Modes of direct modulation by taurine of the glutamate NMDA receptor in rat cortex.

Taurine is an endogenous brain substance with robust neuromodulatory and possible neuroprotective properties. Though other mechanisms of action have been reported, its interaction with the NMDA (N-methyl-D-aspartic acid) receptor is undocumented. We investigated taurine's interaction with the NMDA receptor using electrophysiological and receptor binding approaches. The effects of taurine on field potential responses in layer-5 of prelimbic cortex in rat brain slices evoked by single-pulse electrical stimulation of ventral medial cortex were determined. Picrotoxin (80 µM) was present in all control and drug solutions to block the Cl(-) channels associated with the GABA-, taurine-, and strychnine sensitive glycine- receptors. A typical response consisted of an NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo-[f]-quinoxaline-7-sulfonamide)-sensitive negative wave (N1) followed by a positive wave (P1) and a broad negativity (N2), both sensitive to dl-AP5 (dl-2-amino-5-phosphonopentanoic acid) inhibition. Taurine exerted a 41.5 ± 8.3% (n = 9) voltage reduction within the late phase of N2. This taurine action was prevented by 100 µM AP5, but not by 10 µM nifedipine, supporting a direct modulation of NMDA receptor function by taurine, without requiring the involvement of the L-type Ca(2+) channel. Taurine did not alter specific [(3)H] MK-801 binding to rat cortical membranes in the presence of glycine or glutamate; but inhibited spermine-potentiated specific [(3)H] MK-801 binding to NMDA receptors by 15-20% in the presence of glycine. In addition, taurine reduced the apparent affinity of the NMDA receptor for glycine (in the presence of spermine) by 10-fold. These results show that taurine interacts directly with the NMDA receptor by multiple mechanisms.

Neuropsychopharmacological actions of taurine.

Taurine, an endogenous amino sulfonic acid, exhibits numerous neuropsychopharmacological activities. Previous studies in our laboratory have shown that it is an effective anti-cataleptic and neuro-protective agent. Current investigations show that acute or chronic administration of psychotropic drug cocaine may increase extracellular release of endogenous taurine which may protect against deleterious effects of the substances of abuse. Taurine administration was found to prevent cocaine-induced addiction by suppressing spontaneous locomotor activity and conditioned place preference. Taurine markedly delayed tail-flick response in rats which was significantly different from that in the group of animal receiving the same volume of saline, thereby indicating that taurine is a potentially valuable analgesic agent. Both taurine and endomorphin-1 were found to suppress the delayed broad negative evoked field potentials in anterior insular cortex (upper layer 5) by partially inhibiting NMDA receptor system. Thus, taurine is a unique psychopharmacological compound with potential for a variety of therapeutic uses including as a neuro-protective, anti-cataleptic, anti-addicting, and analgesic agent.

Direct interaction of taurine with the NMDA glutamate receptor subtype via multiple mechanisms.

Taurine has neuroprotective capabilities against glutamate-induced excitotoxicity through several identified mechanisms including opening of the Cl(-)channel associated with GABA(A)and glycine receptors, or a distinct Cl(-)channel. No existing work has however shown a direct interaction of taurine with the glutamate NMDA receptor. Here we demonstrate such direct interactions using electrophysiological and receptor binding techniques on rat medial prefrontal cortical (mPFC) slices and well-washed rat cortical membrane. Electrically evoked field potential responses were recorded in layer 4/5 of mPFC in the presence of picrotoxin to prevent opening of Cl(-)channels gated by GABA or taurine. Applied taurine markedly diminished evoked-response amplitude at the peak and latter phases of the response. These phases were predominantly sensitive to the NMDA antagonist, MK-801, but not the AMPA/kainate receptor antagonist CNQX. Furthermore, this taurine effect was blocked by APV pretreatment. Taurine (0.1 mM) decreased spermine-induced enhancement of specific ((3)H) MK-801 binding to rat cortical membrane in the presence of glycine, though it was ineffective in the absence of spermine. Our preliminary work shows that taurine diminished the apparent affinity of NMDA receptor to glycine in the presence of spermine. These results indicate that taurine may directly interact with the NMDA receptor through multiple mechanisms.

Cocaine challenge enhances release of neuroprotective amino acid taurine in the striatum of chronic cocaine treated rats: a microdialysis study.

Drug addiction is a serious public health problem. There is increasing evidence on the involvement of augmented glutamatergic transmission in cocaine-induced addiction and neurotoxicity. We investigated effects of acute or chronic cocaine administration and cocaine challenge following chronic cocaine exposure on the release of excitotoxic glutamate and neuroprotective taurine in the rat striatum by microdialysis. Cocaine challenge, following withdrawal after repeated cocaine exposure markedly increased the release of glutamate, which may cause neurotoxicity. Simultaneously, cocaine challenge after withdrawal also significantly increased the release of taurine, which counteracts glutamate-mediated excitotoxicity and possibly cell death. Thus, the mammalian brain has an endogenous self-protective mechanism against cocaine-mediated neurotoxicity and potentially addiction.

Mechanisms for metoclopramide-mediated sensitization and haloperidol-induced catalepsy in rats.

Typical antipsychotics such as the dopamine D(2) receptor antagonist, haloperidol are known to cause movement disorders or catalepsy in experimental animals. Catalepsy is believed to result from blockade of dopamine D(2) receptors. In this study two drugs that differ in antipsychotic potency but are similar in blocking dopamine D(2) receptors were used to investigate the mechanism for catalepsy and its sensitization. Metoclopramide is a strong postsynaptic dopamine D(2) receptor blocker with no antipsychotic potency. At low doses of 5 or 10 mg/kg given subcutaneously (s.c.), metoclopramide did not produce catalepsy or movement disturbance for seven days after drug treatment. Also metoclopramide at 10 mg/kg given for five days, failed to induce catalepsy. Haloperidol, another potent dopamine D(2) receptor blocker at 0.5 mg/kg (s.c.) rapidly produced catalepsy and suppressed movement 1 h after a single dose of the drug. Chronic as well as acute treatment with metoclopramide caused sensitization of haloperidol-induced catalepsy. Neurochemical analyses revealed significant dopamine D(2) receptor up-regulation in both frontal cortex and striatum of rats chronically treated with metoclopramide. However, no changes in dopamine D(2) receptor numbers were noted in these areas after chronic treatment with low doses of haloperidol. Significant increases in N-methyl-D-aspartate (NMDA) receptor numbers were observed in both frontal cortex and striatum of metoclopramide treated animals, while haloperidol elicited significant decreases in NMDA receptor numbers in both brain areas. These observations plus previous reports have led us to propose a model for catalepsy and its sensitization. According to this model the increase in NMDA receptors by metoclopramide sensitizes the brain to haloperidol-induced catalepsy. Thus, catalepsy appears to be elicited by simultaneous activation of glutamatergic NMDA and dopamine D(1) receptors as well as a blockade of dopamine D(2) receptors.

Clozapine protection against gestational cocaine-induced neurochemical abnormalities.

Clozapine was found to be effective in attenuating cocaine-induced neurochemical effects. We investigate whether clozapine influences in utero cocaine exposure-induced changes in striatal dopamine levels and cortical N-methyl-D-aspartate (NMDA) receptor density in mouse and rat brains. Pregnant mice or rats were injected with cocaine (5 or 10 mg/kg intraperitoneally) or saline every 24 h throughout gestation and continued for 6 weeks following the delivery. Striatal dopamine levels measured by high-pressure liquid chromatography were found to decrease 24 to 33% in gestational cocaine exposed between the ages of 3 to 15 days, but not in 42-day-old pups. The cortical NMDA receptor densities assessed either in the presence of 100 microM glutamate or 30 microM glycine were significantly increased in 15-day-old gestational cocaine-exposed rats. Simultaneous daily administration of 3 mg/kg clozapine with 5 mg/kg cocaine to pregnant mice protected against the decrease in striatal dopamine levels or an increase in the concentration of NMDA receptor measured in the presence of 100 microM glutamate in 15-day-old pups. Clozapine did not affect striatal dopamine levels by itself or when coadministered with cocaine in 42-day-old pups. The results show gestational cocaine may induce neurochemical abnormalities in brain exhibited as an increased glutamate NMDA receptor density together with a decreased striatal dopamine level. These effects of gestational cocaine exposure may be prevented by simultaneous administration of clozapine. Thus clozapine, which is a partial agonist at the NMDA receptor, may be of value in protecting against gestational cocaine-induced adverse effects in the brain.