Characterization of 5-HT 1A/1B / mice: An animal model sensitive to anxiolytic treatments Jean-Philippe Guilloux a, * , Denis J.P. David a , Lin Xia a , Hai Thanh Nguyen a , Quentin Rainer a , Bruno P. Guiard a , Christelle Repérant a , Thierry Deltheil a , Miklos Toth b , René Hen c , Alain M. Gardier a, * a Univ Paris-Sud EA 3544, Faculté de Pharmacie, 5, rue JB Clément, Châtenay-Malabry Cedex F-92296, France b Department of Pharmacology, Weill Medical College of Cornell University,1300 York Avenue, New York, NY 10065, USA c Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA article info Article history: Received 10 September 2010 Received in revised form 7 February 2011 Accepted 9 February 2011 Keywords: 5-HT 1A receptor 5-HT 1B receptor KO mice Anxiety SSRI Paroxetine Anxiety Depression Electrophysiology Neurochemistry Behavior abstract Selective serotonin (5-HT) re-uptake inhibitors (SSRIs) are commonly used in the treatment of gener- alized anxiety disorder in Humans. However, because only few animal models display overt anxious-like behavior, detailed preclinical studies of the anxiolytic properties of antidepressants are still lacking. Here, we studied the neurochemical and behavioral effects of a double 5-HT 1A/1B receptor knockout in mice (5-HT 1A/1B /) as compared to their wild-type littermates (5-HT 1A/1B þ/þ). It is known that single deletion of either 5-HT 1A or 5-HT 1B receptor induces behavioral changes that are not correlated with differences in brain serotonergic tone. Deletion of both receptors resulted in (i) higher emotionality of animals, as observed in three unconditioned paradigms of anxiety (open field, elevated plus maze and novelty suppressed feeding tests); (ii) a z200% increase in the mean spontaneous firing rate of 5-HT neurons in the dorsal raphe nucleus (DRN) compared to 5-HT 1A/1B þ/þ mice; (iii) elevated basal dialysate levels of 5-HT in the DRN and frontal cortex; (iv) an exaggerated response to acute paroxetine admin- istration in microdialysis experiments, and (v) increased basal core body temperature. These findings suggest that the deletion of both autoreceptors induces a strong anxious-like behavioral state associated with increased 5-HT neurotransmission. Interestingly, 5-HT 1A/1B / mice are still sensitive to the acute administration of diazepam. Moreover, while deletion of both receptors impacted on the response to acute SSRI treatment in the forced swim test, anxiolytic-like effects of a chronic SSRI treatment were still observed in 5-HT 1A/1B / mice. Thus, the 5-HT 1A/1B / mouse model could be of great interest to unveil the mechanisms of action of the anxiolytic effects of SSRIs. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction General anxiety disorders are best treated with benzodiaze- pines, but these drugs induce several side effects such as dependency after chronic administration (Lader, 1994). Serotonin- selective reuptake inhibitors (SSRIs) antidepressants, as well as the serotoninenoradrenaline reuptake inhibitor venlafaxine, are also effective in the treatment of general anxiety disorders (Ball et al., 2005; Bielski et al., 2005; Rickels et al., 2003; Stein et al., 2005). However, compared to benzodiazepines, the decrease in side effects of SSRI is counterbalanced by their slower onset of thera- peutic action (Klein et al., 1995; Rickels et al., 2003). The anxiolytic properties of SSRIs are difficult to demonstrate in preclinical studies, because current animal models of anxiety are poorly predictive (Borsini et al., 2002). The generation of knockout (KO) mice has however showed promise in this regard. For example, 5-HT 1A receptor KO mice (5-HT 1A /) display an anxious phenotype (Heisler et al., 1998; Parks et al., 1998; Ramboz et al., 1998), associated with decreased exploratory activity, increased fear of aversive environments (Klemenhagen et al., 2006) and other aspects of anxiety, such as autonomic activation, increased stress responsiveness, and neuroendocrine abnormalities (see Toth, 2003 for a review). Moreover, increased 5-HT turnover (Ase et al., 2000) and increased 5-HT neuron firing (Richer et al., 2002) have been reported in 5-HT 1A / mice, even though not associated with increased basal extracellular 5-HT levels ([5-HT]ext), as measured by microdialysis in the striatum (He et al., 2001; Knobelman et al., 2001b), dorsal raphe nucleus (DRN) and frontal cortex (Bortolozzi et al., 2004; Guilloux et al., 2006). Moreover, acute treatment with an SSRI, which increases [5-HT]ext levels in the DRN and frontal cortex of both 5-HT 1A / and 5 HT 1A þ/þ mice (Guilloux et al., 2006), has a greater effect on the forced swim test * Corresponding authors. Tel.: þ33 1 46 83 54 16; fax: þ33 1 46 83 53 55. E-mail addresses: jean-philippe.guilloux@u-psud.fr (J.-P. Guilloux), alain.gardier@ u-psud.fr (A.M. Gardier). Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm 0028-3908/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2011.02.009 Neuropharmacology xxx (2011) 1e11 Please cite this article in press as: Guilloux, J.-P., et al., Characterization of 5-HT 1A/1B / mice: An animal model sensitive to anxiolytic treat- ments, Neuropharmacology (2011), doi:10.1016/j.neuropharm.2011.02.009