Behavioral pharmacology (S)-amisulpride as a discriminative stimulus in C57BL/6 mice and its comparison to the stimulus effects of typical and atypical antipsychotics Timothy J. Donahue a , Todd M. Hillhouse a , Kevin A. Webster a , Richard Young b , Eliseu O. De Oliveira c , Joseph H. Porter a,n a Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA b Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA c Center for Drug Discovery, Georgetown University, Washington, DC, USA article info Article history: Received 8 November 2013 Received in revised form 10 March 2014 Accepted 20 March 2014 Available online 12 April 2014 Keywords: Amisulpride Benzamides Antipsychotic drugs Drug discrimination Schizophrenia C57BL/6 mice abstract Amisulpride, a substituted benzamide derivative, exerts atypical antipsychotic and antidepressant clinical effects and its (S)-stereoisomer is thought to underlie these actions. In the present study, male C57BL/6 mice were trained to discriminate (S)-amisulpride (10 mg/kg, s.c.) from vehicle in a two-lever drug discrimination task for food reward. The (S)-amisulpride stimulus was rapidly acquired and was shown to be dose-related, time dependent (effective between 30 and 120 min) and stereoselective: (S)- amisulpride (ED 50 ¼1.77 mg/kg; 4.2 mmol/kg) was about three times more potent than rac-amisulpride (ED 50 ¼4.94 mg/kg; 13.4 mmol/kg) and ten times more potent than (R)-amisulpride (ED 50 ¼15.84 mg/kg; 42.9 mmol/kg). In tests of stimulus generalization, the (S)-amisulpride stimulus generalized completely to sulpiride (ED 50 ¼12.67 mg/kg; 37.1 mmol/kg), a benzamide analog that also is purported to be an atypical antipsychotic, but did not fully generalize to the typical antipsychotic drug haloperidol (maximum of 45% drug-lever responding) nor to the atypical antipsychotic drugs clozapine (partial substitution of 65% drug-lever responding) or aripiprazole ( 30% drug-lever responding). These results demonstrated that (S)-amisulpride appears to exert a unique discriminative stimulus effect that is similar to other benzamides, but which differs from other structural classes of antipsychotic drugs. & 2014 Elsevier B.V. All rights reserved. 1. Introduction Amisulpride (Solian s ), a substituted benzamide derivative (Fig. 1), is classified as an atypical antipsychotic drug that is prescribed for the treatment of schizophrenia in which positive symptoms (delusions, hallucination, thought disorders) and nega- tive symptoms (e.g. blunted affect, social withdrawal) are pronounced; atypical antipsychotics exhibit a reduced risk of drug-induced extrapyramidal motor side effects (Noble and Benfield, 1999). Amisulpride may produce attenuation of such symptoms because of its antagonism of dopamine D 2 and D 3 receptors. Amisulpride is prescribed at much lower doses for the treatment of depressive disorders such as dysthymia and this effect may be produced by antagonism of pre-synaptic dopamine auto- receptors and consequent increased activity of post-synaptic dopamine receptors (Coukell et al., 1996; Cudennec et al., 1997; Schoemaker et al., 1997). More recently, Abbas et al. (2009) reported a receptor binding profile and functional effects of amisulpride that confirmed its high affinity binding at dopamine D 2/3 receptors and at serotonin 5-HT 2B and 5-HT 7 receptors and concluded that it exerts antidepressant action via antagonism of 5-HT 7 receptors. Lastly, the chemical structure of amisulpride contains a chiral center and, thus, is a mixture of two optical isomers: (S)-amisulpride and (R)-amisul- pride (Fig. 1). The enantiomers bind at dopamine D 2/3 and α 2 - adrenoceptors in a stereoselective manner with marked differences in affinity: (S)-amisulpride displays high affinity binding at both D 2 and D 3 receptors and is approximately twice as potent as rac- amisulpride and 20–50 times more potent than (R)-amisulpride at these receptors (Castelli et al., 2001; Marchese et al., 2002a,b). On the other hand, the isomers display reversed stereoselectivity (but weaker affinity) at α 2 -adrenoceptors: R( þ )amisulpride is twice as potent as racemic amisulpride and four times more potent than S(  ) amisulpride (Marchese et al., 2002a). Drug discrimination is a powerful in vivo assay to determine the subjective effects and receptor mechanisms that mediate the Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/ejphar European Journal of Pharmacology http://dx.doi.org/10.1016/j.ejphar.2014.03.047 0014-2999/& 2014 Elsevier B.V. All rights reserved. n Correspondence to: Department of Psychology, PO BOX 842018, 806 West, Franklin Street. Virginia Commonwealth University, Richmond, VA 23284-2018, USA. Tel.: þ1 804 828 0096; fax: þ1 804 828 2237. E-mail address: jporter@vcu.edu (J.H. Porter). European Journal of Pharmacology 734 (2014) 15–22