PEREZ MARIELA FERNANDA
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Título:
. REPEATED COCAINE ADMINISTRATION DECREASES DOPAMINE D2-CLASS RECEPTOR (D2R)-MEDIATED INHIBITION OF CALCIUM PLATEAU POTENTIALS IN RAT NUCLEUS ACCUMBENS NEURONS
Autor/es:
PEREZ MF, GREVERS CM AND HU X-T
Lugar:
Atlanta, USA
Reunión:
Congreso; Society for Neuroscience; 2006
Institución organizadora:
Society for Neuroscience
Resumen:
The nucleus accumbens (NAc) is an important forebrain region involved in sensitization, withdrawal effects, and self-administration of cocaine. Dopamine (DA) regulates activity of medium spiny neurons (MSN) in the NAc. Both DA D1Rs and D2Rs are thought to play important roles in the development of cocaine addiction. Our recent studies have demonstrated that repeated cocaine administration decreases intrinsic excitability in NAc neurons of drug-withdrawn rats. The decreased excitability is characterized by a reduction in whole-cell voltage-sensitive Na+ currents and high-voltage activated (HVA-) N- and R-type Ca2+ currents (ICa), along with enhanced voltage-gated K+ currents. However, although the reduced ICa in cocaine-withdrawn NAc neurons appears to be primarily modulated by enhanced activity of the D1R/PKA/PP1 pathway via indirect dephosphorylation of non-L-type Ca2+ channels, D2R modulation of Ca2+ channel function in these cells is not clearly understood. In the present study, we performed visualized whole-cell current-clamp recordings in brain slices containing the NAc to determine whether chronic cocaine exposure alters D2R modulation of Ca2+ plateau potential in NAc MSN located in the core region. Adolescent rats received saline or repeated cocaine administration for 5 consecutive days (15 mg/kg/day, i.p.) followed by either a short-term (3-day) or long-term (3-week) withdrawal. In saline-withdrawn rats, D2R stimulation by quinpirole suppressed HVA-Ca2+ potentials in NAc neurons in a dose-dependent manner (10-200 mM). This inhibitory effect of D2Rs on Ca2+ potentials was also mimicked by calcineurin (protein phosphatase 2B, PP2B) and blocked by inhibition of calcineurin activity. However, the D2R-mediated inhibition in Ca2+ potentials was almost abolished after repeated cocaine administration with either a short- or long-term withdrawal. Combined with our previous findings, these results indicate that (1) D2R stimulation suppresses HVA-Ca2+ potentials by activating calcineurin that dephosphorylates Ca2+ channels, (2) repeated cocaine administration diminishes this D2R effect on inhibiting Ca2+ potentials by decreasing calcineurin function, and (3) chronic cocaine-induced maladaptations in D2R function could last for at least three weeks of withdraw
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