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

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

L-DOPA-Induced Dyskinesia and Abnormal Signaling in Striatal Medium Spiny Neurons: Focus on Dopamine D1 Receptor-Mediated Transmission

Dyskinesia is a serious motor complication caused by prolonged administration of l-DOPA to patients affected by Parkinson’s disease. Accumulating evidence indicates that l-DOPA-induced dyskinesia (LID) is primarily caused by the development of sensitized dopamine D1 receptor (D1R) transmission in the medium spiny neurons (MSNs) of the striatum. This phenomenon, combined with chronic administration of l-DOPA, leads to persistent and intermittent hyper-activation of the cAMP signaling cascade. Activation of cAMP signaling results in increased activity of the cAMP-dependent protein kinase (PKA) and of the dopamine- and cAMP-dependent phosphoprotein of 32 kDa (DARPP-32), which regulate several downstream effector targets implicated in the control of the excitability of striatal MSNs. Dyskinesia is also accompanied by augmented activity of the extracellular signal-regulated kinases (ERK) and the mammalian target of rapamycin complex 1 (mTORC1), which are involved in the control of transcriptional and translational efficiency. Pharmacological or genetic interventions aimed at reducing abnormal signal transduction at the level of these various intracellular cascades have been shown to attenuate LID in different animal models. For instance, LID is reduced in mice deficient for DARPP-32, or following inhibition of PKA. Blockade of ERK obtained genetically or using specific inhibitors is also able to attenuate dyskinetic behavior in rodents and non-human primates. Finally, administration of rapamycin, a drug which blocks mTORC1, results in a strong reduction of LID. This review focuses on the abnormalities in signaling affecting the D1R-expressing MSNs and on their potential relevance for the design of novel anti-dyskinetic therapies

cjun n terminal kinase jnk mediates cortico striatal signaling in a model of parkinson s disease

Abstract The cJun N-terminal kinase (JNK) signaling pathway has been extensively studied with regard to its involvement in neurodegenerative processes, but little is known about its functions in neurotransmission. In a mouse model of Parkinson's disease (PD), we show that the pharmacological activation of dopamine D1 receptors (D1R) produces a large increase in JNK phosphorylation. This effect is secondary to dopamine depletion, and is restricted to the striatal projection neurons that innervate directly the output structures of the basal ganglia (dSPN). Activation of JNK in dSPN relies on cAMP-induced phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), but does not require N -methyl- d -aspartate (NMDA) receptor transmission. Electrophysiological experiments on acute brain slices from PD mice show that inhibition of JNK signaling in dSPN prevents the increase in synaptic strength caused by activation of D1Rs. Together, our findings show that dopamine depletion confers to JNK the ability to mediate dopamine transmission, informing the future development of therapies for PD

Dopamine D1 vs D5 receptor-dependent induction of seizures in relation to DARPP-32, ERK1/2 and GluR1-AMPA signalling.

Recent reports have shown that the selective dopamine D(1)-like agonist SKF 83822 [which stimulates adenylate cyclase, but not phospholipase C] induces prominent behavioral seizures in mice, whereas its benzazepine congener SKF 83959 [which stimulates phospholipase C, but not adenylate cyclase] does not. To investigate the relative involvement of D(1) vs D(5) receptors in mediating seizures, ethological behavioral topography and cortical EEGs were recorded in D(1), D(5) and DARPP-32 knockout mice in response to a convulsant dose of SKF 83822. SKF 83822-induced behavioral and EEG seizures were gene dose-dependently abolished in D(1) knockouts. In both heterozygous and homozygous D(5) knockouts, the latency to first seizure was significantly increased and total EEG seizures were reduced relative to wild-types. The majority (60%) of homozygous DARPP-32 knockouts did not have seizures; of those having seizures (40%), the latency to first seizure was significantly increased and the number of high amplitude, high frequency polyspike EEG events was reduced. In addition, immunoblotting was performed to investigate downstream intracellular signalling mechanisms at D(1)-like receptors following challenge with SKF 83822 and SKF 83959. In wild-types administered SKF 83822, levels of ERK1/2 and GluR1 AMPA receptor phosphorylation increased two-fold in both the striatum and hippocampus; in striatal slices DARPP-32 phosphorylation at Thr34 increased five-fold relative to vehicle-treated controls. These findings indicate that D(1), and to a lesser extent D(5), receptor coupling to DARPP-32, ERK1/2 and glutamatergic signalling is involved in mediating the convulsant effects of SKF 83822

Expression of X-chromosome linked inhibitor of apoptosis protein in mature purkinje cells and in retinal bipolar cells in transgenic mice induces neurodegeneration

Transgenic mice with overexpression of the caspase-inhibitor, X-chromosome-linked inhibitor of apoptosis protein (XIAP) in Purkinje cell (PC) and in retinal bipolar cells (RBCs) were produced to study the regulation of cell death. Unexpectedly, an increased neurodegeneration was observed in the PCs in these L7-XIAP mice after the third postnatal week with the mice exhibiting severe ataxia. The loss of PCs was independent of Bax as shown by crossing the L7-XIAP mice with Bax gene–deleted mice. Electron microscopy revealed intact organelles in PCs but with the stacking of ER cisterns indicative of cell stress. Immunostaining for cell death proteins showed an increased phosphorylation of c-Jun in the PCs, suggesting an involvement in cell degeneration. Apart from PCs, the number of RBCs was decreased in adult retina in line with the expression pattern for the L7 promoter. The data show that overexpression of the anti-apoptotic protein XIAP in vulnerable neurons leads to enhanced cell death. The mechanisms underlying this neurodegeneration can be related to the effects of XIAP on cell stress and altered cell signaling.Supported by Sigrid Juselius Foundation, Academy of Finland, EU Biotech Grant, Liv och Hälsa, Maud Kuistila, Ylppö Foundation, Uppsala University and Minerva Foundation. We thank Dr. Urmas Arumäe for discussions, and Dr. Patrik Ernfors for the Bax KO mice, and Eeva Lehto for technical assistance. L7AUG was a kind gift from Dr. J. Oberdick, Ohio State University, USA.Peer reviewe

Dopamine receptors in GtoPdb v.2023.1

Dopamine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Dopamine Receptors [373]) are commonly divided into D1-like (D1 and D5) and D2-like (D2, D3 and D4) families, where the endogenous agonist is dopamine

Distinct Changes in cAMP and Extracellular Signal-Regulated Protein Kinase Signalling in L-DOPA-Induced Dyskinesia

Background: In rodents, the development of dyskinesia produced by L-DOPA in the dopamine-depleted striatum occurs in response to increased dopamine D1 receptor-mediated activation of the cAMP- protein kinase A and of the Rasextracellular signal-regulated kinase (ERK) signalling pathways. However, very little is known, in non-human primates, about the regulation of these signalling cascades and their association with the induction, manifestation and/or maintenance of dyskinesia. Methodology/Results: We here studied, in the gold-standard non-human primate model of Parkinson’s disease, the changes in PKA-dependent phosphorylation of DARPP-32 and GluR1 AMPA receptor, as well as in ERK and ribosomal protein S6 (S6) phosphorylation, associated to acute and chronic administration of L-DOPA. Increased phosphorylation of DARPP-32 and GluR1 was observed in both L-DOPA first-ever exposed and chronically-treated dyskinetic parkinsonian monkeys. In contrast, phosphorylation of ERK and S6 was enhanced preferentially after acute L-DOPA administration and decreased during the course of chronic treatment. Conclusion: Dysregulation of cAMP signalling is maintained during the course of chronic L-DOPA administration, while abnormal ERK signalling peaks during the initial phase of L-DOPA treatment and decreases following prolonged exposure

Convulsant Doses of a Dopamine D1 Receptor Agonist Result in Erk-Dependent Increases in Zif268 and Arc/Arg3.1 Expression in Mouse Dentate Gyrus

Activation of dopamine D1 receptors (D1Rs) has been shown to induce epileptiform activity. We studied the molecular changes occurring in the hippocampus in response to the administration of the D1-type receptor agonist, SKF 81297. SKF 81297 at 2.5 and 5.0 mg/kg induced behavioural seizures. Electrophysiological recordings in the dentate gyrus revealed the presence of epileptiform discharges peaking at 30–45 min post-injection and declining by 60 min. Seizures were prevented by the D1-type receptor antagonist, SCH 23390, or the cannabinoid CB1 receptor agonist, CP 55,940. The effect of SKF 81297 was accompanied by increased phosphorylation of the extracellular signal-regulated protein kinases 1 and 2 (ERK), in the granule cells of the dentate gyrus. This effect was also observed in response to administration of other D1-type receptor agonists, such as SKF83822 and SKF83959. In addition, SKF 81297 increased the phosphorylation of the ribosomal protein S6 and histone H3, two downstream targets of ERK. These effects were prevented by genetic inactivation of D1Rs, or by pharmacological inhibition of ERK. SKF 81297 was also able to enhance the levels of Zif268 and Arc/Arg3.1, two immediate early genes involved in transcriptional regulation and synaptic plasticity. These changes may be involved in forms of activity-dependent plasticity linked to the manifestation of seizures and to the ability of dopamine to affect learning and memory

Nesfatin-1/NUCB2 as a Potential New Element of Sleep Regulation in Rats.

STUDY OBJECTIVES: Millions suffer from sleep disorders that often accompany severe illnesses such as major depression; a leading psychiatric disorder characterized by appetite and rapid eye movement sleep (REMS) abnormalities. Melanin-concentrating hormone (MCH) and nesfatin-1/NUCB2 (nesfatin) are strongly co - expressed in the hypothalamus and are involved both in food intake regulation and depression. Since MCH was recognized earlier as a hypnogenic factor, we analyzed the potential role of nesfatin on vigilance. DESIGN: We subjected rats to a 72 h-long REMS deprivation using the classic flower pot method, followed by a 3 h-long 'rebound sleep'. Nesfatin mRNA and protein expressions as well as neuronal activity (Fos) were measured by quantitative in situ hybridization technique, ELISA and immunohistochemistry, respectively, in 'deprived' and 'rebound' groups, relative to controls sacrificed at the same time. We also analyzed electroencephalogram of rats treated by intracerebroventricularly administered nesfatin-1, or saline. RESULTS: REMS deprivation downregulated the expression of nesfatin (mRNA and protein), however, enhanced REMS during 'rebound' reversed this to control levels. Additionally, increased transcriptional activity (Fos) was demonstrated in nesfatin neurons during 'rebound'. Centrally administered nesfatin-1 at light on reduced REMS and intermediate stage of sleep, while increased passive wake for several hours and also caused a short-term increase in light slow wave sleep. CONCLUSIONS: The data designate nesfatin as a potential new factor in sleep regulation, which fact can also be relevant in the better understanding of the role of nesfatin in the pathomechanism of depression

Dopamine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Dopamine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Dopamine Receptors [363]) are commonly divided into D1-like (D1 and D5) and D2-like (D2, D3 and D4) families, where the endogenous agonist is dopamine