ReviewPsychoactive drugs and regulation of the cAMP/PKA/DARPP-32 cascade in striatal medium spiny neurons
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).
References (64)
- et al.
Identification of soluble protein phosphatases that dephosphorylate voltage-sensitive sodium channels in rat brain
Journal of Biological Chemistry
(1995) - et al.
Phosphorylation of DARPP-32, a dopamine- and cAMP-regulated phosphoprotein, by casein kinase I in vitro and in vivo
Journal of Biological Chemistry
(1995) - et al.
D1 dopamine receptor-deficient mouse: cocaine-induced regulation of immediate-early gene and substance P expression in the striatum
Neuroscience
(1996) - et al.
Expression of the D3 receptor in peptidergic neurons of the nucleus accumbens: comparison with the D1 and D2 dopamine receptors
Neuroscience
(1996) - et al.
Activation of dopamine D2 receptors decreases DARPP-32 phosphorylation in striatonigral and striatopallidal projection neurons via different mechanisms
Neuroscience
(1999) - et al.
Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory
Neuron
(2005) - et al.
The role of DARPP-32 in the actions of drugs of abuse
Neuropharmacology
(2004) - et al.
Quantitative immunocytochemistry of DARPP-32-expressing neurons in the rat caudatoputamen
Brain Research
(1998) - et al.
Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit
Neuron
(1996) - et al.
Activation of adenosine A2A and dopamine D1 receptors stimulates cyclic AMP-dependent phosphorylation of DARPP-32 in distinct populations of striatal projection neurons
Neuroscience
(1998)