Psychopharmacology (2005) 180: 206–214 DOI 10.1007/s00213-005-2150-5 ORIGINAL INVESTIGATION A. E. Kudwa . E. Dominguez-Salazar . D. M. Cabrera . D. R. Sibley . E. F. Rissman Dopamine D5 receptor modulates male and female sexual behavior in mice Received: 9 March 2004 / Accepted: 7 December 2004 / Published online: 5 February 2005 # Springer-Verlag 2005 Abstract Rationale: Dopamine exerts its actions through at least five receptor (DAR) isoforms. In female rats, D5 DAR may be involved in expression of sexual behavior. We used a D5 knockout (D5KO) mouse to assess the role of D5 DAR in mouse sexual behavior. Both sexes of D5KO mice are fertile and exhibit only minor disruptions in exploratory locomotion, startle, and prepulse inhibition responses. Objective: This study was conducted to char- acterize the sexual behavior of male and female D5KO mice relative to their WT littermates. Methods: Female WT and D5KO littermates were ovariectomized and given a series of sexual behavior tests after treatment with es- tradiol benzoate (EB) and progesterone (P). Once sexual performance was optimal the dopamine agonist, apomor- phine (APO), was substituted for P. Male mice were ob- served in pair- and trio- sexual behavior tests. To assess whether the D5 DAR is involved in rewarding aspects of sexual behavior, WT and D5KO male mice were tested for conditioned place preference. Results: Both WT and D5KO females can display receptivity after treatment with EB and P, but APO was only able to facilitate receptivity in EB-primed WT, not in D5KO, mice. Male D5KO mice display normal masculine sexual behavior in mating tests. In conditioned preference tests, WT males formed a con- ditioned preference for context associated with either intromissions alone or ejaculation as the unconditioned stimulus. In contrast, D5KO males only showed a place preference when ejaculation was paired with the context. Conclusions: In females, the D5 DAR is essential for the actions of dopamine on receptivity. In males, D5 DAR influences rewarding aspects of intromissions. Taken to- gether, the work suggests that the D5 receptor mediates dopamine’ s action on sexual behavior in both sexes, per- haps via a reward pathway. Keywords Sexual behavior . Dopamine . Conditioned place preference . Drugs . Motivation . Knockout mice . Reward . Attention deficit hyperactivity disorder Introduction Dopamine exerts its effects via at least five dopamine receptor (DAR) isoforms that are divided into two families: D1-like (D1 and D5) receptors and D2-like (D2, D3, and D4) receptors (Jackson and Westlind-Danielsson 1994; Missale et al. 1998). Within the D1-like family, D1 and D5 dopamine receptors share 78% sequence homology; yet, they have different distributions in the brain, suggesting distinct functional roles (Sunahara et al. 1991; Tiberi et al. 1991). For example, neuropharmacological and molec- ular studies suggest a role for a D1-like DAR, particu- larly the D5, in controlling female rat sex behavior (Pollio et al. 1993; Mani et al. 1994, 1996, 2000; Fienberg and Greengard 2000; Mani 2001). Dopamine can act via cyclic AMP (cAMP) that activates cAMP-dependent protein kinase, which stimulates phosphorylation of several neu- ronal phosphoproteins including dopamine- and cAMP- regulated phosphoprotein-32 (DARPP-32). DARPP-32 in turn may phosphorylate the progesterone receptor (PR) and enhance expression of female sexual behavior (Mani et al. 2000; Auger et al. 2001; Apostolakis et al. 2004). Currently, there are no D1- or D5-specific agonists or antagonists, but the generation of dopamine D1 (Drago et al. 1994; Xu et al. 1994) and D5 (Hollon et al.1998, 2002) A.E. Kudwa and E. Dominguez-Salazar are co-authors. A. E. Kudwa . E. F. Rissman Neuroscience Graduate Program, University of Virginia Medical School, Charlottesville, VA, 22908, USA E. Dominguez-Salazar . E. F. Rissman (*) Department of Biochemistry and Molecular Genetics, University of Virginia Medical School, Charlottesville, VA, 22908, USA e-mail: rissman@virginia.edu Tel.: +1-434-9825611 Fax: +1-434-2438433 D. M. Cabrera . D. R. Sibley Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, 20892, USA