Changes in extracellular dopamine induced by morphine and cocaine: crucial control by D2 receptors.
An increase of extracellular dopamine (DA) concentration is a major neurobiological substrate of the addictive properties of drugs of abuse. In this article we investigated the contribution of the DA D2 receptor (D2R) in the control of this response. Extracellular DA levels were measured in the striatum of mice lacking D2R expression (D2R-/-) by in vivo microdialysis after administration of the psychostimulant cocaine and the opioid morphine. Interestingly, the increase in extracellular DA induced by both drugs was strikingly higher in D2R-/- than in wild-type littermates. This indicates that D2Rs play a key role in the modulation of DA release in response to drugs of abuse. Furthermore, this observation prompted us to investigate the dopaminergic autoreceptor function in the absence of D2 receptor in D2R-/- mice. Results obtained using complementary microdialysis and voltammetry analyses show that the autoreceptor function regulating DA release is totally abolished in the absence of D2R, despite unchanged DA uptake and basal DA efflux. Finally, we propose that the short isoform D2S receptor of the D2 receptors is the one controlling change in DA release induced by drugs of abuse. Indeed, the neurochemical effects of cocaine and morphine are unchanged in animals with a selective deletion of the long isoform D2L receptor. Thus, deregulated expression of D2R isoforms might be involved in the vulnerability of an individual to drug abuse.
Rouge-Pont
Francoise
F
Institut National de la Santé et de la Recherche Médicale (INSERM) U259, Université Victor Segalen Bordeaux 2, 33077 Bordeaux Cedex, France.
Usiello
Alessandro
A
Benoit-Marand
Marianne
M
Gonon
Francois
F
Piazza
Pier Vincenzo
PV
Borrelli
Emiliana
E
D000818:Animals; D017660:Autoreceptors / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D003433:Crosses, Genetic; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D005110:Extracellular Space / Q000378:metabolism; D008474:Medial Forebrain Bundle / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017551:Microdialysis; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D017660:Autoreceptors; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D009294:Narcotics; D020033:Protein Isoforms; D017448:Receptors, Dopamine D2; C113776:dopamine D2L receptor; D009020:Morphine; D003042:Cocaine; D004298:Dopamine