RGD Reference Report - Cocaine alters vesicular dopamine sequestration and potassium-stimulated dopamine release: the role of D2 receptor activation. - Rat Genome Database

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Cocaine alters vesicular dopamine sequestration and potassium-stimulated dopamine release: the role of D2 receptor activation.

Authors: Farnsworth, SJ  Volz, TJ  Hanson, GR  Fleckenstein, AE 
Citation: Farnsworth SJ, etal., J Pharmacol Exp Ther. 2009 Mar;328(3):807-12. Epub 2008 Nov 26.
RGD ID: 5130996
Pubmed: PMID:19038779   (View Abstract at PubMed)
PMCID: PMC2682259   (View Article at PubMed Central)
DOI: DOI:10.1124/jpet.108.146159   (Journal Full-text)

Cocaine is a psychostimulant that inhibits the inward transport of dopamine (DA) via the neuronal DA transporter, thereby increasing DA concentrations in the synaptic cleft. Cocaine administration also causes a redistribution of striatal vesicular monoamine transporter (VMAT)-2-containing vesicles that co-fractionate with synaptosomal membranes after osmotic lysis (referred to herein as membrane-associated vesicles) to a nonmembrane-associated, cytoplasmic subcellular fraction. Although previous studies from our laboratory have focused on the impact of cocaine on cytoplasmic vesicles, the present report describes the pharmacological effects of cocaine on the membrane-associated vesicle population. Results revealed that the redistribution of VMAT-2 and associated vesicles away from synaptosomal membranes is associated with a decrease in total DA transport and DA content in the membrane-associated VMAT-2-containing subcellular fraction. Cocaine also decreases the velocity and magnitude of K+-stimulated exocytotic DA release from whole striatal suspensions. The cocaine-induced VMAT-2 redistribution, decrease in DA release, and decrease in total DA transport are mediated by D2 receptors as these events were prevented by pretreatment with the D2 receptor antagonist, eticlopride [S-(-)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-met hoxybenzamide hydrochloride]. These data suggest that after cocaine administration, D2 receptors are activated because of increased synaptic DA, resulting in a redistribution of DA-containing vesicles away from synaptosomal membranes, thus leading to less DA released after a depolarizing stimulus. These findings provide insight into not only the mechanism of action of cocaine but also mechanisms underlying the regulation of dopaminergic neurons.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Slc18a2Ratresponse to cocaine  IEP  RGD 

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Slc18a2Ratsynaptic vesicle membrane  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Slc18a2  (solute carrier family 18 member A2)


Additional Information