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We describe here the pha macological properties of RP 67580 {(3aR,7aR)-7,7-diphenyl-2-[1-imlno-2-(2- To understand how SP acts in the central and peripheral nervous system, various agonists (either endogenous TKs or their analogues) were used to identify three types of SP receptors, which were called neurokinin receptors types 1, 2, and 3 (NK1, NK2, and NK3 receptors, respectively). All three receptors have been cloned and sequenced (7-9). SP binds most strongly to the NK1 receptors, whereas neurokinin A (NKA) and neurokinin B (NKB), two other mammalian TKs, preferentially bind to NK2 and NK3 receptors, respectively (for review, see refs. 10 and 11). However, it was only with the identification of antagonists that specifically block the actions of SP that the physiological and pathological functions of SP could be investigated. In the last decade, various SP antagonists, which are, in fact, chemical analogues of SP, have been described (12). However, these peptides have major disadvantages: they are metabolically unstable, only weakly active, and not selective with respect to the different receptor subtypes (for review, see refs. 12 and 13). More recently, a nonpeptide SP antagonist was described but its antinoceptive properties were not reported (14).The present report describes the binding and pharmacological properties of RP 67580, a potent nonpeptide SP antagonist derived from the perhydroisoindole chemical series and selective for the NK1 receptor. Its chemical name is (3aR, 7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)-ethyl] perhydroisoindol-4-one.The undecapeptide substance P (SP), first isolated in 1931 from extracts of horse brain and intestine (1) Abbreviations: SP, substance P; NK, neurokinin; TK, tachykinin. 10208The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Nitric oxide (NO) is a messenger molecule that is produced in the brain from the metabolism of L-arginine to L-citruline. Growing evidence suggests a physiological role for NO in long-term potentiation (LTP). Since LTP is a form of synaptic plasticity thought to be involved in learning and memory, we have tested whether inhibition of endogenous NO production affects memory capacities ofrats. We found that the NO synthase [L-arginine, NADPH:oxygen oxidoreductase (nitric oxide-forming), EC 1.14.13.39] inhibitor N01-nitro-Larginine, at doses blocking LTP in hippocampal slices, impairs spatial learning in a radial arm maze and olfactory memory in a social recognition test. In contrast, N"-nitro-L-arginine left shock-avoidance learning unaffected. These results indicate that NO is involved in some but not all forms of memory and further support the existence of a causal link between LTP and spatial learning.Nitric oxide (NO) is a diffusible molecule endowed with intercellular messenger properties in several biological systems including the brain (1, 2). NO mediates the stimulation of soluble guanylate cyclase upon activation of N-methyl-Daspartate (NMDA) receptors (3) and serves as its own negative feedback effector by blocking NMDA-evoked responses (4, 5). This messenger is produced from the enzymatic conversion of L-arginine to L-citrulline by a constitutive NO synthase [NOS; L-arginine, NADPH:oxygen oxidoreductase (nitric oxide-forming), EC 1.14.13.39] which can readily be blocked by arginine analogs, such as Nl-nitro-Larginine [Arg(NO2); also called NG-nitro-L-arginine, where G refers to the guanidino-carbon] (6, 7).Long-term potentiation (LTP) is a persistent increase, which can last for days or weeks, in the synaptic efficacy of pathways produced by brief periods of high-frequency stimulations (HFS) (8). This phenomenon, best characterized in the hippocampus, is thought to be a cellular event involved in the acquisition, storage, or retrieval of information in the brain (9-12). We and others reported recently that NOS inhibitors and NO scavengers block hippocampal LTP in rat brain slices (13)(14)(15)(16) to irreversibly block brain NOS enzymatic activity (7). Separate groups of animals were used for each experiment. Vehicle-treated animals were used as controls.Electrophysiology. Sixteen hours after the last injection, transverse hippocampal slices (0.5-mm thick) were prepared from Sprague-Dawley rats (150-200 g) pretreated with Arg(NO2) (25-100 mg/kg of body weight i.p.) or vehicle. Slices were maintained in a submersion-type recording chamber under superfusion (2.5-3 ml/min) with gassed (95% 02/5% C02) medium containing 124 mM NaCl, 5 mM KCl, 2 mM MgSO4, 2 mM CaCl2, 26 mM NaHCO3, 1.25 mM KH2PO4, and 10 mM glucose at 32°C as described (18). Stimulation and recording electrodes were positioned in the CAl-stratum radiatum, and field excitatory postsynaptic potentials (EPSPs) were evoked every 5 s. The stimulus strength (0.1-ms duration at 2-20 V) was adjusted to evoke EPSPs of at least 0.3-mV amplitude w...

The neuroprotective effects of riluzole, a novel antiglutamate, has been demonstrated in a model of ischemia induced in female Mongolian gerbils by transient bilateral carotid occlusion. Riluzole was administered at a dose of 4 mg/kg, i.p., just before, 4 hr after, and for the 14 d following the transient bilateral carotid occlusion (10 min). The functional sequelae of ischemic damage were assessed using a memory test (passive avoidance) and the extent of neuronal damage by histological examination and quantitative autoradiography of muscarinic cholinergic receptors in the hippocampus. The performance of the ischemic gerbils in the memory test was about half that of control animals. This memory deficit was completely reversed in animals treated with riluzole. This protective effect of riluzole was confirmed by histological and autoradiographic studies. The neuronal degeneration of CA1 pyramidal cells in the hippocampus observed in the ischemic group was not seen in the riluzole-treated animals, which resembled the control group. This neuronal degeneration in the CA1 area was confirmed by a quantitative measurement of muscarinic receptors: The binding was decreased by a third in the lacunosum moleculare, the stratum oriens, and the stratum radiatum. By contrast in riluzole-treated gerbils, this decrease was reversed by 50%. Finally, a clear-cut correlation was found between the deficit in the memory test and the decrease in muscarinic receptor binding in the CA1 fields. These results are compatible with the idea that glutamic acid may be involved in the neuronal degeneration of the hippocampus following ischemia, and could be foreseeable.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitric oxide production in the cerebellum and induction of long-term potentiation (LTP) in the hippocampus have some characteristics in common: both phenomena are induced by activation of N-methyl-d-aspartate receptors and both are highly dependent on calcium-mediated processes. Here we provide evidence that endogenous nitric oxide production is necessary for synaptic plasticity in the CA1 hippocampus of the rat. LTP recorded in slices was blocked in a concentration-dependent manner by the nitric oxide synthase inhibitors l-NG-nitroarginine and l-NG-nitroarginine methyl ester, but l-NG-monomethylarginine was only marginally active. Bathing the slices with haemoglobin, a protein that scavenges nitric oxide, also resulted in a concentration-dependent blockade of LTP. Nitric oxide released locally from hydroxylamine produced a stable potentiation of synaptic transmission that was not additive with LTP induced by high-frequency stimulation. These results are fully consistent with the presumed retrograde messenger role of nitric oxide in LTP.