ORIGINAL INVESTIGATION Activation of serotonin 5-HT2 A receptors inhibits high compulsive drinking on schedule-induced polydipsia Silvia Victoria Navarro & Valeria Gutiérrez-Ferre & Pilar Flores & Margarita Moreno Received: 4 April 2014 /Accepted: 28 July 2014 /Published online: 26 August 2014 # Springer-Verlag Berlin Heidelberg 2014 Abstract Rationale Schedule-induced polydipsia (SIP) is an established model for studying compulsive behaviour in rats. Serotoninergic drugs effectively reduce compulsive drinking on SIP, and high compulsive drinker rats selected by SIP have shown differences in serotoninergic brain activity. However, the specific serotoninergic receptors that modulate compulsive SIP remain unclear. Objective We investigated the functional role of serotonin 5- hydroxytryptamine 2A or C (5-HT 2A/C ) receptors in compul- sive SIP behaviour. Methods Rats were selected for low (LD) versus high drink- ing (HD) behaviour on SIP. The effects of the systemic ad- ministration of the selective serotonin reuptake inhibitor citalopram, selective norepinephrine reuptake inhibitor atomoxetine, serotonin 5-HT 2A/C receptor agonist DOI hydro- chloride ((±)-2,5-dimethoxy-4-iodoamphetamine), serotonin 5-HT 2C receptor antagonist SB242084, serotonin 5-HT 2A re- ceptor antagonist ketanserin and M100907 were assessed on SIP. Subsequently, the effects of DOI were tested after the pre- administration of SB242084, ketanserin and M100907 on SIP. Results Citalopram and DOI reduced compulsive drinking in HD compared with LD rats on SIP. In contrast, SB242084 increased compulsive drinking in HD compared with LD rats on SIP. Atomoxetine, ketanserin and M100907 had no effect on SIP. The reduction in water intake produced by DOI was blocked by ketanserin and M100907, but not by SB242084 administration, in HD rats. Conclusions These findings highlight the contribution of se- rotoninergic 5-HT 2A/C receptors compared with noradrenergic mechanisms on SIP and reveal the “therapeutic” activation of serotonin 5-HT 2A in the inhibition of the compulsive drinking behaviour in HD rats. Thus, it may represent a potentially new marker of vulnerability and provides additional insight for potential treatments on compulsive behaviours in neuropsy- chiatric populations. Keywords Schedule-induced polydipsia . Compulsivity . Serotonin . Serotonin 5-HT 2A receptor . Serotonin 5-HT 2C receptor . Obsessive–compulsive disorder . Animal model Introduction Compulsivity is defined as an inappropriate perseveration of response, in which the individual is unable to resist despite adverse consequences (Robbins and Crockett 2010). While obsessive–compulsive disorder (OCD) is one of the most characteristic clinical examples of compulsivity, this behav- iour is present across different neuropsychiatric disorders, such as attention deficit–hyperactivity disorder (ADHD), schizophrenia, depression, compulsive gambling, eating dis- orders and substance abuse (Skodol and Oldham 1996). Fur- thermore, compulsivity is also present in excoriation and binge-eating disorder, both of which have been recently categorised as such in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association 2013). Among the potential mechanisms under- lying compulsive behaviours, pharmacological treatments in clinical and pre-clinical observations in OCD suggest the involvement of serotonergic dysfunctions (Angoa-Pérez et al. 2012; Goddard et al. 2008; Robbins and Crockett 2010). Indeed, convergent evidence from animal and human studies has suggested a key role of serotonin 5- hydroxytryptamine 2A/C (5-HT 2A/C ) receptor subtypes in compulsive behaviours (for a review, see Aznar and Klein S. V. Navarro : V. Gutiérrez-Ferre : P. Flores : M. Moreno (*) Department of Psychology, University of Almería, Campus de Excelencia Internacional Agroalimentario CeiA3, Carretera de Sacramento s/n, 04120 Almería, Spain e-mail: mgmoreno@ual.es Psychopharmacology (2015) 232:683–697 DOI 10.1007/s00213-014-3699-7