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2.
Brain Behav Immun ; 111: 277-291, 2023 07.
Article in English | MEDLINE | ID: mdl-37100211

ABSTRACT

Dysregulated inflammation within the central nervous system (CNS) contributes to neuropathology in infectious, autoimmune, and neurodegenerative disease. With the exception of microglia, major histocompatibility complex (MHC) proteins are virtually undetectable in the mature, healthy central nervous system (CNS). Neurons have generally been considered incapable of antigen presentation, and although interferon gamma (IFN-γ) can elicit neuronal MHC class I (MHC-I) expression and antigen presentation in vitro, it has been unclear whether similar responses occur in vivo. Here we directly injected IFN-γ into the ventral midbrain of mature mice and analyzed gene expression profiles of specific CNS cell types. We found that IFN-γ upregulated MHC-I and associated mRNAs in ventral midbrain microglia, astrocytes, oligodendrocytes, and GABAergic, glutamatergic, and dopaminergic neurons. The core set of IFN-γ-induced genes and their response kinetics were similar in neurons and glia, but with a lower amplitude of expression in neurons. A diverse repertoire of genes was upregulated in glia, particularly microglia, which were the only cells to undergo cellular proliferation and express MHC classII (MHC-II) and associated genes. To determine if neurons respond directly via cell-autonomous IFN-γ receptor (IFNGR) signaling, we produced mutant mice with a deletion of the IFN-γ-binding domain of IFNGR1 in dopaminergic neurons, which resulted in a complete loss of dopaminergic neuronal responses to IFN-γ. Our results demonstrate that IFN-γ induces neuronal IFNGR signaling and upregulation of MHC-I and related genes in vivo, although the expression level is low compared to oligodendrocytes, astrocytes, and microglia.


Subject(s)
Interferon-gamma , Neurodegenerative Diseases , Mice , Animals , Interferon-gamma/metabolism , Neurodegenerative Diseases/metabolism , Central Nervous System/metabolism , Astrocytes/metabolism , Mesencephalon/metabolism
3.
J Parkinsons Dis ; 12(s1): S137-S147, 2022.
Article in English | MEDLINE | ID: mdl-35253783

ABSTRACT

Patients with Parkinson's disease (PD) and other synucleinopathies often exhibit autoimmune features, including CD4+ and some CD8+ T lymphocytes that recognize epitopes derived from alpha-synuclein. While neurons have long been considered to not present antigens, recent data indicate that they can be induced to do so, particularly in response to interferons and other forms of stress. Here, we review literature on neuronal antigen presentation and its potential role in PD. Although direct evidence for CD8+ T cell-mediated neuronal death is lacking in PD, neuronal antigen presentation appears central to the pathology of Rasmussen's encephalitis, a pediatric neurological disorder driven by cytotoxic T cell infiltration and neuroinflammation. Emerging data suggest that T cells enter the brain in PD and other synucleinopathies, where the majority of neuromelanin-containing substantia nigra and locus coeruleus neurons express MHC Class I molecules. In cell culture, CD8+ T cell recognition of antigen:MHC Class I complexes on neuronal membranes leads to cytotoxic responses and neuronal cell death. Recent animal models suggest the possibility of T cell autoreactivity to mitochondrial antigens in PD. It remains unclear if neuronal antigen presentation plays a role in PD or other neurodegenerative disorders, and efforts are underway to better elucidate the potential impact of autoimmune responses on neurodegeneration.


Subject(s)
Parkinson Disease , Synucleinopathies , Animals , Epitopes , Histocompatibility Antigens Class I , Interferons , Neurons/metabolism , Parkinson Disease/metabolism , alpha-Synuclein/metabolism
4.
Elife ; 112022 01 31.
Article in English | MEDLINE | ID: mdl-35098924

ABSTRACT

Dopaminergic neurons modulate neural circuits and behaviors via dopamine (DA) release from expansive, long range axonal projections. The elaborate cytoarchitecture of these neurons is embedded within complex brain tissue, making it difficult to access the neuronal proteome using conventional methods. Here, we demonstrate APEX2 proximity labeling within genetically targeted neurons in the mouse brain, enabling subcellular proteomics with cell-type specificity. By combining APEX2 biotinylation with mass spectrometry, we mapped the somatodendritic and axonal proteomes of midbrain dopaminergic neurons. Our dataset reveals the proteomic architecture underlying proteostasis, axonal metabolism, and neurotransmission in these neurons. We find that most proteins encoded by DA neuron-enriched genes are localized within striatal dopaminergic axons, including ion channels with previously undescribed axonal localization. These proteomic datasets provide a resource for neuronal cell biology, and this approach can be readily adapted for study of other neural cell types.


Subject(s)
Brain/cytology , DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism , Dopaminergic Neurons/metabolism , Endonucleases/metabolism , Multifunctional Enzymes/metabolism , Proteomics , Animals , DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics , Endonucleases/genetics , Female , Male , Mice , Multifunctional Enzymes/genetics , Synaptosomes/metabolism
5.
Cell Rep ; 38(2): 110208, 2022 01 11.
Article in English | MEDLINE | ID: mdl-35021090

ABSTRACT

Midbrain dopaminergic (mDA) neurons exhibit extensive dendritic and axonal arborizations, but local protein synthesis is not characterized in these neurons. Here, we investigate messenger RNA (mRNA) localization and translation in mDA neuronal axons and dendrites, both of which release dopamine (DA). Using highly sensitive ribosome-bound RNA sequencing and imaging approaches, we find no evidence for mRNA translation in mDA axons. In contrast, mDA neuronal dendrites in the substantia nigra pars reticulata (SNr) contain ribosomes and mRNAs encoding the major components of DA synthesis, release, and reuptake machinery. Surprisingly, we also observe dendritic localization of mRNAs encoding synaptic vesicle-related proteins, including those involved in exocytic fusion. Our results are consistent with a role for local translation in the regulation of DA release from dendrites, but not from axons. Our translatome data define a molecular signature of sparse mDA neurons in the SNr, including the enrichment of Atp2a3/SERCA3, an atypical ER calcium pump.


Subject(s)
Dopaminergic Neurons/metabolism , Protein Biosynthesis/physiology , RNA, Messenger/metabolism , Animals , Axons/metabolism , Dendrites/metabolism , Dopamine/metabolism , Female , Male , Mesencephalon/physiology , Mice , Mice, Inbred C57BL , Neuronal Plasticity/physiology , Protein Biosynthesis/genetics , RNA, Messenger/genetics , Ribosomes/metabolism , Sequence Analysis, RNA/methods , Substantia Nigra/metabolism
6.
Elife ; 92020 08 26.
Article in English | MEDLINE | ID: mdl-32844746

ABSTRACT

Puromycin is an amino-acyl transfer RNA analog widely employed in studies of protein synthesis. Since puromycin is covalently incorporated into nascent polypeptide chains, anti-puromycin immunofluorescence enables visualization of nascent protein synthesis. A common assumption in studies of local messenger RNA translation is that the anti-puromycin staining of puromycylated nascent polypeptides in fixed cells accurately reports on their original site of translation, particularly when ribosomes are stalled with elongation inhibitors prior to puromycin treatment. However, when we attempted to implement a proximity ligation assay to detect ribosome-puromycin complexes, we found no evidence to support this assumption. We further demonstrated, using biochemical assays and live cell imaging of nascent polypeptides in mammalian cells, that puromycylated nascent polypeptides rapidly dissociate from ribosomes even in the presence of elongation inhibitors. Our results suggest that attempts to define precise subcellular translation sites using anti-puromycin immunostaining may be confounded by release of puromycylated nascent polypeptide chains prior to fixation.


Subject(s)
Peptide Chain Elongation, Translational/drug effects , Protein Synthesis Inhibitors , Puromycin , Ribosomes , Animals , Cell Line, Tumor , Mice , Protein Synthesis Inhibitors/metabolism , Protein Synthesis Inhibitors/pharmacology , Proteins/chemistry , Proteins/metabolism , Puromycin/metabolism , Puromycin/pharmacology , RNA, Messenger/chemistry , RNA, Messenger/metabolism , RNA, Transfer, Amino Acyl/chemistry , RNA, Transfer, Amino Acyl/metabolism , Ribosomes/drug effects , Ribosomes/metabolism
7.
eNeuro ; 6(3)2019.
Article in English | MEDLINE | ID: mdl-31118205

ABSTRACT

Flow cytometry and fluorescence-activated sorting are powerful techniques that hold great promise for studying heterogeneous populations of submicron particles such as synaptosomes, but many technical challenges arise in these experiments. To date, most flow cytometry studies of synaptosomes have relied on particle detection using forward scatter (FSC) measurements and size estimation with polystyrene (PS) bead standards. However, these practices have serious limitations, and special care must be taken to overcome the poor sensitivity of conventional flow cytometers in the analysis of submicron particles. Technical artifacts can confound these experiments, especially the detection of multiple particles as a single event. Here, we compared analysis of P2 crude synaptosomal preparations from murine forebrain on multiple flow cytometers using both FSC-triggered and fluorescence-triggered detection. We implemented multicolor fluorescent dye-based assays to quantify coincident particle detection and aggregation, and we assessed the false colocalization of antigens in immunostaining analyses. Our results demonstrate that fluorescence triggering and proper dilution can control for coincident particle detection, but not particle aggregation. We confirmed previous studies showing that FSC-based size estimation with PS beads underestimates biological particle size, and we identified pervasive aggregation in the FSC range analyzed in most synaptosome flow cytometry studies. We found that analyzing P2 samples in sucrose/EDTA/tris (SET) buffer reduces aggregation compared to PBS, but does not completely eliminate the presence of aggregates, especially in immunostaining experiments. Our study highlights challenges and pitfalls in synaptosome flow cytometry and provides a methodological framework for future studies.


Subject(s)
Flow Cytometry/methods , Prosencephalon/cytology , Synaptosomes/chemistry , Animals , Artifacts , Flow Cytometry/standards , Fluorescent Dyes/analysis , Male , Mice, Inbred C57BL , Particle Size , Polystyrenes/analysis , Reference Standards , Scattering, Radiation
8.
Cell Rep ; 26(12): 3313-3322.e5, 2019 03 19.
Article in English | MEDLINE | ID: mdl-30893603

ABSTRACT

FMRP (fragile X mental retardation protein) is a polysome-associated RNA-binding protein encoded by Fmr1 that is lost in fragile X syndrome. Increasing evidence suggests that FMRP regulates both translation initiation and elongation, but the gene specificity of these effects is unclear. To elucidate the impact of Fmr1 loss on translation, we utilize ribosome profiling for genome-wide measurements of ribosomal occupancy and positioning in the cortex of 24-day-old Fmr1 knockout mice. We find a remarkably coherent reduction in ribosome footprint abundance per mRNA for previously identified, high-affinity mRNA binding partners of FMRP and an increase for terminal oligopyrimidine (TOP) motif-containing genes canonically controlled by mammalian target of rapamycin-eIF4E-binding protein-eIF4E binding protein-eukaryotic initiation factor 4E (mTOR-4E-BP-eIF4E) signaling. Amino acid motif- and gene-level analyses both show a widespread reduction of translational pausing in Fmr1 knockout mice. Our findings are consistent with a model of FMRP-mediated regulation of both translation initiation through eIF4E and elongation that is disrupted in fragile X syndrome.


Subject(s)
Cerebral Cortex , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome , Peptide Chain Elongation, Translational , Signal Transduction , Animals , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Fragile X Mental Retardation Protein/metabolism , Fragile X Syndrome/genetics , Fragile X Syndrome/metabolism , Fragile X Syndrome/pathology , Mice , Mice, Knockout
9.
Psychopharmacology (Berl) ; 236(2): 699-708, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30392131

ABSTRACT

RATIONALE AND OBJECTIVES: Adenosine signaling through adenosine A2A receptors (A2ARs) is known to influence cocaine-induced behaviors. These studies sought to elucidate how two A2AR antagonists distinguished by their antagonist effects at presynaptic and postsynaptic A2AR influence cocaine-induced locomotion and cocaine seeking. METHODS: Sprague-Dawley rats were used to assess the differential effects of SCH 442416 and istradefylline that antagonize presynaptic and postsynaptic A2AR, respectively. We evaluated the effects of these antagonists on both basal and cocaine-induced locomotion in cocaine-naïve rats and rats that received seven daily cocaine treatments. The effects of SCH 442416 or istradefylline on cocaine seeking were measured in animals extinguished from cocaine self-administration. We assessed the effects of the A2AR antagonists to induce cocaine seeking when administered alone and their effects on cocaine seeking induced by a cocaine-priming injection. Lastly, we evaluated the effects of the antagonists on sucrose seeking in animals extinguished from sucrose self-administration. RESULTS: Neither istradefylline nor SCH 442416 significantly altered basal locomotion. Istradefylline enhanced acute cocaine-induced locomotion but had no effect on the expression of locomotor sensitization. SCH 44216 had no effect on acute cocaine-induced locomotion but inhibited the expression of locomotor sensitization. Istradefylline was sufficient to induce cocaine seeking and augmented both cocaine-induced seeking and sucrose seeking. SCH 442416 inhibited cocaine-induced seeking, but had no effect on sucrose seeking and did not induce cocaine seeking when administered alone. CONCLUSIONS: These findings demonstrate differential effects of two A2AR antagonists distinguished by their effects at pre- and postsynaptic A2AR on cocaine-induced behaviors.


Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Cocaine/administration & dosage , Drug-Seeking Behavior/drug effects , Locomotion/drug effects , Animals , Cocaine-Related Disorders/psychology , Dose-Response Relationship, Drug , Drug-Seeking Behavior/physiology , Locomotion/physiology , Male , Motor Activity/drug effects , Motor Activity/physiology , Rats , Rats, Sprague-Dawley , Self Administration
10.
Neuron ; 99(3): 540-554.e4, 2018 08 08.
Article in English | MEDLINE | ID: mdl-30057204

ABSTRACT

Neural circuits are formed and refined during childhood, including via critical changes in neuronal excitability. Here, we investigated the ontogeny of striatal intrinsic excitability. We found that dopamine neurotransmission increases from the first to the third postnatal week in mice and precedes the reduction in spiny projection neuron (SPN) intrinsic excitability during the fourth postnatal week. In mice developmentally deficient for striatal dopamine, direct pathway D1-SPNs failed to undergo maturation of excitability past P18 and maintained hyperexcitability into adulthood. We found that the absence of D1-SPN maturation was due to altered phosphatidylinositol 4,5-biphosphate dynamics and a consequent lack of normal ontogenetic increases in Kir2 currents. Dopamine replacement corrected these deficits in SPN excitability when provided from birth or during a specific period of juvenile development (P18-P28), but not during adulthood. These results identify a sensitive period of dopamine-dependent striatal maturation, with implications for the pathophysiology and treatment of neurodevelopmental disorders.


Subject(s)
Corpus Striatum/growth & development , Critical Period, Psychological , Dopamine/pharmacology , Neurons/physiology , Age Factors , Animals , Animals, Newborn , Corpus Striatum/cytology , Corpus Striatum/drug effects , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Neurons/drug effects , Random Allocation
11.
Semin Immunol ; 30: 36-44, 2017 04.
Article in English | MEDLINE | ID: mdl-28865877

ABSTRACT

Food allergy is a pathological, potentially deadly cascade of immune responses to molecules or molecular fragments that are normally innocuous when encountered in foods, such as milk, egg, or peanut. As the incidence and prevalence of food allergy rise, the standard of care is poised to advance beyond food allergen avoidance coupled with injectable epinephrine treatment of allergen-induced systemic reactions. Recent studies provide evidence that oral immunotherapy may effectively redirect the atopic immune responses of food allergy patients as they ingest small but gradually increasing allergen doses over many months, eliciting safer immune responses to these antigens. Research into the molecular and cellular bases of pathological and therapeutic immune responses, and into the possibilities for their safe and effective modulation, is generating tremendous interest in basic and clinical immunology. We synthesize developments, innovations, and key challenges in our understanding of the immune mechanisms associated with atopy and oral immunotherapy for food allergy.


Subject(s)
Allergens/therapeutic use , Desensitization, Immunologic/methods , Egg Proteins, Dietary/therapeutic use , Food Hypersensitivity/immunology , Administration, Oral , Allergens/immunology , Animals , Egg Proteins, Dietary/immunology , Food , Food Hypersensitivity/therapy , Humans
12.
J Allergy Clin Immunol ; 139(3): 844-854, 2017 Mar.
Article in English | MEDLINE | ID: mdl-27658763

ABSTRACT

BACKGROUND: An emerging paradigm holds that resistance to the development of allergic diseases, including allergic rhinoconjunctivitis, relates to an intact epithelial/epidermal barrier during early childhood. Conceivably, the immunologic and genomic footprint of this resistance is preserved in nonatopic, nonallergic adults and is unmasked during exposure to an aeroallergen. OBJECTIVE: The aim of this study was to obtain direct support of the epithelial/epidermal barrier model for allergic rhinoconjunctivitis. METHODS: Twenty-three adults allergic to house dust mites (HDMs) (M+) and 15 nonsensitive, nonallergic (M-) participants completed 3-hour exposures to aerosolized HDM (Dermatophagoides pteronyssinus) powder on 4 consecutive days in an allergen challenge chamber. We analyzed: (1) peripheral blood leukocyte levels and immune responses; and (2) RNA sequencing-derived expression profiles of nasal cells, before and after HDM exposure. RESULTS: On HDM challenge: (1) only M+ persons developed allergic rhinoconjunctivitis symptoms; and (2) peripheral blood leukocyte levels/responses and gene expression patterns in nasal cells were largely concordant between M+ and M- participants; gross differences in these parameters were not observed at baseline (pre-exposure). Two key differences were observed. First, peripheral blood CD4+ and CD8+ T-cell activation levels initially decreased in M- participants versus increased in M+ participants. Second, in M- compared with M+ participants, genes that promoted epidermal/epithelial barrier function (eg, filament-aggregating protein [filaggrin]) versus inflammation (eg, chemokines) and innate immunity (interferon) were upregulated versus muted, respectively. CONCLUSION: An imprint of resistance to HDM challenge in nonatopic, nonallergic adults was muted T-cell activation in the peripheral blood and inflammatory response in the nasal compartment, coupled with upregulation of genes that promote epidermal/epithelial cell barrier function.


Subject(s)
Allergens/immunology , Antigens, Dermatophagoides/immunology , Conjunctivitis, Allergic/immunology , Pyroglyphidae/immunology , Rhinitis, Allergic/immunology , Administration, Inhalation , Adult , Animals , Conjunctivitis, Allergic/genetics , Disease Resistance , Epithelial Cells/immunology , Epithelial Cells/metabolism , Female , Filaggrin Proteins , Humans , Leukocyte Count , Male , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Rhinitis, Allergic/genetics , Transcriptome
13.
Psychopharmacology (Berl) ; 231(16): 3179-88, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24562064

ABSTRACT

RATIONALE: Adenosine receptor stimulation and blockade have been shown to modulate a variety of cocaine-related behaviors. OBJECTIVES: These studies identify the direct effects of adenosine receptor stimulation on cocaine seeking during extinction training and the persistent effects on subsequent reinstatement to cocaine seeking. METHODS: Rats self-administered cocaine on a fixed ratio one schedule in daily sessions over 3 weeks. Following a 1-week withdrawal, the direct effects of adenosine receptor modulation were tested by administering the adenosine A1 receptor agonist, N(6)-cyclopentyladenosine (CPA, 0.03 and 0.1 mg/kg), the adenosine A2A agonist, CGS 21680 (0.03 and 0.1 mg/kg), the presynaptic adenosine A2A receptor antagonist, SCH 442416 (0.3, 1, and 3 mg/kg), or vehicle prior to each of six daily extinction sessions. The persistent effects of adenosine receptor modulation during extinction training were subsequently tested on reinstatement to cocaine seeking induced by cues, cocaine, and the dopamine D2 receptor agonist, quinpirole. RESULTS: All doses of CPA and CGS 21680 impaired initial extinction responding; however, only CPA treatment during extinction produced persistent impairment in subsequent cocaine- and quinpirole-induced seeking. Dissociating CPA treatment from extinction did not alter extinction responding or subsequent reinstatement. Administration of SCH 442416 had no direct effects on extinction responding but produced dose-dependent persistent impairment of cocaine- and quinpirole-induced seeking. CONCLUSIONS: These findings demonstrate that adenosine A1 or A2A receptor stimulation directly impair extinction responding. Interestingly, adenosine A1 receptor stimulation or presynaptic adenosine A2A receptor blockade during extinction produces lasting changes in relapse susceptibility.


Subject(s)
Cocaine-Related Disorders/psychology , Drug-Seeking Behavior/drug effects , Extinction, Psychological/drug effects , Receptor, Adenosine A1/drug effects , Receptor, Adenosine A2A/drug effects , Adenosine/analogs & derivatives , Adenosine/pharmacology , Adenosine A1 Receptor Agonists/pharmacology , Adenosine A2 Receptor Agonists/pharmacology , Adenosine A2 Receptor Antagonists/pharmacology , Animals , Cues , Dopamine Agonists/pharmacology , Dose-Response Relationship, Drug , Male , Phenethylamines/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Quinpirole/pharmacology , Rats , Rats, Sprague-Dawley , Recurrence , Self Administration
14.
Neuropsychopharmacology ; 38(10): 1974-83, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23598433

ABSTRACT

AMPAR (α-amino-3-hydroxy-5-methylisoxazole-4-propionate glutamate receptor) stimulation in the nucleus accumbens (NAc) is critical in cocaine seeking. Here, we investigate the functional interaction between D1 dopamine receptors (D1DR) and AMPARs in the NAc, and explore how A1 adenosine receptor (A1AR) stimulation may reduce dopamine-induced facilitation of AMPARs and cocaine seeking. All animals were trained to self-administer cocaine and were tested for reinstatement of cocaine seeking following extinction procedures. The role of AMPARs in both AMPA- and D1DR-induced cocaine seeking was assessed using viral-mediated gene transfer to bi-directionally modulate AMPAR activity in the NAc core. The ability of pharmacological AMPAR blockade to modulate D1DR-induced cocaine seeking also was tested. Immunoblotting was used to determine whether stimulating D1DR altered synaptic AMPA GluA1 phosphorylation (pGluA1). Finally, the ability of an A1AR agonist to modulate D1DR-induced cocaine seeking and synaptic GluA1 receptor subunit phosphorylation was explored. Decreasing AMPAR function inhibited both AMPA- and D1DR-induced cocaine seeking. D1DR stimulation increased AMPA pGluA1(S845). Administration of the A1AR agonist alone decreased synaptic GluA1 expression, whereas coadministration of the A1AR agonist inhibited both cocaine- and D1DR-induced cocaine seeking and reversed D1DR-induced AMPA pGluA1(S845). These findings suggest that D1DR stimulation facilitates AMPAR function to initiate cocaine seeking in D1DR-containing direct pathway NAc neurons. A1AR stimulation inhibits both the facilitation of AMPAR function and subsequent cocaine seeking, suggesting that reducing AMPA glutamate neurotransmission in direct pathway neurons may restore inhibitory control and reduce cocaine relapse.


Subject(s)
Cocaine/pharmacology , Drug-Seeking Behavior/drug effects , Nucleus Accumbens/metabolism , Receptor, Adenosine A1/metabolism , Receptors, AMPA/metabolism , Receptors, Dopamine D1/metabolism , 6-Cyano-7-nitroquinoxaline-2,3-dione/administration & dosage , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Adenosine/administration & dosage , Adenosine/analogs & derivatives , Adenosine/pharmacology , Animals , Benzazepines/administration & dosage , Benzazepines/pharmacology , Cocaine/administration & dosage , Dopamine Agonists/pharmacology , Drug Interactions , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Extinction, Psychological , Gene Transfer Techniques , Male , Microinjections , Nucleus Accumbens/drug effects , Phosphorylation/drug effects , Purinergic P1 Receptor Agonists/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Rats , Receptors, AMPA/genetics , Self Administration , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology
15.
Neuropharmacology ; 63(6): 1172-81, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22749927

ABSTRACT

Adenosine receptors co-localize with dopamine receptors on medium spiny nucleus accumbens (NAc) neurons where they antagonize dopamine receptor activity. It remains unclear whether adenosine receptor stimulation in the NAc restores cocaine-induced enhancements in dopamine receptor sensitivity. The goal of these studies was to determine whether stimulating A(1) or A(2A) receptors in the NAc reduces the expression of cocaine sensitization. Rats were sensitized with 7 daily treatments of cocaine (15 mg/kg, i.p.). Following one-week withdrawal, the effects of intra-NAc microinjections of the adenosine kinase inhibitor (ABT-702), the adenosine deaminase inhibitor (deoxycoformycin; DCF), the specific A(1) receptor agonist (CPA) and the specific A(2A) receptor agonist (CGS 21680) were tested on the behavioral expression of cocaine sensitization. The results indicate that intra-NAc pretreatment of ABT-702 and DCF dose-dependently blocked the expression of cocaine sensitization while having no effects on acute cocaine sensitivity, suggesting that upregulation of endogenous adenosine in the accumbens is sufficient to non-selectively stimulate adenosine receptors and reverse the expression of cocaine sensitization. Intra-NAc treatment of CPA significantly inhibited the expression of cocaine sensitization, which was reversed by both A(1) and A(2A) receptor antagonism. Intra-NAc treatment of CGS 21680 also significantly inhibited the expression of cocaine sensitization, which was selectively reversed by A(2A), but not A(1), receptor antagonism. Finally, CGS 21680 also inhibited the expression of quinpirole cross-sensitization. Together, these findings suggest that adenosine receptor stimulation in the NAc is sufficient to reverse the behavioral expression of cocaine sensitization and that A(2A) receptors blunt cocaine-induced sensitization of postsynaptic D(2) receptors.


Subject(s)
Cocaine/antagonists & inhibitors , Cocaine/pharmacology , Dopamine Uptake Inhibitors/antagonists & inhibitors , Dopamine Uptake Inhibitors/pharmacology , Nucleus Accumbens/drug effects , Receptors, Dopamine D2/drug effects , Receptors, Purinergic P1/drug effects , Adenosine/analogs & derivatives , Adenosine/pharmacology , Adenosine A1 Receptor Agonists/pharmacology , Adenosine Deaminase/metabolism , Adenosine Deaminase Inhibitors/pharmacology , Adenosine Kinase/metabolism , Animals , Dopamine Agonists/pharmacology , Male , Microinjections , Morpholines/pharmacology , Motor Activity/drug effects , Phenethylamines/pharmacology , Pyrimidines/pharmacology , Quinpirole/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Adenosine A2A/drug effects , Stimulation, Chemical
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