7-Nitro Indazole, a Neuron-specific Nitric Oxide Synthase Inhibitor, Produces Amnesia in the Chick

7-Nitro i n d a z o l e (7-NI), w h i c h is se lec t ive for t h e n e u r o n a l i s o f o r m of n i t r i c ox ide s y n t h a s e (NOS), was t e s t ed in a pass ive a v o i d a n c e task in t he ch ick . I n j ec t i on o f 50 m g / k g i.p. p r e t r a i n i n g h a d a m n e s i c effects for t he task w h e n t e s t ed 30 m i n , 2 o r 24 h r af ter t r a in ing . I n j ec t i ons p o s t t r a i n i n g h a d n o effect. Because 7-NI does n o t i n h i b i t t he e n d o t h e l i a l i s o f o r m o f NOS, it d o e s n o t affect b l o o d vesse l r e laxa t ion , as n o n s p e c i t i c i n h i b i t o r s do. Th i s effect o n b l o o d vesse ls c o u l d exp la in t he an lnes t i c effects p r o d u c e d b y n o n s p e c i f i c NOS inh ib i t o r s . The r e su l t s s u p p o r t t h e t h e o r y t ha t NO is a n e u r o n a l t r a n s m i t t e r tha t is i m p o r t a n t in p r o c e s s e s o f synap t i c p las t ic i ty a n d l e a r n i n g . The messenger nitric oxide (NO) is considered to play a vital role in synaptic plastic events and in learning and memory formation. The enzyme NO synthase (NOS) has been found in rat neurons (Bredt and Snyder 1992; Vincent and Kimura 1992), and endogenous NO product ion occurs in neuronal cultures (Ma et al. 1991) and in cerebellar slices (Shibuki and Odada 1991). In the chick, the localization of NO synthase was investigated employing the NADPH diaphorase technique (Bredt and Snyder 1992; Vincent and Kimura 1992), and neurons and a dense meshwork of neurophil in areas that are of importance in learning of the passive avoidance task employed here were found to stain for NADPH diaphorase (Briining 1993). Inhibition of NO synthesis prevents long-term potentiation or long-term depression in slice preparations (BOhme et al. 1991; Schuman and Madison 1991; Bon et al. 1992), but see Linden and Connor (1992). Such changes in synaptic transmission are thought to be necessary processes that occur during learning and memory formation (for discussion, see Bliss and Collingridge 1993). To show that NO actually plays a role in learning and memory formation, the inhibitors that prevent long-term potentiation and long-term depression had to be tested in learning tasks. In previous studies, inhibitors of NOS proved to impair learning in the chick (H61scher and Rose 1992, 1993) or rat (Chapman et al. 1992; BOhme et al. 1993). However, NO also plays a role in dilating blood vessels. It is produced in the endothelial tissue by a NOS isoform that is specific to this tissue (Garthwaite et al. 1988; Lambert et al. 1991). It cannot be ruled out that inhibition of NOS and prevention of blood vessel relaxation are the reason for the amnesic effects, as the NOS inhibitors used in learning tasks in previous investigations also have effects of blood pressure (Macrae et al. 1993). The novel inhibitor 7-nitro indazole (7-NI) is selective for the neuron isoform of NOS and does not affect blood pressure (Moore et al. 1993). To investigate whether the amnesia observed after injection of nonspecific NOS inhibitors is attributable to prevention of blood vessel relaxation and increase of blood pressure and not to a block of synaptic LEARNING & MEMORY 1:213-216 © 1994 by Cold Spring Harbor Laboratory Press ISSN1072-0502/94 $5.00 L E A R N I N G I M E M 0 R Y Cold Spring Harbor Laboratory Press on October 11, 2017 Published by learnmem.cshlp.org Downloaded from