Metabotropic glutamate receptors

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Table of contents

LIST OF TABLES
ABBREVIATION LIST
INTRODUCTION
PART I. GLUTAMATE: A FUNDAMENTAL NEUROTRANSMITTER
1. Generalities about neurotransmission
2. History of glutamate identification as a neurotransmitter
3. Glutamate receptors and related signaling
3.1 Ionotropic glutamate receptors
3.2 Metabotropic glutamate receptors
4. Glutamate transporters
4.1 Plasma membrane glutamate transporters
4.2 Vesicular neurotransmitter transporters
PART II. VESICULAR GLUTAMATE TRANSPORTER TYPE 3 (VGLUT3)
1. Vesicular glutamate transporters
1.1 A history of VGLUTs
1.2 VGLUTs cellular and subcellular distributions
1.3 VGLUTs structure
1.4 Mechanism of glutamate uptake by VGLUTs
1.5 VGLUTs during development
1.6 VGLUTs pharmacology
2. Vesicular glutamate transporter type 3 (VGLUT3)
2.1 Anatomical distribution
2.1.1 Regional distribution
2.1.2 Ultrastructural distribution
2.1.3 Neuronal subtypes distribution
2.2 Functional roles: overview
2.2.1 Dual release of transmitters
2.2.2 Vesicular synergy
2.2.3 Related phenotypes
PART III. THE STRIATUM
1. Anatomy of the striatum
1.1 Matrix versus striosomes
1.2 Functional compartmentalization
1.3 Striatal cytoarchitecture
1.3.1 Medium spiny neurons
1.3.2 Striatal interneurons
2. Striatal connectivity
2.1 Striatal afferents
2.1.1 Glutamatergic innervation
2.1.2 Midbrain DA neuromodulation
2.1.3 Serotonergic innervation
2.1.4 Cholinergic innervation
2.1 Striatal activity modulation
2.1.1 DAergic modulation
2.1.2 Cholinergic modulation
2.1.3 Acetylcholine / dopamine activity during behavior
2.2 Striatal efferent to basal ganglia
2.2.1 Basal ganglia
2.2.2 The striatonigral (direct) pathway
2.2.3 The striatopallidal (indirect) pathway
2.2.4 The striosomal pathway
2.2.1 Current view on striatal function
PART IV. STRIATAL DYSREGULATIONS AND ASSOCIATED PATHOLOGIES
1. The reward system
1.1 Reward circuitry
1.2 Mode of action of drugs
1.3 Drug addiction
1.4 Molecular basis of drug addiction
1.5 Role of VGLUT3 in addiction
1.6 Amphetamine
2. Dorsal striatum defects
2.1 Parkinson’s disease
2.2 Obsessive-compulsive disorders
3. Stereotypies
3.1 Definition and general considerations
3.2 Animal models to elicit stereotypies
3.2.1 L‑DOPA‑induced dyskinesia
3.2.1 Drug‑induced stereotypies
3.3 Functional and biochemical correlates of stereotypies
3.4 Methods to assess drug‑induced stereotypies
3.5 Role of VGLUT3 in LID
MATERIALS AND METHODS
1. Animal models
1.1 VGLUT3—/—
1.2 VGLUT3LoxP/LoxP
1.3 VGLUT3 conditional knock‑out: genetic approach
1.3.1 SERT‑Cre conditional knock‑out
1.3.2 ChAT‑IRES‑Cre conditional knock‑out
1.4 VGLUT3 conditional knock‑out: viral approach
1.4.1 Surgical procedure
1.4.2 Cre‑expressing virus
2. Behavioral experiments
2.1 Spontaneous locomotor activity
2.2 Anxiety tests
2.2.1 Open field
2.2.2 O maze
2.3 Behavioral sensitizations
2.3.1 Behavioral sensitization to amphetamine
2.3.2 Locomotor sensitization to cocaine
2.4 Stereotypy scoring
2.4.1 Categorial scoring
2.4.2 Rating‑scale‑based scoring of general stereotypies
2.4.3 Rating‑scale‑based scoring of orofacial stereotypies
3. Drug treatments
4. Anatomical studies by immunohistochemistry
4.1 Immunofluorescence
4.1.1 Conditional knock‑outs validation: VGLUT3, VAChT and 5‑HT
4.1.2 ΔFosB immunofluorescence
4.2 Immunoautoradiography
5. Statistics
6. Experiments color code
RESULTS
PART I. VGLUT3 FULL KNOCK‑OUT AND AMPHETAMINE
1. Basal characterization
1.1 Number of VGLUT3–/– used
1.2 VGLUT3–/– mice weight
1.3 Spontaneous locomotion
2. VGLUT3–/– and amphetamine 1 mg/kg
2.1 Acute injection of amphetamine 1 mg/kg
2.1 Repeated injections of amphetamine 1 mg/kg
3. VGLUT3–/– and amphetamine 3 mg/kg
3.1 Acute injection of amphetamine 3 mg/kg
3.1 Repeated injections of amphetamine 3 mg/kg
4. VGLUT3–/– and amphetamine 5 mg/kg
4.1 Effect on locomotion
4.1.1 Acute injection of amphetamine 5 mg/kg
4.1.2 Repeated injections of amphetamine 5 mg/kg
4.2 Effect on stereotypies
4.2.1 General stereotypies
4.2.2 Orofacial stereotypies
5. Discussion
PART II. CONTRIBUTION OF VGLUT3‑POSITIVE SYSTEMS IN THE RESPONSE TO AMPHETAMINE
1. The VGLUT3‑positive serotonergic drive of the striatum .
1.1 Anatomical characterization of cKO-VGLUT35-HT
1.2 Behavioral characterization of cKO-VGLUT35-HT
1.2.1 Weight
1.2.2 Basal locomotion
1.2.3 Anxiety tests
1.2.4 Spontaneous locomotion before sensitization
1.3 cKO-VGLUT35-HT and amphetamine 5 mg/kg
1.3.1 Effect on locomotion
1.3.2 Effect on stereotypies
2. The VGLUT3‑positive cholinergic drive of the striatum
2.1 Anatomical characterization of cKO-VGLUT3ACh
2.2 Behavioral characterization of cKO-VGLUT3ACh
2.2.1 Weight
2.2.2 Basal locomotion
2.2.3 Anxiety tests
2.2.4 Spontaneous locomotion before sensitization
2.3 cKO-VGLUT3ACh and amphetamine 5 mg/kg
2.3.1 Effect on locomotion
2.3.2 Effect on stereotypies
2.4 cKO-VGLUT3ACh and cocaine 10 mg/kg
3. Discussion
PART III. STUDY OF THE ROLE OF VGLUT3 IN THE NUCLEUS ACCUMBENS IN THE RESPONSE TO COCAINE
1. Development of viral injections
1.1 Choice of virus
1.2 Experimental groups
2. Anatomical validation
3. Behavioral characterization
3.1 Mice weight
3.2 Basal locomotion
3.3 Anxiety levels
4. Locomotor sensitization to cocaine
5. Discussion
GENERAL CONCLUSION
APPENDICES II
1. Temporal course of AMPH injections
1.1 VGLUT3–/– and AMPH 1 mg/kg ii
1.2 VGLUT3–/– and AMPH 3 mg/kg iii
1.3 VGLUT3–/– and AMPH 5 mg/kg iv
1.4 cKO-VGLUT35-HT and AMPH 5 mg/kg v
1.5 cKO-VGLUT3ACh and AMPH 5 mg/kg vi
2. Publications
REFERENCES