* 0.05; ** 0.01; *** 0.001. Likewise, clasping behavior was not elicited by acute FLX treatment (= 0.9307) but by chronic FLX treatment (= 0.0001) (Fig. (DA) systems modulate numerous brain functions and are implicated in the pathophysiology of affective, stress, and movement disorders. Both systems interact by mutually innervating brain regions/circuits and reciprocally modulating each other. This 5-HT/DA conversation plays a critical role in the action of antidepressant drugs. 5-HT-selective reuptake inhibitors MAFF (SSRIs) for example, block 5-HT transporter (5-HTT) function to increase 5-HT signaling, but may also induce side effects typically associated with reduced DA signaling, such as anhedonia, apathy, reduced libido, akathisia, and extrapyramidal motor symptoms (EPSs) (Settle, 1998; Cassano and Fava, 2004; Damsa et al., 2004; Preskorn et al., 2004). These side effects can lead to Germacrone discontinuation even when treatment is usually efficacious (Kaplan, 1997; Chelben et al., 2001) and reduce response rates (Rush et al., 2006). Increased mechanistic understanding of 5-HT/DA conversation should allow for improved treatment strategies and drug design. 5-HT neurons of the dorsal and median raphe nuclei densely innervate DAergic nuclei and their projection areas (Michelsen et al., 2007). In mouse and rat, the densest afferent 5-HT innervation is present in the substantia nigra pars compacta (SNc) and pars reticulata (SNr)both integral parts of the basal ganglia (BG) (Miller et al., 1975; Dray et al., 1978; Imai et al., 1986; Vertes, 1991; Moukhles et al., 1997). The SNc DAergic neurons project to the striatum and provide DAergic modulatory input into the direct and indirect pathways of the BG. The SNr is the main output region of the BG and contains mostly GABAergic neurons projecting to the thalamus and the SNc (Bolam et al., 2000). The latter projection provides opinions inhibition to DAergic activity (Tepper and Lee, 2007). Based on this circuitry, we investigated the impact of 5-HTT blockade around Germacrone the nigrostriatal DA system and BG function. We focused our studies on BG-dependent motor behavior as a proxy for BG function because of its well-characterized sensitivity to alterations in DAergic activity (Brooks and Dunnett, 2009). Here we show that mutation ((except as noted). Animals were maintained on a 12 h light/dark cycle (8:00 A.M./8:00 P.M.) Animal testing was conducted in accordance with the National Institutes of Health guidelines (test or one- or two-way ANOVA. The criterion for significance for all those analyses was 0.05. The criterion for any pattern Germacrone was 0.05 0.1. comparisons were conducted using the StudentCNewmanCKeuls test. Results from data analyses are expressed as mean SEM. Results ablation impairs BG-dependent motor behavior To study the consequences of increased 5-HT signaling on BG function, we first investigated the effect of = 0.0014 and = 0.0196, respectively) (Fig. 1= 0.1820; and = 0.5446, respectively). The beam-walking test required mice to traverse an elevated beam from a lit to a dark compartment. = 0.0060 and 0.0001, respectively) (Fig. 1 0.0001 and = 0.0004, respectively) (Fig. 1 0.0001), with increased clasping over time as revealed by an conversation between genotype and time ( 0.0001) (Fig. 1= 0.0696; excess weight in beam-walking test group, = 0.0823; excess weight in rotarod test group, = 0.0719; grip strength, 0.5526) (Fig. 1= 17C18 mice per group). = 6C16 mice per group). = 22C26 mice per group). = 23C26 mice per group). = 6C15 mice per group). * 0.05; ** 0.01; *** 0.001. All screening was carried out in adult mice, but given the constitutive nature of genetic ablations, we sought to assess the ontogeny of the = 0.0005) but behavioral differences manifested themselves only at 14 weeks of age (as identified by comparisons) (Fig. 2 0.0001), with a more.