dizocilpine-maleate and tert-butylbicyclophosphorothionate

Evidence from clinical and preclinical studies implicates dysfunction of

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Dizocilpine Maleate; Elevated Plus Maze Test; HEK293 Cells; Humans; Male; Pregnenolone; Rats, Long-Evans; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Reflex, Startle; Schizophrenia; Steroids

MK-801 is an uncompetitive allosteric antagonist that interferes with glutamate-gated calcium ion conductance through the NMDA receptor-associated ionophore. In an outbred strain of mouse, MK-801 elicits episodes of explosive "popping" behaviors that may serve as a preclinical screening paradigm for novel antipsychotic medications. This investigation examined the effects of MK-801, at doses associated with the elicitation of popping, on the GABAA receptor complex in cerebral cortex, and flurazepam's ability to antagonize electrically precipitated seizures. Twenty four hours after MK-801 administration, there was an increased density of the radiolabeled antagonist-preferring conformation of the central benzodiazepine binding site and a potentiation of flurazepam's antiseizure efficacy. The data show that interference with NMDA receptor-mediated calcium ion conductance is associated with a relatively selective change in the GABAA receptor complex in cerebral cortex, and has functional behavioral consequences. Moreover, the data provide additional evidence for a delicate balance between GABAergic and glutamatergic transmission. Disturbance of this balance can have behavioral consequences for the animal.

Topics: Animals; Anticonvulsants; Behavior, Animal; Benzodiazepinones; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Convulsants; Dizocilpine Maleate; Drug Synergism; Electroshock; Flurazepam; Isoquinolines; Kinetics; Male; Mice; Receptors, GABA-A

The effect of GABAA receptor stimulation on N-methyl-D-aspartate(NMDA)-induced [45Ca2+]influx has been examined using primary cultured cerebral cortical neurons. NMDA induced a dose-dependent increase in [45Ca2+]influx, which was blocked by MK-801 in a dose-dependent manner. GABAA receptor agonists significantly enhanced the NMDA-induced [45Ca2+]influx, and this enhancement was dose-dependently inhibited by bicuculline, although picrotoxin and tert-butyl-bicyclo[2.2.2]phosphoro-thionate (TBPS) exhibited no alterations in this stimulatory action of GABAA receptor agonists. Blockers of L-type voltage-dependent calcium channels significantly reduced the NMDA-induced [45Ca2+]influx. The increased [45Ca2+]influx by both NMDA and GABAA receptor agonists was also reduced by verapamil and nifedipine. These results suggest that the enhancement of NMDA-induced [45Ca2+]influx by GABAA receptor stimulation in immature cerebral cortical neurons may be due to the increased opening of voltage-dependent calcium channel by synergestic actions between NMDA and GABAA receptors.

Topics: Animals; Bicuculline; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Calcium; Calcium Channel Blockers; Calcium Channels; Cells, Cultured; Cerebral Cortex; Chloride Channels; Dizocilpine Maleate; Dose-Response Relationship, Drug; GABA Agonists; Isonicotinic Acids; Mice; Muscimol; N-Methylaspartate; Neurons; Picrotoxin; Potassium; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate

The effect of long-term treatment with ethanol was investigated on the function of gamma-aminobutyric acid A (GABAA) and N-methyl-d-aspartic acid (NMDA) receptors. Rats were rendered ethanol-dependent by repeated forced administration of a 20% ethanol solution (12 to 18 g/kg/day po) for 6 days and tested while still intoxicated or at different time intervals after withdrawal. t-[35S]Butylbicyclophosphorothionate (35S-TBPS) binding was increased by 30% in cortical homogenates of rats killed 1 to 3 hr after last ethanol administration, when compared with saline-treated animals. However, GABA-stimulated 36Cl- uptake and its enhancement by flunitrazepam was decreased in the ethanol-treated animals. 35S-TBPS binding and 36Cl- influx measured 9 to 24 hr following the last ethanol injection, when withdrawal signs were present, were unmodified with respect to saline-treated rats. Moreover, the effects of both isoniazid and FG 7142 on 35S-TBPS binding were unchanged in ethanol-dependent rats tested at 1 to 3 and 9 to 24 hr, compared with controls. In contrast, ethanol-withdrawn rats tested at 9 to 24 hr showed a dramatic enhancement in their sensitivity to the convulsant action of isoniazid (50 to 250 mg/kg, sc). The same animals were also more susceptible to the convulsant action of NMDA (0.5 to 5 micrograms/5 microliters/rat intracerebroventricularly) and kainic acid (12 mg/kg, ip), and this effect was paralleled by an enhancement (+25%) in the density of 3H-MK 801 recognition sites in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alcohol Withdrawal Delirium; Alcoholism; Animals; Brain; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Chloride Channels; Convulsants; Dizocilpine Maleate; Ethanol; Isoniazid; Kainic Acid; Male; Membrane Proteins; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Seizures; Synaptic Transmission

Topics: Animals; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Chlorides; Dizocilpine Maleate; Down-Regulation; Isoniazid; Kindling, Neurologic; Male; Pentylenetetrazole; Rats; Rats, Inbred Strains; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate

Topics: Alcoholic Intoxication; Animals; Brain Chemistry; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Chlorides; Dizocilpine Maleate; Ethanol; Hippocampus; Ion Channels; Kinetics; Male; Rats; Rats, Inbred Strains; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome

Chemical kindling was induced in the rat by chronic treatment with pentylenetetrazol (PTZ, 30 mg/kg, IP, three times a week for eight weeks). PTZ kindling was associated with a reduction in central GABAergic function, as reflected by a significant decrease in the density of 35S-t-butylbicyclophosphorothionate (35S-TBPS) binding sites in the cerebral cortex. The pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (1 mg/kg, IP, 40 min before each PTZ injection) prevented the development of kindling as well as the reduction in 35S-TBPS binding. The results suggest that NMDA receptors may play a role in the alterations of GABAergic function observed in PTZ-kindled rats.

Topics: Animals; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Convulsants; Disease Susceptibility; Dizocilpine Maleate; Kindling, Neurologic; Male; Pentylenetetrazole; Rats; Rats, Inbred Strains; Seizures; Sulfur Radioisotopes