a 2 -Adrenoceptor antagonist SL 84.0418 reduces the expression of neocortical spike-and-wave spindling episodes in DBA/2J mice Anna Capasso a, * , Alberto Loizzo b a Department of Pharmaceutical Sciences, University of Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy b Istituto Superiore di Sanita `, Rome, Italy Accepted 18 November 2002 Abstract The present work was undertaken to study the effects of a 2 -adrenoceptor antagonist 2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahydro- 2-propyl-pyrrolo[3,2,1-hi]-indole hydrochloride (SL 84.0418) on the neocortical spike-and-wave spindling episodes (S and W) in the cortical electroencephalogram (ECoG) of DBA/2J mice. Our data indicate that SL 84.0418 (0.1 – 1.0 – 10 mg/kg ip) dose-dependently reduces the S and W of DBA/2J mice. This effect appears 30 min after drug administration and lasts for the duration of the recording period (240 min). The reducing effect of the SL 84.0418 on the S and W of mice was comparable to that induced by tolazoline (10 – 20 – 40 mg/kg ip), a well-known a 2 -adrenoceptor antagonist, whereas the a 2 -adrenoceptor agonist clonidine (0.02 – 0.1 – 0.5 mg/kg ip) significantly increased it. The present results indicate that SL 84.0418 administration induces significant reduction on S and W of DBA/2J mice suggesting a possible involvement of noradrenergic system in the development of S and W of DBA/2J mice. D 2002 Elsevier Science Inc. All rights reserved. Keywords: a 2 -Adrenergic receptor; Brain excitability; DBA/2J mice; Noradrenaline 1. Introduction DBA/2J mice spontaneously generate neocortical spike- and-wave spindling episodes (S and W) of 7–8 cycle per second (cps) spindles during quiet waking, active waking and slow-wave sleep but not during rapid eye movement (REM) sleep (Ryan, 1984). Numerous factors have led to a recent increased consideration of the DBA/2J mice as a model for studying cerebral excitability (Ryan and Sharp- less, 1979). Genetic contributions to human epilepsy are becoming increasingly apparent (Newmark and Penry, 1980). Consequently, genetically seizure-prone animals are assuming more importance as models of the pathophysiol- ogy of human epilepsy. Ryan and Sharpless (1979) sug- gested that DBA/2J mice may provide a useful animal model for studying the basis of the inheritance of a pre- sumed epileptiform. Studies on animal models of epilepsy and in human epilepsy established a modulatory role for the noradrenergic as well as dopaminergic system (Ryan, 1985; Maynert et al., 1975; Callaghan and Schwark, 1979; Chauvel and Trottier, 1986; Chermat et al., 1981; Crunelli et al., 1981) since the finding that administration of amphetamine suppresses petit mal absence seizures and the administration of reserpine aggravates convulsive and nonconvulsive epilepsies (May- nert et al., 1975). In experimental models of seizures, studies have shown that noradrenaline has mostly an inhib- itory effect (Callaghan and Schwark, 1979; Chauvel and Trottier, 1986; Chermat et al., 1981; Crunelli et al., 1981). The above studies have shown inhibitory control of nora- drenaline in the spontaneous generalized nonconvulsive epilepsy (GNCE) model in the Wistar rat. In fact, facilitation of a-noradrenergic neurotransmission with a-1 agonist (cirazoline, ST 587) or an a-2 antagonist (yohimbine) reduces synchronous spike-and-wave bursts (SWD) duration on the cortical electroencephalogram (ECoG) whereas the reduction of a-adrenergic neurotrans- mission with an a-1 antagonist (prazosin) or an a-2 agonist 0278-5846/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII:S0278-5846(02)00345-7 Abbreviations: cps, cycle per second; ECoG, cortical electroencephalo- gram; GNCE, generalized nonconvulsive epilepsy; REM, rapid eye movement; SL 84.0418, 2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahy- dro-2-propyl-pyrrolo[3,2,1-hi]-indole hydrochloride; S and W, synchronous spike-and-waves bursts; SWD, synchronous spike-and-wave discharges. * Corresponding author. Tel./fax: +39-89-964357. E-mail address: annacap@unisa.it (A. Capasso). www.elsevier.com/locate/pnpbp Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 141 – 145