Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Neuropharmacology ; 196: 108692, 2021 09 15.
Article in English | MEDLINE | ID: mdl-34217776

ABSTRACT

Group II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) shape mechanisms of methamphetamine addiction, but the individual role played by the two subtypes is unclear. We measured methamphetamine-induced conditioned place preference (CPP) and motor responses to single or repeated injections of methamphetamine in wild-type, mGlu2-/-, and mGlu3-/-mice. Only mGlu3-/-mice showed methamphetamine preference in the CPP test. Motor response to the first methamphetamine injection was dramatically reduced in mGlu2-/-mice, unless these mice were treated with the mGlu5 receptor antagonist, MTEP. In contrast, methamphetamine-induced sensitization was increased in mGlu3-/-mice compared to wild-type mice. Only mGlu3-/-mice sensitized to methamphetamine showed increases in phospho-ERK1/2 levels in the nucleus accumbens (NAc) and free radical formation in the NAc and medial prefrontal cortex. These changes were not detected in mGlu2-/-mice. We also measured a series of biochemical parameters related to the mechanism of action of methamphetamine in naïve mice to disclose the nature of the differential behavioural responses of the three genotypes. We found a reduced expression and activity of dopamine transporter (DAT) and vesicular monoamine transporter-2 in the NAc and striatum of mGlu2-/-and mGlu3-/-mice, whereas expression of the DAT adaptor, syntaxin 1A, was selectively increased in the striatum of mGlu3-/-mice. Methamphetamine-stimulated dopamine release in striatal slices was largely reduced in mGlu2-/-, but not in mGlu3-/-, mice. These findings suggest that drugs that selectively enhance mGlu3 receptor activity or negatively modulate mGlu2 receptors might be beneficial in the treatment of methamphetamine addiction and associated brain damage.


Subject(s)
Amphetamine-Related Disorders/metabolism , Behavior, Animal/drug effects , Central Nervous System Stimulants/pharmacology , Conditioning, Classical/drug effects , Methamphetamine/pharmacology , Receptors, Metabotropic Glutamate/genetics , Amphetamine-Related Disorders/physiopathology , Animals , Behavior, Animal/physiology , Disease Models, Animal , Dopamine/metabolism , Dopamine Plasma Membrane Transport Proteins/metabolism , Male , Mice , Mice, Knockout , Mitogen-Activated Protein Kinase 1/drug effects , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/drug effects , Mitogen-Activated Protein Kinase 3/metabolism , Neostriatum/drug effects , Neostriatum/metabolism , Phosphorylation , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Pyridines/pharmacology , Receptor, Metabotropic Glutamate 5/antagonists & inhibitors , Receptors, Metabotropic Glutamate/metabolism , Syntaxin 1/drug effects , Syntaxin 1/metabolism , Thiazoles/pharmacology , Vesicular Monoamine Transport Proteins/metabolism
2.
Eur Arch Psychiatry Clin Neurosci ; 268(6): 555-563, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29404686

ABSTRACT

We investigated the effects of clozapine and haloperidol, drugs that are widely used in the treatment of schizophrenia, on gene expression in six cortical and subcortical brain regions of adult rats. Drug treatments started at postnatal day 85 and continued over a 12-week period. Ten animals received haloperidol (1 mg/kg bodyweight) and ten received clozapine (20 mg/kg bodyweight) orally each day. Ten control rats received no drugs. The ten genes selected for this study did not belong to the dopaminergic or serotoninergic systems, which are typically targeted by the two substances, but coded for proteins of the cytoskeleton and proteins belonging to the synaptic transmitter release machinery. Quantitative real-time PCR was performed in the prelimbic cortex, cingulate gyrus (CG1) and caudate putamen and in the hippocampal cornu ammonis 1 (CA1), cornu ammonis 3 (CA3) and dentate gyrus. Results show distinct patterns of gene expression under the influence of the two drugs, but also distinct gene regulations dependent on the brain regions. Haloperidol-medicated animals showed statistically significant downregulation of SNAP-25 in CA3 (p = 0.0134) and upregulation of STX1A in CA1 (p = 0.0133) compared to controls. Clozapine-treated animals showed significant downregulation of SNAP-25 in CG1 (p = 0.0013). Our results clearly reveal that the drugs' effects are different between brain regions. These effects are possibly indirectly mediated through feedback mechanisms by proteins targeted by the drugs, but direct effects of haloperidol or clozapine on mechanisms of gene expression cannot be excluded.


Subject(s)
Antipsychotic Agents/pharmacology , Cerebral Cortex/drug effects , Clozapine/pharmacology , Gene Expression Regulation/drug effects , Gene Expression/drug effects , Haloperidol/pharmacology , Neostriatum/drug effects , Animals , Antipsychotic Agents/administration & dosage , CA1 Region, Hippocampal/drug effects , CA3 Region, Hippocampal/drug effects , Clozapine/administration & dosage , Dentate Gyrus/drug effects , Gyrus Cinguli/drug effects , Haloperidol/administration & dosage , Male , Rats , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , Synaptosomal-Associated Protein 25/drug effects , Syntaxin 1/drug effects
3.
J Cell Biol ; 182(2): 355-66, 2008 Jul 28.
Article in English | MEDLINE | ID: mdl-18644890

ABSTRACT

Phosphatidylinositol 4,5-bisphosphate (PI 4,5-P(2)) on the plasma membrane is essential for vesicle exocytosis but its role in membrane fusion has not been determined. Here, we quantify the concentration of PI 4,5-P(2) as approximately 6 mol% in the cytoplasmic leaflet of plasma membrane microdomains at sites of docked vesicles. At this concentration of PI 4,5-P(2) soluble NSF attachment protein receptor (SNARE)-dependent liposome fusion is inhibited. Inhibition by PI 4,5-P(2) likely results from its intrinsic positive curvature-promoting properties that inhibit formation of high negative curvature membrane fusion intermediates. Mutation of juxtamembrane basic residues in the plasma membrane SNARE syntaxin-1 increase inhibition by PI 4,5-P(2), suggesting that syntaxin sequesters PI 4,5-P(2) to alleviate inhibition. To define an essential rather than inhibitory role for PI 4,5-P(2), we test a PI 4,5-P(2)-binding priming factor required for vesicle exocytosis. Ca(2+)-dependent activator protein for secretion promotes increased rates of SNARE-dependent fusion that are PI 4,5-P(2) dependent. These results indicate that PI 4,5-P(2) regulates fusion both as a fusion restraint that syntaxin-1 alleviates and as an essential cofactor that recruits protein priming factors to facilitate SNARE-dependent fusion.


Subject(s)
Cell Membrane/metabolism , Exocytosis/physiology , Membrane Fusion/physiology , Phosphatidylinositol 4,5-Diphosphate/metabolism , SNARE Proteins/metabolism , Transport Vesicles/metabolism , Animals , Cell Membrane/drug effects , Cell Membrane/ultrastructure , Dose-Response Relationship, Drug , Exocytosis/drug effects , Liposomes/metabolism , Membrane Fusion/drug effects , Membrane Microdomains/drug effects , Membrane Microdomains/metabolism , Membrane Microdomains/ultrastructure , PC12 Cells , Phosphatidylinositol 4,5-Diphosphate/pharmacology , Rats , Syntaxin 1/drug effects , Syntaxin 1/metabolism , Transport Vesicles/drug effects , Transport Vesicles/ultrastructure
4.
EMBO Rep ; 8(4): 414-9, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17363971

ABSTRACT

Syntaxin and Munc18 are, in tandem, essential for exocytosis in all eukaryotes. Recently, it was shown that Munc18 inhibition of neuronal syntaxin 1 can be overcome by arachidonic acid, indicating that this common second messenger acts to disrupt the syntaxin-Munc18 interaction. Here, we show that arachidonic acid can stimulate syntaxin 1 alone, indicating that it is syntaxin 1 that undergoes a structural change in the syntaxin 1-Munc18 complex. Arachidonic acid is incapable of dissociating Munc18 from syntaxin 1 and, crucially, Munc18 remains associated with syntaxin 1 after arachidonic-acid-induced syntaxin 1 binding to synaptosomal-associated protein 25 kDa (SNAP25). We also show that the same principle operates in the case of the ubiquitous syntaxin 3 isoform, highlighting the conserved nature of the mechanism of arachidonic acid action. Neuronal soluble N-ethyl maleimide sensitive factor attachment protein receptors (SNAREs) can be isolated from brain membranes in a complex with endogenous Munc18, consistent with a proposed function of Munc18 in vesicle docking and fusion.


Subject(s)
Arachidonic Acid/pharmacology , Munc18 Proteins/drug effects , Syntaxin 1/drug effects , Amino Acid Sequence , Animals , Brain Chemistry , Cell Membrane/chemistry , Cell Membrane/metabolism , Dissociative Disorders , Molecular Sequence Data , Munc18 Proteins/isolation & purification , Munc18 Proteins/metabolism , Protein Interaction Mapping , Qa-SNARE Proteins/chemistry , Qa-SNARE Proteins/metabolism , Rats , SNARE Proteins/drug effects , SNARE Proteins/isolation & purification , SNARE Proteins/metabolism , Synaptosomal-Associated Protein 25/drug effects , Synaptosomal-Associated Protein 25/isolation & purification , Synaptosomal-Associated Protein 25/metabolism , Syntaxin 1/isolation & purification , Syntaxin 1/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...