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1.
Neurosci Lett ; 641: 70-76, 2017 02 22.
Article in English | MEDLINE | ID: mdl-28109776

ABSTRACT

Semaphorins are secreted or membrane-bound proteins implicated in neurodevelopmental processes of axon guidance and cell migration. Exploratory behaviour and motor learning was examined ethologically in Semaphorin 6A (Sema6A) mutant mice. The ethogram of initial exploration in Sema6A knockout mice was characterised by increased rearing to wall with decreased sifting; over subsequent habituation, locomotion, sniffing and rearing to wall were increased, with reduced habituation of rearing seated. Rotarod analysis indicated delayed motor learning in Sema6A heterozygous mutants. Disruption to the axonal guidance and cell migration processes regulated by Sema6A is associated with topographically specific disruption to fundamental aspects of behaviour, namely the ethogram of initial exploration and subsequent habituation to the environment, and motor learning.


Subject(s)
Exploratory Behavior/physiology , Learning/physiology , Motor Skills/physiology , Semaphorins/metabolism , Animals , Axons/physiology , Brain/physiology , Cell Movement , Habituation, Psychophysiologic/physiology , Heterozygote , Mice , Mice, Knockout , Semaphorins/genetics , Synapses/physiology
2.
Neuropsychopharmacology ; 34(7): 1710-20, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19158668

ABSTRACT

The antipsychotic agent haloperidol regulates gene transcription in striatal medium spiny neurons (MSNs) by blocking dopamine D2 receptors (D2Rs). We examined the mechanisms by which haloperidol increases the phosphorylation of histone H3, a key step in the nucleosomal response. Using bacterial artificial chromosome (BAC)-transgenic mice that express EGFP under the control of the promoter of the dopamine D1 receptor (D1R) or the D2R, we found that haloperidol induced a rapid and sustained increase in the phosphorylation of histone H3 in the striatopallidal MSNs of the dorsal striatum, with no change in its acetylation. This effect was mimicked by raclopride, a selective D2R antagonist, and prevented by the blockade of adenosine A2A receptors (A2ARs), or genetic attenuation of the A2AR-associated G protein, Galpha(olf). Mutation of the cAMP-dependent phosphorylation site (Thr34) of the 32-kDa dopamine and cAMP-regulated phosphoprotein (DARPP-32) decreased the haloperidol-induced H3 phosphorylation, supporting the role of cAMP in H3 phosphorylation. Haloperidol also induced extracellular signal-regulated kinase (ERK) phosphorylation in striatopallidal MSNs, but this effect was not implicated in H3 phosphorylation. The levels of mitogen- and stress-activated kinase 1 (MSK1), which has been reported to mediate ERK-induced H3 phosphorylation, were lower in striatopallidal than in striatonigral MSNs. Moreover, haloperidol-induced H3 phosphorylation was unaltered in MSK1-knockout mice. These data indicate that, in striatopallidal MSNs, H3 phosphorylation is controlled by the opposing actions of D2Rs and A2ARs. Thus, blockade of D2Rs promotes histone H3 phosphorylation through the A2AR-mediated activation of Galpha(olf) and inhibition of protein phosphatase-1 (PP-1) through the PKA-dependent phosphorylation of DARPP-32.


Subject(s)
Corpus Striatum/cytology , Histones/metabolism , Neurons/metabolism , Receptor, Adenosine A2A/metabolism , Receptors, Dopamine D2/metabolism , Acetylation/drug effects , Adenosine A2 Receptor Antagonists , Analysis of Variance , Animals , Dopamine Antagonists/pharmacology , Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , GTP-Binding Protein alpha Subunits/deficiency , Gene Expression/drug effects , Gene Expression Regulation, Enzymologic/drug effects , Green Fluorescent Proteins/genetics , Haloperidol/pharmacology , Male , Mice , Mice, Transgenic , Neurons/drug effects , Phosphorylation/drug effects , Purines/pharmacology , Receptors, Dopamine D1/genetics , Receptors, Dopamine D2/genetics , Ribosomal Protein S6 Kinases, 90-kDa/deficiency , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Threonine/metabolism
3.
Neuropharmacology ; 54(7): 1051-61, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18367215

ABSTRACT

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.


Subject(s)
Dopamine and cAMP-Regulated Phosphoprotein 32/physiology , Mitogen-Activated Protein Kinase 3/metabolism , Receptors, AMPA/metabolism , Receptors, Dopamine D1/physiology , Receptors, Dopamine D5/physiology , Seizures/metabolism , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Animals , Benzazepines/pharmacology , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dopamine and cAMP-Regulated Phosphoprotein 32/genetics , Dose-Response Relationship, Drug , Electroencephalography/methods , Hippocampus/drug effects , Hippocampus/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Phosphorylation/drug effects , Reaction Time/drug effects , Receptors, Dopamine D1/genetics , Receptors, Dopamine D5/genetics , Seizures/chemically induced , Seizures/genetics , Seizures/pathology , Signal Transduction/physiology , Threonine/metabolism , Time Factors
4.
Physiol Behav ; 92(1-2): 8-14, 2007 Sep 10.
Article in English | MEDLINE | ID: mdl-17585965

ABSTRACT

The selection and execution of appropriate motor behavior result in large part from the ability of the basal ganglia to collect, integrate and feedback information coming from the cerebral cortex. The GABAergic medium spiny neurons (MSNs) of the striatum represent the main receiving station of the basal ganglia. These cells are innervated by excitatory glutamatergic fibers from cortex and thalamus, and modulatory dopaminergic fibers from the midbrain. MSNs comprise two populations of projection neurons, which give rise to the direct, striatonigral pathway, and indirect, striatopallidal pathway. Changes in transmission at the level MSNs affect the activity of thalamocortical projection neurons, thereby influencing motor behavior. For instance, the cardinal symptoms of Parkinson's disease, such as tremor, rigidity and bradykinesia, are caused by the selective degeneration of dopaminergic neurons originating in the substantia nigra pars compacta, which modulate the activity of MSNs in the dorsal striatum. The therapy for Parkinson's disease relies on the use of levodopa, but is hampered by neuroadaptive changes affecting dopaminergic and glutamatergic transmission in striatonigral neurons. MSNs are also the target of many psychoactive drugs. For example, caffeine affects motor activity by blocking adenosine receptors in the basal ganglia, thereby affecting neurotransmission in striatopallidal neurons. The present review focuses on studies performed in our laboratory, which provide a molecular framework to understand the effects on motor activity of adenosine and caffeine.


Subject(s)
Basal Ganglia/physiology , Dopamine and cAMP-Regulated Phosphoprotein 32/physiology , Dyskinesia, Drug-Induced/physiopathology , Synaptic Transmission/physiology , Animals , Basal Ganglia/cytology , Basal Ganglia/drug effects , Basal Ganglia/physiopathology , Humans , Motor Activity/drug effects , Motor Activity/physiology , Neurons/cytology , Neurons/drug effects , Neurons/enzymology , Presynaptic Terminals/drug effects , Presynaptic Terminals/enzymology , Signal Transduction/drug effects , Signal Transduction/physiology , Synaptic Transmission/drug effects
5.
Int Rev Psychiatry ; 18(2): 133-43, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16777667

ABSTRACT

Tardive dyskinesia (TD) is a movement disorder described in individuals who have been treated with anti-dopaminergic agents. The pathophysiology of this condition remains to be fully elucidated. Several mechanisms like dopaminergic supersensitivity, dysfunction of striatonigral, GABAergic neurons and disturbed balance between dopaminergic and cholinergic systems have been described. Essential fatty acids (EFAs) are important components of neuronal membrane and the EFA content of these membranes can significantly influence neuronal functioning. Lower levels of EFAs have been reported in red blood cells (RBC) and plasma of individuals with moderate to severe TD. Supplementation with EFAs (omega-3 and omega-6 and ethyl-EPA) have been tried to alleviate TD in open and double-blind clinical trials and in some animal models of TD. In addition, antioxidants (Vitamin E) and melatonin have been tried. However, smaller numbers of patients and shortened length of clinical studies make it difficult to draw any definitive conclusions. Large multi-centre studies with sound methodology of both EFAs and antioxidants are needed.


Subject(s)
Dyskinesia, Drug-Induced/physiopathology , Fatty Acids, Essential/physiology , Animals , Antioxidants/administration & dosage , Antipsychotic Agents/adverse effects , Clinical Trials as Topic , Corpus Striatum/drug effects , Corpus Striatum/physiopathology , Dopamine Antagonists/adverse effects , Double-Blind Method , Drug Therapy, Combination , Dyskinesia, Drug-Induced/drug therapy , Fatty Acids, Essential/administration & dosage , Humans , Receptors, Cholinergic/drug effects , Receptors, Cholinergic/physiology , Receptors, Dopamine/drug effects , Receptors, Dopamine/physiology , Risk Factors , Substantia Nigra/drug effects , Substantia Nigra/physiopathology
6.
J Neurochem ; 96(2): 482-8, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16336634

ABSTRACT

In the striatum, stimulation of dopamine D2 receptors results in attenuation of glutamate responses. This effect is exerted in large part via negative regulation of AMPA glutamate receptors. Phosphorylation of the GluR1 subunit of the AMPA receptor has been proposed to play a critical role in the modulation of glutamate transmission, in striatal medium spiny neurons. Here, we have examined the effects of blockade of dopamine D2-like receptors on the phosphorylation of GluR1 at the cAMP-dependent protein kinase (PKA) site, Ser845, and at the protein kinase C and calcium/calmodulin-dependent protein kinase II site, Ser831. Administration of haloperidol, an antipsychotic drug with dopamine D2 receptor antagonistic properties, increases the phosphorylation of GluR1 at Ser845, without affecting phosphorylation at Ser831. The same effect is observed using eticlopride, a selective dopamine D2 receptor antagonist. In contrast, administration of the dopamine D2-like agonist, quinpirole, decreases GluR1 phosphorylation at Ser845. The increase in Ser845 phosphorylation produced by haloperidol is abolished in dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) knockout mice, or in mice in which the PKA phosphorylation site on DARPP-32 (i.e. Thr34) has been mutated (Thr34-->Ala mutant mice), and requires tonic activation of adenosine A2A receptors. These results demonstrate that dopamine D2 antagonists increase GluR1 phosphorylation at Ser845 by removing the inhibitory tone exerted by dopamine D2 receptors on the PKA/DARPP-32 cascade.


Subject(s)
Phosphorylation , Receptors, AMPA/metabolism , Receptors, Dopamine D2/physiology , Adenosine A2 Receptor Antagonists , Amino Acid Sequence , Animals , Dopamine Antagonists/pharmacology , Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism , Haloperidol/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Phosphorylation/drug effects , Purines/pharmacology , Quinpirole/pharmacology , Receptors, Dopamine D2/genetics , Serine , Threonine
7.
Ann Neurol ; 57(1): 17-26, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15514976

ABSTRACT

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson's disease. Although changes affecting D(1) and D(2) dopamine receptors have been studied in association with this condition, no causal relationship has yet been established. Taking advantage of a monkey brain bank constituted to study levodopa-induced dyskinesia, we report changes affecting D(1) and D(2) dopamine receptors within the striatum of normal, parkinsonian, nondyskinetic levodopa-treated parkinsonian, and dyskinetic levodopa-treated parkinsonian animals. Whereas D(1) receptor expression itself is not related to dyskinesia, D(1) sensitivity per D(1) receptor measured by D(1) agonist-induced [(35)S]GTPgammaS binding is linearly related to dyskinesia. Moreover, the striata of dyskinetic animals show higher levels of cyclin-dependent kinase 5 (Cdk5) and of the dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32). Our data suggest that levodopa-induced dyskinesia results from increased dopamine D(1) receptor-mediated transmission at the level of the direct pathway.


Subject(s)
Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced/etiology , Levodopa/adverse effects , Receptors, Dopamine D1/metabolism , Signal Transduction/drug effects , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Analysis of Variance , Animals , Autoradiography/methods , Behavior, Animal , Blotting, Western/methods , Cyclin-Dependent Kinase 5 , Cyclin-Dependent Kinases , Disease Models, Animal , Dopamine Plasma Membrane Transport Proteins , Dopamine and cAMP-Regulated Phosphoprotein 32 , Dose-Response Relationship, Drug , Drug Interactions , Dyskinesia, Drug-Induced/metabolism , Female , Guanosine 5'-O-(3-Thiotriphosphate)/pharmacokinetics , Immunohistochemistry/methods , In Situ Hybridization/methods , Isotopes/pharmacokinetics , Macaca fascicularis , Membrane Glycoproteins/metabolism , Membrane Transport Proteins/metabolism , Motor Activity/drug effects , Nerve Tissue Proteins/metabolism , Nortropanes/pharmacokinetics , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/physiopathology , Phosphoproteins/metabolism , Radioligand Assay/methods , Receptors, Dopamine D1/agonists , Receptors, Dopamine D1/genetics , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism , Substantia Nigra/drug effects , Substantia Nigra/metabolism , Time Factors , Tyrosine 3-Monooxygenase/metabolism
8.
Eur J Neurosci ; 20(4): 1108-12, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15305880

ABSTRACT

The typical neuroleptic haloperidol increases the state of phosphorylation and activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines. Here we show that the increases in TH phosphorylation produced by haloperidol at Ser31 and Ser40, two sites critically involved in the regulation of enzymatic activity, are abolished in dopamine D2 receptor-null mice and mimicked by the selective dopamine D2 receptor antagonist, eticlopride. Moreover, the ability of haloperidol and eticlopride to stimulate phosphorylation at both seryl residues is prevented by treatment with SL327, a compound that blocks activation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). We also show that chronic administration of haloperidol reduces the basal levels of phosphoSer31-TH and decreases the ability of the drug to stimulate Ser40 phosphorylation. These results provide a model accounting for the stimulation exerted by haloperidol on dopamine synthesis. According to this model, haloperidol increases TH activity via blockade of dopamine D2 receptors, disinhibition of dopaminergic projection neurons and ERK1/2-dependent phosphorylation of TH at Ser31 and Ser40. These studies also show that lower levels of phosphorylated TH are associated with chronic neuroleptic treatment and may be related to depressed dopaminergic transmission in nigrostriatal neurons.


Subject(s)
Corpus Striatum/drug effects , Corpus Striatum/enzymology , Haloperidol/administration & dosage , Tyrosine 3-Monooxygenase/metabolism , Animals , Dose-Response Relationship, Drug , Drug Administration Schedule , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Phosphorylation/drug effects , Receptors, Dopamine D2/deficiency , Receptors, Dopamine D2/genetics , Tyrosine 3-Monooxygenase/genetics
9.
Parkinsonism Relat Disord ; 10(5): 281-6, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15196506

ABSTRACT

The dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) is abundantly expressed in the medium spiny neurons of the striatum. Phosphorylation catalysed by cAMP-dependent protein kinase (PKA) converts DARPP-32 into an inhibitor of protein phosphatase-1. In contrast, phosphorylation catalysed by cyclin dependent kinase-5 on Thr75 converts DARPP-32 into an inhibitor of PKA. Changes in the state of phosphorylation of DARPP-32 reinforce the behavioral effects produced by stimulation or inhibition of the cAMP pathway. Dopamine, via D(1) receptors, and adenosine, via A(2A) receptors, affect motor behavior by acting on medium spiny neurons, via G(olf) mediated stimulation of the cAMP signaling cascade. The involvement of DARPP-32 in dopamine and adenosine transmission and the possible role played by abnormal regulation of DARPP-32 phosphorylation in levodopa-induced dyskinesia are discussed.


Subject(s)
Cyclic AMP/metabolism , Dyskinesia, Drug-Induced/metabolism , Motor Activity/physiology , Nerve Tissue Proteins/metabolism , Phosphoproteins/metabolism , Animals , Dopamine and cAMP-Regulated Phosphoprotein 32 , Humans , Levodopa/adverse effects , Levodopa/toxicity , Signal Transduction/physiology
10.
J Neurochem ; 86(2): 451-9, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12871586

ABSTRACT

The two mitogen-activated protein kinases (MAPKs), extracellular signal-regulated protein kinase 1 and 2 (ERK1/2), are involved in the control of gene expression via phosphorylation and activation of the transcription factors cyclic AMP response element binding protein (CREB) and Elk-1. Here, we have examined the effect of haloperidol and clozapine, two anti-psychotic drugs, and eticlopride, a selective dopamine D2 receptor antagonist, on the state of phosphorylation of ERK1/2, CREB and Elk-1, in the mouse dorsal striatum. Administration of the typical anti-psychotic haloperidol stimulated the phosphorylation of ERK1/2, CREB and Elk-1. Virtually identical results were obtained using eticlopride. In contrast, the atypical anti-psychotic clozapine reduced ERK1/2, CREB and Elk-1 phosphorylation. This opposite regulation was specifically exerted by haloperidol and clozapine on ERK, CREB, and Elk-1 phosphorylation, as both anti-psychotic drugs increased the phosphorylation of the dopamine- and cyclic AMP-regulated phosphoprotein of 32 kDa (DARPP-32) at the cyclic AMP-dependent protein kinase (PKA) site. The activation of CREB and Elk-1 induced by haloperidol appeared to be achieved via different signalling pathways, as inhibition of ERK1/2 activation abolished the stimulation of Elk-1 phosphorylation without affecting CREB phosphorylation. This study shows that haloperidol and clozapine induce distinct patterns of phosphorylation in the dorsal striatum. The results provide a novel biochemical paradigm elucidating the molecular mechanisms underlying the distinct therapeutic actions of typical and atypical anti-psychotic agents.


Subject(s)
Antipsychotic Agents/pharmacology , Corpus Striatum/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , DNA-Binding Proteins , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinases/metabolism , Nerve Tissue Proteins , Proto-Oncogene Proteins/metabolism , Transcription Factors , Animals , Clozapine/pharmacology , Corpus Striatum/drug effects , Dopamine Antagonists/pharmacology , Dopamine and cAMP-Regulated Phosphoprotein 32 , Drug Interactions , Haloperidol/pharmacology , Male , Mice , Mice, Inbred C57BL , Mitogen-Activated Protein Kinase 3 , Phosphoproteins/metabolism , Phosphorylation/drug effects , Salicylamides/pharmacology , ets-Domain Protein Elk-1
11.
Nat Neurosci ; 6(5): 501-6, 2003 May.
Article in English | MEDLINE | ID: mdl-12665799

ABSTRACT

Long-term treatment with the dopamine precursor levodopa (L-DOPA) induces dyskinesia in Parkinson's disease (PD) patients. We divided hemiparkinsonian rats treated chronically with L-DOPA into two groups: one showed motor improvement without dyskinesia, and the other developed debilitating dyskinesias in response to the treatment. We then compared the plasticity of corticostriatal synapses between the two groups. High-frequency stimulation of cortical afferents induced long-term potentiation (LTP) of corticostriatal synapses in both groups of animals. Control and non-dyskinetic rats showed synaptic depotentiation in response to subsequent low-frequency synaptic stimulation, but dyskinetic rats did not. The depotentiation seen in both L-DOPA-treated non-dyskinetic rats and intact controls was prevented by activation of the D1 subclass of dopamine receptors or inhibition of protein phosphatases. The striata of dyskinetic rats contained abnormally high levels of phospho[Thr34]-DARPP-32, an inhibitor of protein phosphatase 1. These results indicate that abnormal information storage in corticostriatal synapses is linked with the development of L-DOPA-induced dyskinesia.


Subject(s)
Corpus Striatum/physiopathology , Dyskinesia, Drug-Induced/physiopathology , Levodopa/adverse effects , Nerve Tissue Proteins , Neuronal Plasticity/physiology , Synaptic Transmission , Animals , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dopamine and cAMP-Regulated Phosphoprotein 32 , Dyskinesia, Drug-Induced/metabolism , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , In Vitro Techniques , Levodopa/therapeutic use , Male , Neuronal Plasticity/drug effects , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/physiopathology , Phosphoproteins/metabolism , Phosphorylation , Rats , Rats, Wistar , Synaptic Transmission/drug effects , Synaptic Transmission/physiology
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