Deciphering the Actions of Antiparkinsonian and Antipsychotic Drugs on cAMP/DARPP-32 Signaling

Abstract

The basal ganglia are affected by several neuropsychiatric and neurodegenerative diseases, many of which are treated with drugs acting on the dopamine system. For instance, the loss of dopaminergic input to the striatum, which is the main pathological feature of Parkinson's disease, is counteracted by administering the dopamine precursor, L-DOPA. Furthermore, psychotic disorders, including schizophrenia, are treated with drugs that act as antagonists at the D2-type of dopamine receptor (D2R). The use of L-DOPA and typical antipsychotic drugs, such as haloperidol, is limited by the emergence of motor side-effects, particularly after prolonged use. Striatal medium spiny neurons (MSNs) represent an ideal tool to investigate the molecular changes implicated in these conditions. MSNs receive a large glutamatergic innervation from cortex, thalamus, and limbic structures, and are controlled by dopaminergic projections originating in the midbrain. There are two large populations of striatal MSNs, which differ based on their connectivity to the output nuclei of the basal ganglia and on their ability to express dopamine D1 receptors (D1Rs) or D2Rs. Administration of L-DOPA promotes cAMP signaling and activates the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) in the D1R-expressing MSNs, which form the striatonigral, or direct pathway. Conversely, haloperidol activates the cAMP/DARPP-32 cascade in D2R-expressing MSNs, which form the striatopallidal, or indirect pathway. This review describes the effects produced on downstream effector proteins by stimulation of cAMP/DARPP-32 signaling in these two groups of MSNs. Particular emphasis is given to the regulation of the GluR1 subunit of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptor, the extracellular signal-regulated protein kinases 1 and 2, focusing on functional role and potential pathological relevance.

Keywords: DARPP-32; ERK; L-DOPA; dopamine D1 receptor; dopamine D2 receptor; haloperidol; medium spiny neurons.

Figure 1

Diagram summarizing the effects produced by L-DOPA and haloperidol on cAMP signaling in the striatal MSNs of the direct and indirect pathway. In PD, loss of dopamine in the striatum leads to increased responsiveness of D1Rs, expressed in the direct MSNs of the striatonigral pathway. Administration of L-DOPA increases the production of dopamine and activates D1Rs, which stimulate the cAMP/PKA pathway, thereby phosphorylating DARPP-32 (D32) at Thr34 (Picconi et al., ; Santini et al., 2007, 2010). A similar effect is produced by haloperidol in the indirect MSNs of the striatopallidal pathway via blockade of D2Rs and disinhibition of A2AR-mediated activation of cAMP signaling (Svenningsson et al., 2000). The activation of the PKA/DARPP-32 cascade produced by L-DOPA and haloperidol increases the phosphorylation of targets located in the cytoplasm/plasma membrane, such as the GluR1 subunit of the glutamate AMPA receptor (Håkansson et al., ; Santini et al., 2007). In direct MSNs, L-DOPA promotes ERK signaling. This effect may be exerted via PKA/DARPP-32-mediated regulation of Ras-GRF1 (Mattingly, 1999) and/or striatal-enriched protein tyrosine phosphatase (Valjent et al., 2005), which are involved in the regulation of ERK phosphorylation. ERK-dependent activation of MSK1 results in phosphorylation of histone H3 at Ser10 and enhanced expression of c-fos (Santini et al., 2007). Activation of ERK also increases the expression of zif268 and ΔfosB, which has been associated to LID (Andersson et al., ; Carta et al., 2005). Increased ΔFosB, in turn, leads to enhanced levels of dynorphin (Andersson et al., 1999). In the indirect striatopallidal MSNs, the regulation of histone H3 and gene expression exerted by haloperidol occurs independently of the ERK/MSK1 cascade. Thus, histone H3 is regulated via PKA-catalyzed phosphorylation and by concomitant suppression of dephosphorylation, via DARPP-32-mediated inhibition of PP-1 (Bertran-Gonzalez et al., 2009). In addition, the ability of haloperidol to activate PKA leads to increased phosphorylation of the cAMP-response element binding protein (CREB), which may be involved in the control of Fos expression (Konradi and Heckers, 1995). The control of multiple signaling pathways exerted by L-DOPA and haloperidol in the MSNs of the direct and indirect pathway may ultimately modify the activity of these neuronal populations, leading to abnormal motor responses, including L-DOPA-induced dyskinesia and extrapyramidal side-effects. Broken lines indicate indirect effects. See text for abbreviations.