromazine. In contrast, promazine, which is structurally similar to chlorpromazine but lacking both D2-effects and antipsychotic potency, had no influence on NMDA receptors. In addition, sulpiride and metoclopramide, drugs with high affinity for D2-dopamine receptors but with weak or no antipsychotic efficacy, also lack effects at the NMDA receptor. Thus, the drugs with clinical efficacy that were tested in the present and previous studies all share unique influence on NMDA receptors. Further work with other antipsychotic agents will be necessary to determine if influence on NMDA receptors contributes to antipsychotic effectiveness.

Glutamate agonist activity: implications for antipsychotic drug action and schizophrenia.

Antagonist action at dopamine D2 receptors appears to explain many, but not all of the effects of antipsychotic drugs. Because of the interactions of dopamine with glutamate, and the implication of the latter in the etiology of schizophrenia, possible effects of antipsychotic drugs on glutamate receptors were assessed in the present experiments. These studies showed that, at clinically relevant concentrations, the conventional neuroleptic haloperidol and the atypical antipsychotic clozapine had potent augmenting influences on the NMDA receptor. These data suggest that unique action at glutamate receptors may contribute to antipsychotic efficacy and emphasize the potential importance of glutamatergic dysfunction in the etiology of schizophrenia.

Taurine prevents haloperidol-induced changes in striatal neurochemistry and behavior.

Repeated daily administration of haloperidol produces changes in striatal neurochemistry (decreased dopamine synthesis, upregulation of D2 receptors) and behavior (increasing catalepsy). Coadministration of taurine greatly attenuated these neuroleptic-induced changes. Possible mechanisms of taurine's mitigating effects are its attenuating influences on glutamatergic transmission and its actions as a GABAA agonist. The possibility was discussed of adding taurine to chronic antipsychotic regimens to block the side-effects typically accompanying such therapy.

Anti-glutamatergic effects of clozapine.

Clozapine (Cz) is unique in its efficacy with treatment refractory patients and its freedom from motor side effects. The present work shows that Cz, even after dopamine depletion, suppresses responses evoked via the monosynaptic glutamatergic corticostriatal pathway. In addition, Cz is effective in displacing [3H]MK-801 from striatal homogenates. These data indicate that Cz is a glutamate antagonist. It is unclear, however, if this pharmacological action could explain Cz's lack of motor effects and it's antipsychotic potency.