DARPP-32 cascade in striatal medium spiny neurons

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Neuroscience and Biobehavioral Reviews 31 (2007) 79–88 www.elsevier.com/locate/neubiorev

Review

Psychoactive drugs and regulation of the cAMP/PKA/DARPP-32 cascade in striatal medium spiny neurons Anders Borgkvist, Gilberto Fisone Department of Neuroscience, Karolinska Institutet, Retzius va¨g 8, 17177 Stockholm, Sweden Received 7 January 2006; received in revised form 13 March 2006; accepted 13 March 2006

Abstract Changes in activity of the medium spiny neurons (MSNs) of dorsal and ventral striatum result in alterations of motor performance, ranging from rapid increases or decreases in locomotor activity, to long-term modifications of motor behaviours. In the dorsal striatum, MSNs can be distinguished based on the organization of their connectivity to substantia nigra pars reticulata (SNpr) and internal segment of the globus pallidus (GPi), which, in turn, control thalamocortical neurons. Approximately half of the MSNs project directly to SNpr and GPi, their activation leading to disinhibition of thalamocortical neurons and increased motor activity. The other subpopulation of MSNs connects to SNpr and GPi indirectly and when activated promotes inhibition of thalamocortical neurons, thereby reducing motor activity. The dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) is a modulator of the cAMP signalling pathway, highly expressed in MSNs. This review discusses the regulation of DARPP-32 exerted by psychoactive substances in specific populations of striatal projection neurons and its involvement in short- and long-term motor responses. r 2006 Elsevier Ltd. All rights reserved. Keywords: Adenosine; Amphetamine; Caffeine; Cannabinoids; Cocaine; Dopamine; Motor activity; Nucleus accumbens; Phosphorylation; Sensitization; Striatonigral pathway; Striatopallidal pathway

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DARPP-32, a modulator of the cAMP signal transduction cascade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of DARPP-32 in dopamine D1 expressing MSNs: involvement in the action of psychostimulants . . . . . . . . . . . . . . 3.1. DARPP-32 phosphorylation at Thr75 and psychomotor sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. DARPP-32 phosphorylation at Thr34 and control of downstream target proteins in the MSNs of the striatonigral pathway and nucleus accumbens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Abnormal regulation of DARPP-32 and sensitivity to psychostimulants: evidence from genetic studies . . . . . . . . . 4. DARPP-32 regulation in striatopallidal MSNs: contrasting action of dopamine D2 and adenosine A2A receptors . . . . . . 4.1. Role of DARPP-32 in the action of caffeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Role of DARPP-32 in cannabinoid transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. DARPP-32 phosphorylation at Thr34 and control of AMPA receptors in striatopallidal MSNs . . . . . . . . . . . . . . 5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Fax: +46 8 320988.

E-mail address: gilberto.fi[email protected] (G. Fisone). 0149-7634/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2006.03.003

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1. Introduction The striatal complex is the largest component of the basal ganglia and includes anatomically distinct subcortical structures innervated by dopaminergic fibers originating from two midbrain regions: the substantia nigra pars compacta (SNpc) and the ventral tegmental area. The dorsolateral region of the striatum is innervated by the neurons of the SNpc and is mainly involved in motor function. The ventral striatum, or nucleus accumbens, together with the dorsomedial striatum, is innervated by the neurons of the ventral tegmental area and plays a major role in mediating motivation and reward. The vast majority of striatal neurons consist of GABAergic medium spiny neurons (MSNs), which, in addition to the dopaminergic input, receive glutamatergic afferents from cerebral cortex, thalamus, limbic areas and hippocampus. In the striatum, dopamine controls the state of excitability of MSNs by modulating glutamatergic transmission via different types of G-protein coupled receptors, which can be divided into two classes, the D1-like (D1 and D5) and D2-like (D2, D3 and D4) receptors, based on their sequence homology, pharmacology and intracellular signalling properties (Missale et al., 1998). Dopamine receptor subtypes are differentially distributed in various populations of MSNs. This is particularly evident at the level of the dorsal striatum, where MSNs can be distinguished based on the organization of their connectivity to the output stations of the basal ganglia, i.e. substantia nigra pars reticulata (SNpr) and internal segment of the globus pallidus (GPi; entopeduncular nucleus in rodents). About 50% of MSNs innervate ‘‘directly’’ SNpr and GPi and form the striatonigral pathway. The rest of the dorsostriatal MSNs project to SNpr and GPi ‘‘indirectly,’’ via external segment of globus pallidus and subthalamic nucleus, and form the striatopallidal pathway. Extensive morphological and functional evidence indicates that the striatonigral neurons of the direct pathway express almost exclusively dopamine D1 receptors, whereas the striatopallidal neurons of the indirect pathway express dopamine D2 receptors (Gerfen, 1992). Such a distinction is absent in the MSNs of the nucleus accumbens, where dopamine D1 and D2-like (e.g. D3) receptors are co-expressed (Le Moine and Bloch, 1996). The different wiring linking striatonigral and striatopallidal MSNs to SNpr and GPi is responsible for the opposite effects exerted by these neurons on thalamocortical neurons, and ultimately on motor function. Thus, activation of the direct pathway results in disinihibtion of thalamocortical neurons and increased motor activity, whereas activation of the indirect pathway enhances the inhibition exerted by SNpr and GPi on thalamocortical neurons and depresses motor function. Among the various signal transduction pathways that participate

in the regulation of the state of excitability of MSNs, the cAMP signalling pathway has received considerable attention. Much of this interest stems from the original observation that dopamine D1-like receptors are coupled to activation, whereas dopamine D2-like receptors are coupled to inhibition, of adenylyl cyclase (Kebabian et al., 1972; Stoof and Kebabian, 1981). Subsequent work has led to the discovery of numerous components that participate in the transduction of cAMP-dependent signalling, starting from activation, or blockade, of dopamine receptors and leading to specific responses elicited in MSNs.

2. DARPP-32, a modulator of the cAMP signal transduction cascade The dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) is one important modulator of the cAMP pathway, highly expressed in both striatonigral and striatopallidal neurons (Ouimet et al., 1998). Early studies demonstrated that DARPP-32 is regulated by dopamine D1 receptors via increase of cAMP production and stimulation of cAMP-dependent protein kinase (PKA) (Walaas et al., 1983). Phosphorylation catalysed by PKA at Thr34 converts DARPP-32 into an inhibitor of protein phosphatase-1 (PP-1) (Hemmings et al., 1984). Activation of dopamine D1 receptors is also accompanied by decreased phosphorylation of DARPP-32 at Thr75 (Nishi et al., 2000). Phosphorylation of Thr75 is catalysed by cyclin-dependent kinase-5 (cdk5), and converts DARPP-32 into an inhibitor of PKA (Bibb et al., 1999). The exact mechanism by which D1 receptor activation reduces DARPP-32 phosphorylation at Thr75 is not clear, but this effect may be mediated via PKA-dependent phosphorylation and activation of protein phosphatase-2A (PP-2A) (Usui et al., 1998), which is responsible for dephosphorylation of DARPP-32 at Thr75 (Bibb et al., 1999; Nishi et al., 2000). Changes in DARPP-32 phosphorylation at Thr34 and Thr75 produced by activation of dopamine D1 receptors have important functional consequences. Increased phosphoThr34-DARPP-32 amplifies the effects of the dopamine D1 receptor/cAMP/PKA signalling cascade by inhibiting PP-1 and reducing dephosphorylation of downstream target proteins, such as ion channels and receptors (see below) (Nairn et al., 2004). Reduction in Thr75 phosphorylation further promotes D1 receptormediated stimulation of the cAMP pathway by removing the inhibition exerted by phosphoThr75-DARPP-32 on PKA (Bibb et al., 1999). The positive feedback on protein phosphorylation provided by DARPP-32 is necessary to elicit full behavioural responses to drugs that promote dopamine D1 receptor transmission at the level of dorsal striatum and nucleus accumbens, such as the psychostimulants cocaine and methamphetamine (Fig. 1).

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Fig. 1. Summary of the effects produced by psychoactive drugs on DARPP-32 phosphorylation and motor behaviour. In the striatum, MSNs can be distinguished by their ability to express different sets of receptors. Striatopallidal MSNs express dopamine D2 and adenosine A2A receptors, whereas striatonigral and accumbal MSNs express dopamine D1 receptors. The MSNs of the ventral striatum (nucleus accumbens) are also enriched in dopamine D3 receptors. Adenosine receptor agonists (e.g. CGS21680), CB1 receptor agonists (e.g. CP55,940) or dopamine D2 receptor antagonists (e.g. raclopride and haloperidol) promote cAMP signalling in striatopallidal MSNs. This effect is intensified by phosphorylation of DARPP-32 at Thr34 and dephosphorylation at Thr75, which mediate the motor depression produced by these drugs (see text). Suppression of cAMP signalling in striatopallidal MSNs produced by caffeine, or by adenosine A2A receptor antagonists (e.g. SCH58261 and KW6002) results in motor stimulation. Concomitant phosphorylation of DARPP-32 at Thr75 and dephosphorylation at Thr 34, further amplifies this motor response. The motor stimulant effects produced by acute administration of cocaine or amphetamine depend on D1 receptor-mediated activation of cAMP signalling, and increased DARPP-32 phosphorylation at Thr34, in striatonigral and accumbal MSNs. Repeated administration of cocaine and amphetamine results in psychomotor sensitization and conditioned place preference and is associated to increased DARPP-32 phosphorylation at Thr75 and decreased phosphorylation at Thr34. The exact role of phosphoThr75- and phosphoThr34-DARPP-32 in these long-term motor responses remains to be elucidated (see text). Green and red arrows indicate activation and inhibition, respectively. Broken lines indicate indirect activation or inhibition.

3. Role of DARPP-32 in dopamine D1 expressing MSNs: involvement in the action of psychostimulants Cocaine and amphetamines increase the levels of extracellular dopamine by inhibiting the reuptake and disrupting the vesicular transport of monoamines. It is well established that a significant proportion of the behavioural effects produced by these psychostimulants are mediated via activation of striatal dopamine D1 receptors. For instance, the hyperlocomotor effect of cocaine is prevented by administration of a dopamine D1 receptor antagonist (Neisewander et al., 1998) and it is absent in dopamine D1 receptor knockout mice (Xu et al., 1994; Drago et al., 1996). Cocaine increases Thr34 (Svenningsson et al., 2000a; Bibb et al., 2001), and decreases Thr75 (Bibb et al., 2001),

phosphorylation via stimulation of dopamine D1 receptors (Svenningsson et al., 2000a). In line with these data, it has been shown that the acute hyperlocomotor response to cocaine is attenuated in DARPP-32 knockout mice (Fienberg et al., 1998), or in mice bearing a mutation on DARPP-32, in which the phosphorylation site for PKA (i.e. Thr34) is replaced by a non-phosphorylatable alanine (Thr34-Ala mutant mice) (Zachariou et al., 2005) (Fig. 1). 3.1. DARPP-32 phosphorylation at Thr75 and psychomotor sensitization Repeated administration of cocaine or amphetamine results in a marked increase in the motor stimulant effect

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produced by these drugs. This behavioural response, generally referred to as psychomotor sensitization, involves adaptive changes affecting the same neuronal circuits, which mediate the rewarding properties of drugs of abuse. Increased cAMP signalling is known to develop in association with behavioural sensitization at the level of the MSNs of the nucleus accumbens (Nestler, 2001). Several studies have shown that DARPP-32 participates in the generation and expression of behavioural sensitization to psychostimulants. It was initially shown that DARPP-32-null mice displayed a potentiation of behavioural sensitization to cocaine (Hiroi et al., 1999). Subsequent studies reported that chronic treatment with cocaine (Bibb et al., 2001; Scheggi et al., 2004), or methamphetamine (Chen and Chen, 2005; but see also Lin et al., 2002) decreased Thr34, and increased Thr75, phosphorylation. This latter effect was attributed to enhanced expression of cdk5 (Bibb et al., 2001; Scheggi et al., 2004) and of its activator, p35 (Bibb et al., 2001; Chen and Chen, 2005). The occurrence, in the ventral striatum, of increased expression of cdk5 in association with cocaine sensitization has been recently challenged (Hope et al., 2005). Moreover, activation of cdk5 produced by acute methamphetamine appears to be unrelated to cdk5 expression (Chen and Chen, 2005). In this regards, it should be noted that increased cdk5 activity has been found to occur in the hippocampus of transgenic mice as a result of p35 overexpression, rather than of cdk5 overexpression (Takahashi et al., 2005). Taken together, the above observations indicate that prolonged treatment with psychostimulants is accompanied by increased p35 expression, increased cdk5 activity, phosphorylation of DARPP-32 at Thr75 and inhibition of PKA. This cascade may represent a homeostatic mechanism that develops during sensitization, in order to counterbalance enhanced cAMP/PKA signalling (Nestler, 2001). In agreement with this interpretation, inhibition of cdk5 (Bibb et al., 2001), or genetic inactivation of DARPP-32 (Hiroi et al., 1999) have been found to enhance cocaine behavioural sensitization. One prediction based on these observations is that mutation of Thr75 of DARPP-32 would also result in exacerbated psychomotor sensitization. Surprisingly, however, it has been recently reported that, in Thr75-Ala DARPP-32 mutant mice, cocaine locomotor sensitization is either unaffected (Valjent et al., 2005) or absent (Zachariou et al.,2005). Therefore, the significance of Thr75 phosphorylation in the action of cocaine has yet to be fully assessed. 3.2. DARPP-32 phosphorylation at Thr34 and control of downstream target proteins in the MSNs of the striatonigral pathway and nucleus accumbens As previously mentioned, increased DARPP-32 phosphorylation at Thr34 is necessary for generating the rapid increase in locomotor activity produced by acute administration of cocaine (Fienberg et al., 1998; Zachariou et al.,

2005). More recently, it has been proposed that enhanced Thr34 phosphorylation also mediates the effects produced by prolonged administration of psychostimulants. One way by which phosphoThr34-DARPP-32 may participate to such adaptive processes is via regulation of the state of phosphorylation of the two mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinases 1 and 2 (ERK). Activation of ERK via phosphorylation catalysed by the MAPK/ERK kinase (MEK) is currently regarded as an important biochemical step involved in drug abuse. Increased phosphorylation of ERK occurs, in the nucleus accumbens, in response to administration of various classes of addictive substances (Valjent et al., 2004) and studies performed using the conditioned place preference paradigm have demonstrated the requirement of phosphoERK for both retrieval (Valjent et al., 2000; Miller and Marshall, 2005) and reconsolidation (Miller and Marshall, 2005) of cocaine-associated contextual memory. ERK phosphorylation results in the activation of transcription factors, such as the cAMP-responsive element binding protein (CREB) and Elk-1, which, in turn, are thought to mediate long-term modification in neurotransmission, particularly at the level of the nucleus accumbens core (Miller and Marshall, 2005). Valjent et al. (2005) have demonstrated that cocaine and D-amphetamine, fail to increase ERK phosphorylation in DARPP-32-null mice. The involvement of DARPP-32 in the regulation of ERK appears to be dependent on Thr34, but not on Thr75, phosphorylation because cocaineinduced phosphorylation of ERK and Elk-1 is absent in Thr34-Ala mutant mice, but still present in Thr75-Ala mutant mice (Valjent et al., 2005). It has been proposed that phosphoThr34-DARPP-32 promotes ERK phosphorylation via inhibition of PP-1 and reduced dephosphorylation of MEK and of the striatal-enriched phosphatase (STEP). Increased levels of phosphoMEK result in stimulation of kinase activity and phosphorylation of ERK. Increased levels of phosphoSTEP result in decreased phosphatase activity and suppression of ERK dephosphorylation (Valjent et al., 2005). The significance of this phosphoThr34-DARPP-32/PP-1/ERK cascade in the longterm effects of substances of abuse is supported by the observation that cocaine psychomotor sensitization (Valjent et al., 2005) and conditioned place preference (Zachariou et al., 2005) are attenuated in Thr34-Ala DARPP-32 mutant mice. The involvement of DARPP-32 in the regulation of ERK is likely to have important consequences on gene expression, particularly at the level of dopamine D1 expressing MSNs. Thus, the increases in expression of mRNAs for the immediate early genes c-fos and zif-268 (or NGFI-A), induced in the nucleus accumbens by a dopamine D1 receptor agonist, is strongly attenuated in DARPP-32 knockout mice (Svenningsson et al., 2000b). Most importantly, the ability of a single injection of Damphetamine to increase the levels of striatal c-Fos-like immunoreactivity is reduced in the striata of DARPP-32

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knockout mice (Fienberg et al., 1998). In addition, Zachariou et al. (2005) have shown that the increase in c-fos mRNA produced by acute cocaine depends on phosphorylation of DARPP-32 at Thr34 , but not at Thr75. Chronic treatment with cocaine and amphetamines, leads to the accumulation of stable Fos isoforms, collectively named DFosB, throughout the striatal complex. This phenomenon is thought to underlie long-term adaptations in MSNs, including changes in dynorphine expression, which participate to the development of addictive states (Nestler, 2001). Interestingly, the ability of chronic cocaine to increase the levels of DFosB is virtually abolished in DARPP-32 knockout mice (Hiroi et al.,1999), or in Thr34-Ala DARPP-32 mutant mice (Zachariou et al., 2005). Phosphorylation of DARPP-32 at Thr34 has been proposed to mediate changes in sodium currents occurring, in nucleus accumbens MSNs, following repeated cocaine administration (Hu et al., 2005). Studies performed in hippocampal neurons have shown that activation of dopamine D1 receptors reduces Na+ currents via PKAmediated phosphorylation (Cantrell et al., 1999). A similar phenomenon is thought to occur in the striatum, were phosphoThr34-DARPP-32 has been found to decrease Na+ channel activity via inhibition of PP-1-catalysed dephosphorylation (Schiffmann et al., 1998). Prolonged cocaine administration reduces the expression of the calcium/calmodulin-dependent protein phosphatase-2B, or calcineurin (Hu et al., 2005). Decreased calcineurin levels have also been observed in association with methamphetamine sensitization (Lin et al., 2002). Besides being involved in the dephosphorylation of Na+ channels (Chen et al., 1995), calcineurin is one of the major protein phosphatases responsible for dephosphorylation of DARPP-32 at Thr34 (Nishi et al., 2002). A decrease in calcineurin activity would therefore increase phosphoThr34-DARPP-32 and reduce PP-1-mediated dephosphorylation of Na+ channels. The resulting increase in phosphorylation would inhibit Na+ channels, change MSNs membrane excitability and contribute to the mechanisms underlying cocaine addiction and withdrawal. Activation of the cAMP/PKA/DARPP-32 cascade produced in MSNs by cocaine and amphetamines is also involved in the regulation of the state of phosphorylation of ionotropic glutamate AMPA receptors. Dopamine D1 receptor activation results in PKA-catalysed phosphorylation of the GluR1 subunit of the AMPA receptor. This effect promotes glutamate transmission by increasing AMPA channel currents (Roche et al., 1996; Banke et al., 2000), and enhancing cell surface expression of the receptor (Mangiavacchi and Wolf, 2004). Another mechanism by which phosphorylation of Ser845 promotes AMPA receptor transmission is by counteracting the gradual reduction in the amplitude of AMPA currents that occurs during prolonged channel activation. Stimulation of dopamine D1 receptors prevents such a current rundown via PKAcatalysed phosphorylation of GluR1. Interestingly, a

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synthetic phosphopeptide corresponding to phosphoThr34-DARPP-32(6-38) mimics the effect dopamine D1 receptor activation, most likely by enhancing the levels of phosphorylated AMPA receptor via inhibition of PP-1catalysed dephosphorylation (Yan et al., 1999). Cocaine and methamphetamine produce large increases in the state of phosphorylation of GluR1 at the PKA site, Ser845, which are attenuated in DARPP-32 knockout mice (Snyder et al., 2000). The ability to regulate GluR1 phosphorylation contributes to explain the importance of the cAMP/ PKA/DARPP-32/PP-1 cascade in the generation and expression of cocaine behavioural sensitization. In fact, repeated administration of cocaine is accompanied by sensitized AMPA receptor transmission (Pierce et al., 1996; Suto et al., 2004) and increased surface expression of AMPA receptors (Boudreau and Wolf, 2005). 3.3. Abnormal regulation of DARPP-32 and sensitivity to psychostimulants: evidence from genetic studies The studies of the involvement of DARPP-32 in the regulation of the state of phosphorylation of downstream target proteins indicate the importance of increased phosphorylation of DARPP-32 at Thr34 in the biochemical and behavioural effects produced by prolonged administration of psychostimulants. It should be noted, however, that most studies have reported reduced, rather than increased, Thr34 phosphorylation in response to repeated administration of cocaine and methamphetamine (Bibb et al., 2001; Scheggi et al., 2004; Chen and Chen, 2005; but see also Lin et al., 2002). Whereas, future work will be necessary to clarify this point, the idea that abnormal regulation of DARPP-32 may confer sensitivity to drugs of abuse has been recently corroborated by genetic studies. Palmer et al. (2005) have found that mice strains selected for higher responsiveness to the hyperlocomotor effect of methamphetamine show enhanced expression of DARPP32 and casein kinase I in the nucleus accumbens. Casein kinase I phosphorylates DARPP-32 at Ser130 (Desdouits et al., 1995b) and decreases the rate of dephosphorylation of Thr34 by calcineurin (Desdouits et al., 1995a). These findings are consistent with the existence of a positive link between DARPP-32 phosphorylation at Thr34 and sensitivity to psychostimulants. The relevance of this hypothesis is strengthened by the finding that human volunteers with higher subjective response to low dose D-amphetamine display higher numbers of a single-nucleotide polymorphism in the casein kinase I epsilon gene (VeenstraVanderWeele et al., 2005). 4. DARPP-32 regulation in striatopallidal MSNs: contrasting action of dopamine D2 and adenosine A2A receptors The involvement of DARPP-32 in the action of cocaine and amphetamines illustrates the importance of the cAMP

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signalling cascade in the control of dopamine D1 expressing MSNs. A large subpopulation of MSNs, however, is devoid or expresses only very low levels of dopamine D1 receptors. These neurons, which belong to the indirect, striatopallidal pathway of the dorsal striatum, are enriched in dopamine D2 receptors (Gerfen, 1992). They also express high levels of the A2A receptor subtype for the inhibitory neuromodulator adenosine (Schiffmann et al., 1991). Adenosine A2A receptors are positively coupled to cAMP production, and their stimulation results in increased phosphorylation of DARPP-32 at Thr34 (Svenningsson et al., 1998) and decreased phosphorylation at Thr75 (Lindskog et al., 2002). The PKAdependent increase in Thr34 phosphorylation produced by the adenosine A2A receptor agonist, CGS21680, is potentiated by concomitant stimulation of group 5 metabotropic glutamate receptors (Nishi et al., 2003) (Fig. 1). Studies performed in striatal slices have shown that the increase in phosphorylation of DARPP-32 at Thr34 produced by CGS21680 is counteracted by quinpirole, a dopamine D2-like receptor agonist (Lindskog et al., 1999). This effect has been proposed to occur via inhibition of adenylyl cyclase and suppression of PKAdependent phosphorylation (Lindskog et al., 1999), but may also result from increased concentration of intracellular calcium, and enhancement of calcineurindependent dephosphorylation of DARPP-32 (Nishi et al., 1997). The negative regulation exerted by dopamine D2 receptors on Thr34 phosphorylation is demonstrated by the observation that, in intact animals, administration of dopamine D2 receptor antagonists, such as eticlopride and haloperidol, increases the levels of phosphoThr34DARPP-32 (Svenningsson et al., 2000a; Ha˚kansson et al., 2006) (Fig. 1). This effect depends on tonic dopamine D2 receptor activation, but also on maintenance of basal cAMP production and PKA activity, which, under normal physiological conditions is provided by endogenous adenosine via A2A receptors. In fact, the eticlopride-induced increase in phosphoThr34-DARPP-32 is abolished by administration of an adenosine A2A receptor antagonist (Svenningsson et al., 2000a), and strongly reduced in adenosine A2A receptor-null mice (Svenningsson et al., 2000a). In summary, the state of phosphorylation of DARPP-32 in striatopallidal MSNs is in large part controlled by the opposing action of adenosine, which stimulates Thr34 phosphorylation via A2A receptors, and dopamine, which reduces Thr34 phosphorylation via D2 receptors. These contrasting regulations of the cAMP/PKA/DARPP-32 cascade are accountable for the opposite regulations of protein phosphorylation (Ha˚kansson et al., 2006) (see below) and gene expression (for a review see Fisone et al., 2004) exerted by A2A and D2 receptors, and offer a critical molecular framework to explain antagonistic interaction between dopamine and adenosine in the dorsal striatum.

4.1. Role of DARPP-32 in the action of caffeine What is the functional significance of changes in the state of phosphorylation of DARPP-32 in the striatopallidal MSNs of the indirect pathway? As previously discussed, these neurons regulate motor function in an opposite way as compared to striatonigral MSNs. Activation of the cAMP/PKA/DARPP-32 cascade in the striatonigral pathway and nucleus accumbens results in enhanced motor activity. A similar activation of cAMP signalling, produced by an adenosine A2A receptor agonist in striatopallidal MSNs, is associated to motor depression. Studies performed in DARPP-32 deficient mice show that, in these animals, the ability of CGS21680 to reduce motor activity is markedly attenuated (Lindskog et al., 2002). Thus, DARPP-32 is able to mediate motor activation or motor depression by amplifying cAMP-dependent signalling occurring in striatonigral/nucleus accumbens MSNs or striatopalliodal MSNs, respectively. The importance of DARPP-32 in adenosine transmission is further demonstrated by studies using adenosine receptor antagonists. The adenosine system is the major target for methylxanthines, a class of substances that includes popular psychostimulants such as caffeine and theophylline. Caffeine binds with high affinity to adenosine A1 and A2A receptors, which under normal conditions are activated by endogenous adenosine. It is now well established that the psychomotor stimulant effect of caffeine depends on its ability to antagonize adenosine A2A receptor transmission at the level of striatopallidal neurons (for a review see Fisone et al., 2004). Blockade of A2A receptors reduces basal cAMP production, thereby suppressing phosphorylation of DARPP-32 at Thr34 (Andersson et al., 2005) and increasing phosphorylation at Thr75 (Lindskog et al., 2002) (Fig. 1). In addition, the motor stimulant effect typically exerted by caffeine, or by a selective adenosine A2A receptor antagonist, is attenuated in DARPP-32-deficient mice (Lindskog et al., 2002). Therefore, DARPP-32 not only promotes responses to drugs that activate cAMP signalling in MSNs, but also amplifies the behavioural effects produced by inhibition of the cAMP/PKA cascade. This latter action is most likely exerted via a parallel pathway involving increased phosphorylation of Thr75, and further inhibition of PKA activity. 4.2. Role of DARPP-32 in cannabinoid transmission Cannabinoids, such as D9-tetrahydrocannabinol, the major psychoactive component of marijuana, are known to produce a complex regulation of the activity of MSNs by acting on the CB1 subtype of cannabinoid receptors. Activation of CB1 receptors reduces glutamate release from corticostriatal nerve terminals, thereby inhibiting excitatory postsynaptic currents evoked on MSNs (Gerdeman and Lovinger, 2001). CB1 receptor agonists are also able to reduce GABA release from recurrent axon

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collaterals of MSNs, thereby inhibiting synaptic transmission intrinsic to the striatum (Szabo et al., 1998). Studies performed using AM404, an inhibitor of the uptake of endogenous cannabinoids (i.e. anandamide and 2-arachidonoyl glycerol), show that the cannabinoid system exerts a negative feedback control on dopamine D2 receptor transmission (Beltramo et al., 2000). At the behavioural level, stimulation of CB1 receptors causes a profound depression of motor activity and generates a state of rigid immobility, referred to as catalepsy. Administration of CP55,940, a selective CB1 receptor agonist, produces a large increase in the state of phosphorylation of DARPP-32 at Thr34 (Andersson et al., 2005) (Fig. 1). CP55,940-induced catalepsy is attenuated in DARPP-32 knockout mice or in Thr34-Ala DARPP-32 mutant mice (Andersson et al., 2005). The ability of CP55,940 to increase Thr34 phosphorylation requires intact dopamine D2 receptor transmission, since the CB1 receptor agonist fails to alter DARPP-32 phosphorylation in dopamine D2 receptor-null mice. The abolishment of Thr34 phosphorylation observed in dopamine D2 receptor knockout mice is paralleled by a reduction in the ability of CP55,940 to induce catalepsy. These findings are consistent with the idea that the action of CP55,940 on MSNs involves negative modulation of dopamine D2 receptors and disinhibition of PKA. As previously discussed, effects produced by suppressing dopamine D2 receptor signalling are dependent on intact adenosine A2A receptor transmission. Interestingly, both Thr34 phosphorylation and catalepsy produced by CP55,940 are attenuated by pharmacological blockade or genetic inactivation of A2A receptors (Andersson et al., 2005). Taken together, these data indicate that a substantial proportion of the motor depressant effect produced by activation of CB1 receptors depends on PKAcatalysed phosphorylation of DARPP-32 at Thr34. This phosphorylation occurs in striatopallidal neurons and may involve reduction of dopamine D2 receptor transmission and facilitation of adenosine A2A receptor-dependent cAMP signalling. 4.3. DARPP-32 phosphorylation at Thr34 and control of AMPA receptors in striatopallidal MSNs A considerable amount of work has been devoted to the identification of phosphoproteins that are regulated by the cAMP/PKA/DARPP-32 pathway in the dopamine D1 expressing MSNs of dorsal striatum and nucleus accumbens. Much less is known about the role of DARPP-32 in the regulation of the state of phosphorylation and activity of downstream effector proteins involved in the control of the state of excitability of striatopallidal MSNs. Dopamine D2 receptors exert a negative modulation of striatal glutamatergic function via inhibition of AMPA receptors transmission. AMPA current amplitude is reduced by quinpirole (Herna´ndez-Echeagaray et al., 2004), and glutamatergic transmission is potentiated in

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dopamine D2 receptor knockout mice (Cepeda et al., 2001). It has been recently demonstrated that, in the dorsal striatum, activation of dopamine D2 receptors decreases phosphorylation of GluR1 at the PKA site, Ser845 (Ha˚kansson et al., 2006). This finding suggests that at least part of the negative control exerted by dopamine D2 receptors on glutamate transmission is mediated via suppression of PKA-catalysed phosphorylation of AMPA receptors. Blockade of dopamine D2 receptors increases GluR1 phosphorylation (Ha˚kansson et al., 2006). This effect is dependent on disinhibition of PKA in striatopallidal MSNs, as it is blocked by an adenosine A2A receptor antagonist, but not by a dopamine D1 receptor antagonist. In addition, eticlopride fails to induced phosphorylation of GluR1 in DARPP-32 knockout mice, or in Thr34-Ala DARPP-32 mutant mice (Ha˚kansson et al., 2006). Thus, in striatopallidal MSNs, dopamine D2 receptor antagonistdependent phosphorylation of AMPA receptors occurs via activation of the cAMP/PKA/DARPP-32/PP-1 cascade. Hypolocomotion induced by dopamine D2 receptor blockade is thought to occur following activation of striatopallidal neurons, inhibition of thalamocortical neurons and reduction of motor cortex activity (Parr-Brownlie and Hyland, 2005). In this context, it is conceivable that the enhancement in glutamate transmission produced, in striatopallidal MSNs, by eticlopride and haloperidol via DARPP-32-dependent GluR1 phosphorylation, is at least in part responsible for the motor depressant effect produced by these drugs. This possibility is supported by the observation that catalepsy produced by raclopride, a potent dopamine D2 receptor antagonist, is attenuated in DARPP-32 deficient mice (Fienberg et al., 1998). 5. Conclusions DARPP-32 is an essential modulator of cAMP signalling in striatal MSNs. Multiple phosphorylation sites confer to this phosphoprotein the ability to produce opposite biochemical effects. Thus, phosphoThr34-DARPP-32 is a selective inhibitor of PP-1, whereas phosphoThr75DARPP-32 reduces PKA activity. The study of the mechanisms of action of psychoactive drugs indicates the importance of identifying the specific populations of MSNs at the level of which changes in phosphorylation of DARPP-32 at Thr34 and Thr75, are occurring. Cocaine and amphetamines produce their acute psychostimulant effects by promoting camp-dependent phosphorylation of DARPP-32 and downstream effector proteins in the MSNs of the striatonigral pathway and nucleus accumbens. The same activation of cAMP signalling produced by an adenosine A2A receptor agonist or by dopamine D2 receptor antagonists in the MSNs of the striatopallidal pathway, mediates motor depression (Fig. 1). The exact localization of changes affecting DARPP-32 phosphorylation should also be considered in relation to the ability of drugs of abuse to modulate cAMP signalling

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in the ventral striatum. It is likely that augmented phosphorylation of DARPP-32 at Thr34 contributes to modification in the state of phosphorylation of downstream target proteins that contribute to the adaptive changes produced by repeated administration of cocaine and amphetamines. These changes affect in particular the MSNs located in the shell and core of the nucleus accumbens. It has been shown that the nucleus accumbens shell mediates primarily the psychostimulant effect of cocaine, whereas the core is involved in the acquisition and maintenance of cocaine-seeking behaviour (Ito et al., 2004). Future studies will be necessary to assess the exact localization of phosphoThr34- and phosphoThr75DARPP-32 in these subregions of the ventral striatum. Acknowledgements G.F. was supported by a grant from the Swedish Research Council (13482). References Andersson, M., Usiello, A., Borgkvist, A., Pozzi, L., Dominguez, C., Fienberg, A.A., Svenningsson, P., Fredholm, B.B., Borrelli, E., Greengard, P., Fisone, G., 2005. Cannabinoid action depends on phosphorylation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa at the protein kinase A site in striatal projection neurons. Journal of Neuroscience 25, 8432–8438. Banke, T.G., Bowie, D., Lee, H., Huganir, R.L., Schousboe, A., Traynelis, S.F., 2000. Control of GluR1 AMPA receptor function by cAMPdependent protein kinase. Journal of Neuroscience 20, 89–102. Beltramo, M., Rodriguez de Fonseca, F., Navarro, M., Calignano, A., Gorriti, M.A., Grammatikopoulos, G., Sadile, A.G., Giuffrida, A., Piomelli, D., 2000. Reversal of dopamine D2 receptor responses by an anandamide transport inhibitor. Journal of Neuroscience 20, 3401–3407. Bibb, J., Snyder, G.L., Nishi, A., Yan, Z., Meijer, L., Fienberg, A.A., Tsai, L.-H., Kwon, Y.T., Girault, J.-A., Czernik, A.J., Huganir, R.L., Hemmings, H.C., Nairn, A.C., Greengard, P., 1999. Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402, 669–671. Bibb, J.A., Chen, J., Taylor, J.R., Svenningsson, P., Nishi, A., Snyder, G.L., Yan, Z., Sagawa, Z.K., Ouimet, C.C., Nairn, A.C., Nestler, E.J., Greengard, P., 2001. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 410, 376–380. Boudreau, A.C., Wolf, M.E., 2005. Behavioral sensitization to cocaine is associated with increased AMPA receptor surface expression in the nucleus accumbens. Journal of Neuroscience 25, 9144–9151. Cantrell, A.R., Scheuer, T., Catterall, W.A., 1999. Voltage-dependent neuromodulation of Na+ channels by D1-like dopamine receptors in rat hippocampal neurons. Journal of Neuroscience 19, 5301–5310. Cepeda, C., Hurst, R.S., Altemus, K.L., Flores-Herna´ndez, J., Calvert, C.R., Jokel, E.S., Grandy, D.K., Low, M.J., Rubinstein, M., Ariano, M.A., Levine, M.S., 2001. Facilitated glutamatergic transsmission in the striatum of D2 dopamine receptor deficient mice. Journal of Neurophysiology 85, 659–670. Chen, P.C., Chen, J.C., 2005. Enhanced Cdk5 activity and p35 translocation in the ventral striatum of acute and chronic methamphetamine-treated rats. Neuropsychopharmacology 30, 538–549. Chen, T.C., Law, B., Kondratyuk, T., Rossie, S., 1995. Identification of soluble protein phosphatases that dephosphorylate voltage-sensitive sodium channels in rat brain. Journal of Biological Chemistry 270, 7750–7756.

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