cyclic-gmp and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol

In this study, we investigated the involvement of the interaction between sigma receptors and the nitric oxide/cyclic GMP pathway in short term memory in mice, assessed through spontaneous alternation behavior in a Y-maze. N(G)-Nitro-L-arginine methyl ester and 7-nitro indazole, both nitric oxide synthase inhibitors, impaired the spontaneous alternation behavior. These impairments were attenuated by (+) SKF 10,047 and (+) pentazocine, sigma(1) receptor agonists. Further, the sigma(1) receptor antagonist, NE-100, reversed the improvements made by sigma receptor agonists. Cyclic GMP levels and nitric oxide synthase activity in the hippocampus were reduced by treatment with N(G)-nitro-L-arginine methyl ester. The suppressive effects of N(G)-nitro-L-arginine methyl ester on the cyclic GMP levels were reversed by co-treatment with (+) SKF 10,047, but the decline in nitric oxide synthase activity was not. These results suggest that the nitric oxide/cyclic GMP pathway in the hippocampus is responsible for spontaneous alternation behavior in a Y-maze. Further, the ameliorating effects of (+) SKF 10,047 on the impairment of spontaneous alternation behavior may be mediated through activation of guanylate cyclase, but not nitric oxide synthase in the hippocampus of mice.

Topics: Analgesics, Opioid; Animals; Anti-Anxiety Agents; Antipsychotic Agents; Behavior, Animal; Brain Chemistry; Cyclic GMP; Enzyme Inhibitors; Guanidines; Indazoles; Male; Methylene Blue; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Pentazocine; Phenazocine; Pyrimidines; Receptors, sigma

BMY-14802 [alpha-(4-flurophenyl)-4-(5-fluoro-pyramidinyl)-1-piperazine butanol], a potent sigma ligand with poor affinity for dopamine and phencyclidine receptors in vitro, attenuated parenteral harmaline- and direct intracerebellar D-serine-induced increases in mouse cerebellar cGMP. Intracerebroventricularly injected BMY-14802 also antagonized the effects of intracerebellar D-serine, indicating a central mechanism. However, direct co-injection of BMY-14802 into the cerebellum failed to antagonize the D-serine-induced increases in cGMP, indicating a locus of action outside the cerebellum. In contrast, quisqualate-induced cGMP increases were not attenuated by BMY-14802. These results indicate a functional modulation of the N-methyl-D-aspartate/glycine/phencyclidine/ion channel complex-mediated events by BMY-14802, possibly through a transsynaptic mechanism, thus representing the first in vivo demonstration of a sigma ligand modulation of a response mediated through the N-methyl-D-aspartate receptor complex.

Topics: Alkaloids; Animals; Cerebellum; Cyclic GMP; Dose-Response Relationship, Drug; Harmaline; Male; Mice; Pyrimidines; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Serine

Cerebellar cyclic guanosine monophosphate (cGMP) levels reflect the ongoing neuronal activity mediated by the N-methyl-D-aspartate (NMDA) receptor complex. Due to the putative role of the NMDA receptor complex in the etiology of ischemic neuronal injury, the effects of two novel anti-ischemic agents, ifenprodil and BMY-14802, were examined on cGMP responses mediated by harmaline, methamphetamine (MA), and pentylenetetrazol (PTZ), agents which modulate the Purkinje cell activity by three distinct pharmacological mechanisms. Similar to the competitive NMDA antagonist, CPP [(+/-)-3-carboxypiperazin-4-yl)propyl-1-phosphonic acid], ifenprodil and BMY-14802 reversed the harmaline-, MA- and PTZ-induced cGMP levels. Unlike CPP, ifenprodil was nearly 3-times less potent at reversing the harmaline-induced increases in cGMP levels than at reversing MA-and PTZ-induced increases in cGMP levels. These results suggest a differential modulation of basket and stellate, and mossy fiber activity by ifenprodil.

Topics: Analysis of Variance; Animals; Cyclic GMP; Harmaline; Male; Methamphetamine; Mice; Mice, Inbred Strains; Neurons; Pentylenetetrazole; Piperazines; Piperidines; Purkinje Cells; Pyrimidines; Radioimmunoassay; Receptors, Amino Acid; Receptors, Cell Surface