Repeated cocaine exposure decreases dopamine D₂-like receptor modulation of Ca(2+) homeostasis in rat nucleus accumbens neurons.
The nucleus accumbens (NAc) is a limbic structure in the forebrain that plays a critical role in cognitive function and addiction. Dopamine modulates activity of medium spiny neurons (MSNs) in the NAc. Both dopamine D₁-like and D₂-like receptors (including D1R or D(1,5)R and D2R or D(2,3,4)R, respectively) are thought to play critical roles in cocaine addiction. Our previous studies demonstrated that repeated cocaine exposure (which alters dopamine transmission) decreases excitability of NAc MSNs in cocaine-sensitized, withdrawn rats. This decrease is characterized by a reduction in voltage-sensitive Na(+) currents and high voltage-activated Ca(2+) currents, along with increased voltage-gated K(+) currents. These changes are associated with enhanced activity in the D1R/cAMP/PKA/protein phosphatase 1 pathway and diminished calcineurin function. Although D1R-mediated signaling is enhanced by repeated cocaine exposure, little is known whether and how the D2R is implicated in the cocaine-induced NAc dysfunction. Here, we performed a combined electrophysiological, biochemical, and neuroimaging study that reveals the cocaine-induced dysregulation of Ca(2+) homeostasis with involvement of D2R. Our novel findings reveal that D2R stimulation reduced Ca(2+) influx preferentially via the L-type Ca(2+) channels and evoked intracellular Ca(2+) release, likely via inhibiting the cAMP/PKA cascade, in the NAc MSNs of drug-free rats. However, repeated cocaine exposure abolished the D₂R effects on modulating Ca(2+) homeostasis with enhanced PKA activity and led to a decrease in whole-cell Ca(2+) influx. These adaptations, which persisted for 21 days during cocaine abstinence, may contribute to the mechanism of cocaine withdrawal.
Perez
Mariela F
MF
IFEC, CONICET, Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende s/n, Ciudad Universitaria, 5000 Córdoba, Argentina.
Ford
Kerstin A
KA
Goussakov
Ivan
I
Stutzmann
Grace E
GE
Hu
Xiu-Ti
XT
D000704:Analysis of Variance; D000818:Animals; D019703:Calcineurin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000166:cytology*; D018408:Patch-Clamp Techniques / Q000379:methods; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012457:Salicylamides / Q000494:pharmacology; D013997:Time Factors
D015220:Calcium Channels; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D012457:Salicylamides; D019257:Quinpirole; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D003042:Cocaine; C045989:eticlopride; D002118:Calcium