Thus, activation of DARPP-32 in direct MSNs is linked to a specific behavioral output produced by PCP and regarded as a surrogate marker of the positive symptoms of schizophrenia. == Statement of Interest == None. == Acknowledgments == This work was supported by the Swedish Research Council (grant number 13482 to Dr Fisone), StratNeuro at Karolinska Institutet (Dr Fisone), the foundation Blanceflor Boncompagni-Ludovisi ne Bildt (Dr Bonito-Oliva), and hln-stiftelsen (Dr Bonito-Oliva) The authors thank Dr Paul Greengard intended for generously providing theDARPP-32F/F, D1Rcre+, andD2RCre+transgenic mice used in this study. == References ==. phosphorylation was determined Spautin-1 by Western blotting. The motor stimulant effects of PCP were determined by measuring locomotion following acute Rabbit polyclonal to PPP1CB and chronic administration. Memory space deficit was evaluated using the passive avoidance test. == Results: == Loss Spautin-1 of DARPP-32 in direct MSNs prevents PCP-induced phosphorylation and abolishes the motor stimulation effects of PCP. In contrast, lack of DARPP-32 in indirect MSNs does not affect the ability of PCP to promote DARPP-32 phosphorylation and to increase motor activity. The impairment in passive avoidance induced by PCP is independent of the expression of DARPP-32 in direct or indirect MSNs. == Conclusions: == The increase in DARPP-32 phosphorylation induced by PCP occurs selectively in the MSNs from the direct pathway, which are also specifically involved in the motor stimulant effects of this drug. The memory space deficit induced by PCP is not linked to the expression of DARPP-32 in striatal MSNs. Keywords: basal ganglia, dopamine and cAMP-regulated phosphoprotein of 32 kDa, motor activity, phencyclidine, schizophrenia == Introduction == The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) is a recognized psychotomimetic that produces behavioral changes similar to those noticed during acute schizophrenic episodes (Luby et al., 1959). Based on these properties of PCP, it has been suggested that alterations of glutamatergic transmission are implicated in the pathophysiology of schizophrenia (Olney et al., 1999) and glutamatergic antagonists, like PCP and ketamine, have been largely used to generate a pharmacological model of this disorder (Javitt and Zukin, 1991; Abi-Saab et al., 1998; Tamminga, 1998; Jentsch and Roth, 1999; Krystal et al., 1999). In rodents, acute and chronic supervision of PCP results in cognitive deficits (Handelmann et al., 1987; Jentsch et al., 1997; Adams and Moghaddam, 1998; Beraki et al., 2008) and disrupted sensorimotor gating (Mansbach and Geyer, 1989), two major symptoms observed in schizophrenic patients. In addition , PCP raises locomotor activity and repetitive movements, which have been proposed to represent a surrogate marker on the positive symptoms of schizophrenia (Sturgeon et ing., 1979; Sams-Dodd, 1996; Bondi et ing., 2012). Studies in human beings and in four-legged friend models reveal that, besides antagonizing NMDA receptors, PCP also helps bring about dopamine transmitting (Giannini ou al., 1984; gren and Goldstein, 1994; Seeman and Lasaga, 2006; Seeman and Guan, 2008). In particular, PCP exerts agonistic action in dopamine D2 receptors (D2Rs; Seeman and Lasaga, 2006; Seeman and Guan, 2008) and enhances dopamine efflux in several mind regions, such as the striatum, an important component of the basal ganglia involved in engine function (Bowyer et ing., 1984; Steinpreis and Salamone, 1993; Hertel et ing., 1995; Moghaddam and Adams, 1998). Consistent with these observations, it has been proven that the capability of PCP to cause repetitive actions and hinder sensorimotor gating depends on the dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32; Svenningsson et ing., 2003), something of dopamine signaling (Fienberg et ing., 1998). In the striatum, DARPP-32 is enriched in the GABAergic medium spiny neurons (MSNs; Ouimet ou al., 1998), which make up the direct and indirect paths to the end result nuclei on the basal ganglia (Albin ou al., 1989; Gerfen, 1992). Activation of dopamine D1 receptors (D1Rs), which are selectively expressed in direct MSNs (Gerfen, 1992), leads to phosphorylation of DARPP-32 at Thr34 (Nishi ou al., 1997; Svenningsson ou al., 1998). This impact is mediated by cAMP-dependent protein kinase (PKA) and converts DARPP-32 into an inhibitor of protein phosphatase-1 (PP-1; Spautin-1 Hemmings et ing., 1984), therefore reducing dephosphorylation of PKA target healthy proteins and amplifying cAMP-mediated reactions (Fienberg ou al., 1998; Greengard, 2001). In contrast, service of D2Rs, which are portrayed in indirect MSNs (Gerfen, 1992), causes inhibition of PKA (Kebabian and Calne, 1979) and reduction of DARPP-32 phosphorylation (Nishi ou al., 1997; Svenningsson ou al., 2000). PCP has been shown to increase DARPP-32 phosphorylation in Thr34 in the striatum (Svenningsson et ing., 2003; Pozzi et ing., 2010). Nevertheless , the specific localization of this impact in direct or indirect MSNs, and also the role these two neuronal populations in the behavioral reactions to PCP, remain to get elucidated. With this study, all of us used transgenic mice by which DARPP-32 was deleted in D1R- or D2R-expressing MSNs (Bateup ou al., 2010) to study the role on the direct and indirect MSNs in the engine and cognitive effects of PCP. == Methods == == Animals == Mice by which DARPP-32 was conditionally removed in D1R- or D2R-expressing MSNs (D32F/FD1RCre+andD32F/FD2RCre+mice) and control mice (D32+/+D1RCre+and D32+/+D2RCre+mice, hereafter referred to as D1RCre and D2RCre mice) were generated seeing that previously identified (Bateup ou al., 2010). Experiments were carried out according to the guidelines of Research Integrity Committee of Karolinska Institutet, Swedish Four-legged friend Welfare Company, and Western european Communities Council Directive 86/609/EEC. == Medicines == Phencyclidine hydrochloride (Sigma-Aldrich) was blended in saline and inserted (3 or 6mg/kg) subcutaneously (s. c. ) in the scruff on the neck in a.