Review
Psychoactive drugs and regulation of the cAMP/PKA/DARPP-32 cascade in striatal medium spiny neurons

https://doi.org/10.1016/j.neubiorev.2006.03.003Get rights and content

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.

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.

Section snippets

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

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

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 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

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 phosphoThr75-DARPP-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

Acknowledgements

G.F. was supported by a grant from the Swedish Research Council (13482).

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