Behavioural Brain Research 130 (2002) 127 – 132 Selective inhibition of neuronal nitric oxide synthesis reduces hyperactivity and increases non-selective attention in the Naples High-Excitability rat G. Grammatikopoulos, M. Pignatelli, F. D’Amico, C. Fiorillo, A. Fresiello, A.G. Sadile * Laboratory of Neurophysiology, Behaiour and Neural Networks, Department of Experimental Medicine, Section of Human Physiology, II Uniersity of Naples, Naples 80138, Italy Received 8 July 2000; accepted 13 August 2001 Abstract The involvement of neuron-derived NO in the process of orienting and scanning times (non-selective attention: NSA) towards environmental stimuli has been investigated in the Naples High-Excitability rat (NHE), a putative animal model of Hyperactivity and Attention Deficit (ADHD). To this aim, orienting and scanning times have been monitored by the frequency and duration of rearing episodes, respectively. Adult male NHE rats were tested in a novelty situation (La `t-maze) for 30 min following single or repeated injections of the non competitive inhibitor 7-Nitroindazole (7-NINA) of the neuronal isoform of the enzyme nitric oxide synthase (n-NOS). In the acute experiments, rats received a single injection of 7-NINA (1 mg/kg) intraperitonealy in a saline vehicle (exp. 1, fast release) or subcutaneously in a lipid carrier, dimethyl sulfoxide (DMSO; exp. 2, slow release) or the vehicles alone as controls 30 min before testing. In the repeated injection experiments, rats received a subcutaneus injection of 1 mg/kg in DMSO or DMSO alone daily for 14 days, and tested 24 h after the last injection (exp. 3, slow release). The results showed a significant differential effect of the drug that was dependent on the release rate, i.p. saline-diluted 7-NINA increased the duration of individual rearing episodes whereas, both single and repeated subcutaneous DMSO-carried 7-NINA exerted an opposite effect. Thus, selective inhibition of n-NOS by an allosteric inhibitor that increases arginine availability without displacing the inhibitor from n-NOS, strengthens the hypothesized role of NO in NSA. These findings may shed light on the mechanism of action of drug treatment of and be useful in the treatment of ADHD in children. (Supported by Telethon-Italy grant E.513). © 2002 Elsevier Science B.V. All rights reserved. Keywords: Neuronal nitric oxide synthase; 7-Nitroindazole; Naples high-excitability rats; Rearing frequency; Rearing duration; NSA; ADHD www.elsevier.com/locate/bbr 1. Introduction An extrasynaptic mode is known to coexist with the synaptic one in the information processing and transfer in the CNS (see e.g. [11]). The former is based on a volume conduction mechanism [11] that implies ions such as K + , peptides, hormones, prostanoids, and gaseous mediators [nitric oxide (NO)] [18] which exerts a diffuse influence on large neuronal populations. The duration of individual rearing episodes on the hindlimbs by rats in a spatial novelty situation has been shown to index NSA [5]. Information processing and transfer in different sen- sory motor domains can be modulated to a great extent by attentive processes. They can be of the selective (SA) or non selective type (NSA). The former has been mostly studied in the visuo-spatial attention that in- volves the pulvinar and the posterior parietal cortex [23]. In contrast, NSA involves orienting, scanning and detection of stimuli followed by analysis in the SA mode. It pertains to salience of stimuli determined by the motivational state of the animal along with the stimulus properties (reward expectancy [29,33]. The neural substrate of NSA is represented by the so-called * Corresponding author. Present address: Laboratory of Neuro- physiology, Behaviour and Neural Networks, Department of Experi- mental Medicine, Section of Human Physiology, II Univ. Naples, Costantinopoli 16, Naples 80138, Italy. Tel./fax: +39-081-5665827. E-mail address: agsadile@tin.it (A.G. Sadile). 0166-4328/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved. PII:S0166-4328(01)00424-7