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7-Nitro Indazole, a Selective Neuronal Nitric Oxide Synthase Inhibitor in Vivo, Impairs Spatial Learning in The

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7-Nitro Indazole, a Selective Neuronal Nitric Oxide Synthase Inhibitor in Vivo, Impairs Spatial Learning in The Downloaded from learnmem.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH 7-Nitro Indazole, a Selective Neuronal Nitric Oxide Synthase Inhibitor in Vivo, Impairs Spatial Learning in the Rat Christian H61scher, 1'3 Liam McGlinchey, 1 Roger Anwyl, 2 and Michael J. Rowan ~Department of Pharmacology and Therapeutics and 2Department of Physiology Trinity College Dublin 2, Republic of Ireland Abstract Introduction Nitric oxide (NO) is an intercellular messen- Nitric oxide (NO) is an intercellular ger that plays a role in many physiological systems. messenger that has been suggested to have In the nervous system, NO acts as a neurotrans- a role in learning and memory formation. mitter (Amir 1992). The enzyme NO synthase Previous studies with nonselective NO (NOS) has been found in neurons (Bredt and Sny- synthase inhibitors have produced der 1992; Vincent and Kimura 1992), and endog- contradictory results in learning enous NO production occurs in neuronal cultures experiments. However, these drugs also (Ma et al. 1991). At least three isoforms of NOS produced blood pressure changes, as NO is have been identified. NOS isoform I is found in an endothelial-derived relaxing factor. A neurons, whereas isoform III has been purified novel NO synthase inhibitor, 7-nitro from endothelial cells (Schmidt et al. 1992). Both indazole (7-NI), as a dose (30 mg/kg i.p.) isoforms are Ca 2+ dependent (Moncada and shown previously to inhibit neuronal NO Palmer 1992). Isoform type II is inducible and synthase by 85% without affecting blood Ca 2+ independent. It is found in most tissues of pressure, produced amnesic effects both in the body (Kilbourn 1991; Nathan 1991). NO has a water maze and in an 8-arm radial maze. been suggested to act as a retrograde messenger Latency as well as distance was greater in (O'Dell et al. 1991; Schuman and Madison 1991), the 7-NI group in the water maze while modulating up-regulation of transmitter release, swim speed was not affected. Latency, which would result in long-term potentiation working memory (WM), and reference (LTP) of synaptic transmission, a phenomenon memory (RF) errors were also higher in the that has been suggested to be the neuronal basis of 7-NI group in the 8-arm maze. At the end of memory formation (for discussion, see Bliss and the second training day, these differences Collingridge 1993). Early investigations claim that were no longer apparent. However, on the NO is an essential messenger in LTP induction. fourth training day, a transfer test in the Inhibition of NO synthesis prevented induction water maze showed that 7-NI had produced of LTP in the CA1 field of rat hippocampal slices a spatial memory deficit, reducing quadrant (B6hme et al. 1991; Bon et al. 1992; Musleh et al. bias and the number of annulus crossings. 1993), or in a cortical slice preparation (Nowicky Learning of a visual cue task was not and Bindman 1993). These positive results were affected. No difference between groups was soon followed by reports that the block of LTP was visible in an open field test. We conclude found only under defined conditions (see, e.g., that neuronal NO sythase activity plays a Williams et al. 1993). role in learning and memory formation in Measuring LTP formation in vivo did not clar- the rat. ify the confusion. Although some research groups found block or impairment of induction of LTP, 3Corresponding author. others did not. In one study the NOS inhibitor LEARNING & MEMORY 2:267-278 91995 by Cold Spring Harbor Laboratory Press ISSN1072-0502/96 $5.00 L E A R N / N G & M E M O R Y 267 Downloaded from learnmem.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press H61scher et al. N-nitro-L-arginine-methyl-ester (L-NAME) pre- (Buxton et al. 1993). Because learning, as well as vented LTP induction in vivo in the rat (Iga et al. motor activity, is dependent on cholinergic trans- 1993; Mizutani et al. 1993), whereas in another mission (Ohno et al. 1994), L-NAME could have study, LTP induction was not affected (Bannerman various other effects than spatial learning on rat et al. 1994b) or only LTP of the population spike performance, as Bannerman et al. presumed from was inhibited (Bannerman et al. 1994c). A third their studies. study found that L-NAME raised the threshold for To avoid these undesired effects, we tested the induction of LTP (P.F. Chapman, pers. comm.). the novel selective neuronal NOS inhibitor 7-nitro As LTP is assumed to represent a cellular pro- indazole (7-NI) on spatial and nonspatial learning cess of memory formation, the question arose of rats in a radial arm maze and in the water maze. whether NO plays a role in learning and memory. This drug has been shown to be specific for NOS in Several studies were conducted involving learning vivo (Babbedge et al. 1993; Moore et al. 1993a) a spatial task in a radial maze or in a water maze as without affecting endothelial NOS. 7-NI has no ef- well as learning nonspatial tasks. Learning tasks in fect on mean arterial pressure at doses ranging the radial arm maze and of a social recognition from 20 to 80 mg/kg i.p. (Moore et al. 1993a,b). olfactory task were inhibited, whereas shock- Infected interperitoneally, 30 mg/kg of 7-NI inhib- avoidance learning was unaffected after injection ited NOS in various brain areas including the hip- of the NOS inhibitor nitro-L-arginine (L-NARG) pocampus 30 min after injection by 85%, 2 hr (B6hme et al. 1993). L-NAME produced learning later by 80%, and 4 hr later by 55% (MacKenzie et impairments of a place-navigation task (Estall et al. al. 1994). Furthermore, recent experiments in our 1993). Learning a passive avoidance trial in chicks laboratory showed an effect of 7-NI on LTP induc- was impaired following L-NARG injection (HOI- tion at this dose. Injecting 30 mg/kg of 7-NI i.p. in scher and Rose 1992, 1993). Chapman et al. the anesthetized rat prevented the induction of (1992) tested the effect of L-NAME on rats learn- LTP and the depotentiation of established LTP by ing a water maze task and on rabbits learning a low frequency stimulation. Injecting L-arginine to- conditioned eye-blink response and found that gether with 7-NI prevented these effects (Doyle et both forms of learning are impaired by the drug. al. 1996). In a previous study 7-NI proved to have Bannerman et al. (1994a), however, further tested amnesic effects in a one-trial passive avoidance the effect on L-NAME on rats learning a water task of the chick (HOlscher 1995). maze and found that though spatial learning was Apart from learning tasks in the water maze impaired, the learning of a visual discrimination we chose to test the effects of 7-NI in the radial task involving two visible platforms was not af- arm maze as well. If the hypothesis by Bannerman fected, but analysis of the early training trims of the et al. (1994a) holds that inhibition of NOS causes visual discrimination task revealed significantly el- more general impairments not directly attributed evated escape latencies in the L-NAME-treated to spatial learning impairment, latency but not rats. The interpretation was that NOS inhibition numbers of errors should differ between 7-NI and might cause more general impairments. Also, train- the control group. ing animals on a one-trial-per-day basis showed that L-NAME-injected rats had no difficulty learn- Materials and Methods ing the task. Furthermore, after learning the task in one water maze, L-NAME-injected rats had no ef- fect on relearning the task in a second water maze MATERIALS with a novel spatial environment. Bannerman et al. (1994a) therefore concluded that the impairment DRUGS caused by L-NAME is not attributable to a specific spatial learning impairment. 7-NI was obtained form Biomol (Plymouth All of the in vivo studies mentioned suffer Meeting, Pennsylvania) and emulsified in warm from one great drawback. The drugs used are not sesame oil (Tesco, UK) by sonication for 5 min. specific for the neuronal isoform of NOS and Rats were injected i.p. 9 mg of 7-NI emulsified in greatly affect blood vessel diameter and blood 0.2 ml of oil, which results in a concentration of 30 pressure (Rees et al. 1990; Snyder and Bredt 1992; mg/kg-8%. Control animals only received 0.2 ml Lot et al. 1993). Furthermore, L-NAME is known to of sesame oil. All injections were carried out 30 antagonize muscarinic acetylcholine receptors min pretraining. L E A R N I N G & M E M 0 R Y 268 Downloaded from learnmem.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press 7-NI IMPAIRS LEARNING IN THE RAT ANIMALS ing the training period (annulus crossings). Ani- mals' heads were marked with a black water-resis- Thirty-two male Wistar rats weighing between tant felt tip marker to enable the program to track 280 and 320 grams were divided into four groups the white rats in the white water. (n=8 each). One control group and one test group were used for the water maze test and fed TRAINING PROTOCOL ad lib. The other two groups were tested in the radial arm maze and received a diet of 12 grams DAYS 1 AND 2 per day, which kept their weight at --85% of their free-feeding weight. Animals were held in opaque On all 4 days, rats were injected i.p.
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