www.frontiersin.org July 2010 | Volume 1 | Article 20 | 1 ORIGINAL RESEARCH ARTICLE published: 19 July 2010 doi: 10.3389/fpsyt.2010.00020 PSYCHIATRY Reduction by the positive allosteric modulator of the GABA B receptor, GS39783, of alcohol self-administration in Sardinian alcohol-preferring rats exposed to the “sipper” procedure Paola Maccioni 1† , Paolo Flore 2† , Mauro A. M. Carai 1 , Claudia Mugnaini 3 , Serena Pasquini 3 , Federico Corelli 3 , Gian Luigi Gessa 1 and Giancarlo Colombo 1 * 1 Consiglio Nazionale delle Ricerche Neuroscience Institute, Cagliari, Italy 2 Department of Neuroscience, University of Cagliari, Cagliari, Italy 3 Department of Pharmaceutical and Applied Chemistry, University of Siena, Siena, Italy The present study was designed to evaluate (a) alcohol self-administration behavior of selectively bred, Sardinian alcohol-preferring (sP) rats exposed to the so-called “sipper” procedure (characterized by the temporal separation between alcohol-seeking and -taking phases), and (b) the effect of the positive allosteric modulator of the GABA B receptor, GS39783, on alcohol self-administration in sP rats exposed to this procedure.To this end, sP rats were initially trained to lever-respond under a reinforcement requirement (RR) 55 (RR55) for alcohol. Achievement of RR55 resulted in the 20-min presentation of the alcohol (15%, v/v)-containing sipper bottle. Once stable levels of lever-responding and alcohol consumption were reached, rats were treated with 0, 25, 50, and 100 mg/kg GS39783 (i.g.) 60 min before the self-administration session. Rats displayed robust alcohol-seeking (as suggested by relatively short latencies to the first lever-response and high frequencies of lever-responding) and -taking (as suggested by alcohol intakes averaging approximately 1.5 g/kg) behaviors. Pretreatment with GS39783 inhibited both alcohol-seeking (the number of rats achieving RR55 and the mean RR value were virtually halved) and -taking (the amount of self-administered alcohol was reduced by approximately 60%).The results of the present study suggest the power of the “sipper” procedure in triggering high levels of alcohol-seeking and -taking behavior in sP rats. Further, these results extend to this additional procedure of alcohol self-administration the capacity of GS39783 to reduce the motivational properties of alcohol and alcohol consumption in sP rats. Keywords: “sipper” procedure of alcohol self-administration, alcohol-seeking and -taking behavior, positive allosteric modulator of the GABA B receptor, GS39783, Sardinian alcohol-preferring (sP) rats self-administration: the fixed ratio (FR) schedule of reinforcement and the progressive ratio (PR) schedule of reinforcement (see Markou et al., 1993). In the FR procedure, the response require- ment (RR) – i.e., the “cost” of each alcohol presentation in terms of number of behavioral responses (lever-pressing, nose-poking, or spout-licking) – is kept fixed throughout the session; in other words, each alcohol access occurs after the animal has emitted the specifically required behavior [e.g., four responses on the lever in the study testing GS39783 (Maccioni et al., 2007)]. In the PR pro- cedure, RR – likewise, the behavior needed to access each alcohol presentation – is progressively increased over the session [e.g.: 4, 9, 12, 15, 20, 25, 32, 40, 50, 62, 77, 95, 118, 145, 178, 219, and so on in the study testing GS39783 (Maccioni et al., 2008)]; the lowest ratio not completed or the highest ratio completed (defined as “break- point”) is taken as the measure of alcohol’s motivational properties. In both FR and PR procedures, alcohol presentations are (a) multiple over each single session, (b) of fixed and relatively small magnitude (0.1 ml is the common volume of each access), and (c) interspersed among sequences of operant behavior (i.e., animals alternate short periods during which they emit the operant behavior with short periods of alcohol consumption). Because of this latter feature, these INTRODUCTION GS39783 (N,N′-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine- 4,6-diamine) is one of the few effective in vivo positive allosteric mod- ulators (PAMs) of the GABA B receptor (GABA B PAMs) synthesized to date (Urwyler et al., 2003; Cryan et al., 2004). Recent experimental data indicate that its administration specifically reduces operant, oral alcohol self-administration in selectively bred, Sardinian alcohol- preferring (sP) rats (Maccioni et al., 2007, 2008). These data are in line with the results of recent studies indicating the capacity of (a) GS39783 to reduce other alcohol-related behaviors, including alcohol drinking (Orrù et al., 2005), and (b) the other presently available GABA B PAMs, CGP7930, BHF177, and rac-BHFF to reduce operant, oral alcohol self-administration in sP and Indiana alcohol-preferring (P) rats (Liang et al., 2006; Maccioni et al., 2009, 2010). These data are also consonant with multiple lines of experimental and clini- cal evidence suggesting a role for the GABA B receptor system in the mediation of the behavioral and pharmacological effects of alcohol (see Maccioni and Colombo, 2009; Leggio et al., 2010). The above-mentioned self-administration studies test- ing GS39783 and all other GABA B PAMs have been conducted using the two most conventional procedures of operant alcohol Edited by: Lorenzo Leggio, Brown University, USA Reviewed by: Malgorzata Filip, Polish Academy of Sciences, Poland Maria E. Quintanilla, Universidad de Chile, Chile *Correspondence: Giancarlo Colombo, Consiglio Nazionale delle Ricerche Neuroscience Institute, Viale Diaz 182, I-09126, Cagliari, Italy. e-mail: colomb@unica.it † Paola Maccioni and Paolo Flore are contributed equally to the work.