cyclic-gmp and 2-amino-7-phosphonoheptanoic-acid

The transient receptor potential vanilloid 1 (TRPV1) can modulate stress-related behaviours, thus representing an interesting target for new antidepressant drugs. TRPV1 can trigger glutamate release and nitric oxide synthesis in the brain, mechanisms also involved in the neurobiology of depression. However, it is not known if these mechanisms are involved in TRPV1-induced behavioural effects. Therefore, the aim of this study was to verify if the antidepressant-like effect induced by a TRPV1 antagonist in mice submitted to the forced swimming test (FST) would be facilitated by combined treatment with neuronal nitric oxide synthase (nNOS) inhibition and N-methyl-D-aspartate (NMDA) blockade. Male Swiss mice were given (intracerebroventricular) injections of capsazepine (CPZ) (TRPV1 antagonist - 0.05/0.1/0.3/0.6 nmol/µl), and AP7 (NMDA antagonist - 1/3/10 nmol/µl) or N-propyl-L-arginine (NPA, nNOS inhibitor - 0.001/0.01/0.1 nmol/µl), and 10 min later, submitted to an open field test, and immediately afterwards, to the FST. An additional group received coadministration of CPZ and AP7 or CPZ and NPA, in subeffective doses. The results demonstrated that CPZ (0.1 nmol/µl), AP7 (3 nmol/µl) and NPA (0.01/0.1 nmol/µl) induced antidepressant-like effects. Moreover, coadministration of subeffective doses of CPZ and AP7 or CPZ and NPA induced significant antidepressant-like effects. Altogether, the data indicate that blockade of TRPV1 receptors by CPZ induces antidepressant-like effects and that both nNOS inhibition and NMDA blockade facilitate CPZ effects in the FST.

Topics: 2-Amino-5-phosphonovalerate; Animals; Antidepressive Agents; Apomorphine; Arginine; Capsaicin; Cyclic GMP; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Enzyme Inhibitors; Exploratory Behavior; Glutamic Acid; Male; Microinjections; Nitric Oxide; Nitroprusside; Rats; Receptors, N-Methyl-D-Aspartate; Statistics, Nonparametric; Swimming

Female Sprague-Dawley rats were maintained on a diet of barbital for 8 weeks, a period of time previously shown to result in tolerance to and dependence on the drug. After completing this course, the barbital was abruptly withdrawn and the selective antagonist of N-methyl-d-aspartate (NMDA), 2-amino-7-phosphonoheptanoic acid (APH), or saline was infused intracerebroventricularly over 48 hr. Control rats which had not received barbital, were similarly infused with either saline or APH. All animals were observed for 12-48 hr following the withdrawal of the barbital; spontaneous convulsions, previously reported to be numerous and severe after withdrawal of the drug, were counted and graded according to severity. Forty-eight hr after withdrawal of barbital, the rats were killed by focussed microwave irradiation and cerebellae were collected for later determination of levels of cGMP. Nine convulsions occurred in 29 rats withdrawn from barbital and infused intracerebroventricularly with APH, this contrasted markedly with 61 convulsions seen in 29 animals withdrawn from the drug and infused with saline. There was a 3-fold elevation of levels of cGMP in the saline-infused, barbital-withdrawn rats when compared to control rats infused with saline. This evaluation was markedly, although not completely, prevented by the intracerebroventricular infusion of APH. These data provide evidence that dicarboxylic amino acid pathways, specifically those acting through NMDA receptors, are involved in seizure activity seen following abrupt abstinence from barbital.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Aspartic Acid; Barbital; Barbiturates; Cerebellum; Cyclic GMP; Female; N-Methylaspartate; Rats; Rats, Inbred Strains; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders

The effect of (+/-)-cis-2,3-piperidine dicarboxylic acid [+/-)-cis-2,3-PDA) on formation of cyclic GMP by immature (7-8 day) rat cerebellar slices has been studied. Using magnesium free medium containing the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX), (+/-)-cis-2,3-PDA behaves as an NMDA partial agonist. Thus in this medium, (+/-)-cis-2,3-PDA stimulates cyclic GMP formation, an effect completely blocked by the potent, specific NMDA antagonist (+/-)-2-amino-7-phosphonoheptanoic acid [+/-)-APH) with a Ki = 17.1 microM. The production of cyclic GMP by the full agonist (+/-)-trans-2,3-PDA, was also blocked by (+/-)-APH, suggesting that in this preparation it activates NMDA receptors. (+/-)-trans-2,3-PDA was approximately half as potent as NMDA. By constructing dose response curves to NMDA in the presence of increasing concentrations of (+/-)-APH or (+/-)-APV, these compounds were shown to be competitive NMDA antagonists using Schild analysis.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Anticonvulsants; Aspartic Acid; Cerebellum; Cyclic GMP; Dose-Response Relationship, Drug; Female; In Vitro Techniques; Magnesium; Male; N-Methylaspartate; Pipecolic Acids; Rats; Rats, Inbred Strains; Valine

The effects of the chronic intracerebroventricular (i.c.v.) infusion of the potent dicarboxylic amino acid antagonist, 2-amino-7-phosphonoheptanoic acid (APH), were examined in female rats as a prelude to the use of this compound in exploring the role of dicarboxylic amino acids in barbiturate dependence and withdrawal. Doses of APH ranging from 2.7 to 54 micrograms/day were examined for signs of toxicity. Weight loss, decreased water intake and locomotor impairment were found only with the largest dose. No significant changes in consumption of food or body temperature were observed with any dose. The chronic administration of the drug (27 micrograms/day) blocked the elevation of the content of cyclic guanosine monophosphate induced by N-methyl-D-aspartate (NMDA) in all regions of the brain examined. The chronically-administered drug also blocked wild running behavior induced by the intracerebroventricular administration of two different drugs n-methyl-D-aspartic acid and cyclohexylbarbiturate acid. However, APH was ineffective in suppressing convulsions induced by the ED50 dose of pentylenetetrazol given subcutaneously.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Anticonvulsants; Aspartic Acid; Barbiturates; Bicuculline; Brain; Brain Chemistry; Cyclic GMP; Female; Injections, Intraventricular; N-Methylaspartate; Pentylenetetrazole; Rats; Rats, Inbred Strains

In order to explore how rapidly locomotor activity induces an elevation in cerebellar cyclic guanosine monophosphate (cGMP) content, Sprague-Dawley rats, pretrained to swim a 2.5-m course, were required to swim from one to 5 laps representing from 7 to 40s of strenuous activity. Immediately after completing the swimming task, each animal was killed by microwave irradiation and the cerebellum was collected for subsequent determination of the cGMP content. There was no difference in the cerebellar cGMP content between rats swimming one lap, i.e. for 7 s, and control rats that did not swim. However, there was a linear increase in the cGMP over control values from 1.8- to 2.4-fold in rats swimming 3 and 5 times, respectively. The first significant elevation of the cerebellar cGMP was seen at 24 s (3 laps). To determine if acidic amino acid pathways were involved in this elevation, a low dosage of a selective NMDA antagonist, 2-amino-7-phosphonoheptanoic acid (APH) was injected intracerebroventricularly 4 min before having rats swim 4 laps. This low dosage of APH, which alone had no effect on the cerebellar cGMP content, completely blocked the swim-induced elevation of this parameter. These data provide the first report of how quickly locomotor activity elevates the cerebellar cGMP content and further suggest that an NMDA receptor-mediated pathway is involved in the activity-induced elevation of this parameter.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Aspartic Acid; Cerebellum; Cyclic GMP; Female; Motor Activity; N-Methylaspartate; Rats; Rats, Inbred Strains; Swimming