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...

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The development of selective ligands targeting neuronal nicotinic acetylcholine receptors to alleviate symptoms associated with neurodegenerative diseases presents the advantage of affecting multiple deficits that are the hallmarks of these pathologies. TC-1734 is an orally active novel neuronal nicotinic agonist with high selectivity for neuronal nicotinic receptors. Microdialysis studies indicate that TC-1734 enhances the release of acetylcholine from the cortex. TC-1734, by either acute or repeated administration, exhibits memory enhancing properties in rats and mice and is neuroprotective following excitotoxic insult in fetal rat brain in cultures and against alterations of synaptic transmission induced by deprivation of glucose and oxygen in hippocampal slices. At submaximal doses, TC-1734 produced additive cognitive effects when used in combination with tacrine or donepezil. Unlike (-)-nicotine, behavioral sensitization does not develop following repeated administration of TC-1734. Its pharmacokinetic (PK) profile (half-life of 2 h) contrasts with the long lasting improvement in working memory (18 h) demonstrating that cognitive improvement extends beyond the lifetime of the compound. The very low acute toxicity of TC-1734 and its receptor activity profile provides additional mechanistic basis for its suggested potential as a clinical candidate. TC-1734 was very well tolerated in acute and chronic oral toxicity studies in mice, rats and dogs. Phase I clinical trials demon-

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