IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Differential effects of methamphetamine and modafinil on the mRNA levels of dopamine and glutamate receptors and voltage-gated Ca2+ channels in the mouse prefrontal cortex
Autor/es:
BISAGNO V; GONZALEZ B; CADET JL; GARCIA-RILL E; URBANO FJ
Lugar:
Chicago, USA
Reunión:
Congreso; 2015 SOCIETY FOR NEUROSCIENCE MEETING, Chicago, Oct. 17-21.; 2015
Institución organizadora:
Society for Neuroscience
Resumen:
Abuse of methamphetamine (METH) can induce cognitive dysfunctions in humans and animal models. On the other hand, the psychostimulant Modafinil (which shares with METH the property of being also a DAT blocker) is prescribed as a cognitive enhancer. We have previously demonstrated that Modafinil can attenuate METH-induced deficits in visual memory and improve ERK signaling in the medial prefrontal cortex (mPFC). We have also reported that METH blunted calcium currents in mPFC pyramidal neurons and decreased excitatory transmission through D1/D5 receptor mechanisms. Interestingly, SCH23390 (D1/D5 antagonist) alone was able to produce similar detrimental effects on mPFC physiology. Our studies suggest inverted-U-shaped dopamine (DA) actions in mPFC: low levels of DA are beneficial (i.e. moderate Modafinil actions), high levels are detrimental (massive dopamine release by METH). In order to unveil other potential differences in the actions of METH and Modafnil, we evaluated mRNA expression of glutamate and DA receptors subunits and voltage-gated Ca2+ channels (Cav) induced by METH (acute and chronic, 1 mg/kg) and Modafinil (acute, 90 mg/kg) in the mouse mPFC. We found that METH and Modafinil differ in their effects on mPFC as follows: (a) for DA receptors, METH decreased Drd1 mRNA while Modafinil did not; (b) Modafinil increased the expression of Drd2, METH did not; (c) for the P/Q type Cacna1a (Cav2.1), Modafinil increased its expression while METH did not show any acute effect but produced increased expression after chronic treatment; (d) for L type Cav1.3 Cacna1d, only METH showed reduced expression. On the other hand, glutamate receptor subunits mRNA AMPA Gria1 and Gria2 were increased for both psychostimulants whereas NMDA subunit Grin1 was significantly increased after acute Modafnil but only after chronic METH treatment. Western blot analysis also revealed that both drugs decreased CaMKII phosphorylation in the mPFC. In normal physiological conditions DA levels in the mPFC need to be precisely tuned to maximize signal/noise ratios. Our results support the idea that DA tuning may involve decreasing synaptic transmission (by effects on Ca currents and glutamate transmission) in cortico-cortical and cortico-subcortical networks. These mechanisms appear to be negatively impacted by toxic psychostimulants like METH to contribute to the mPFC hypofunction observed in METH addicts. Thus, some of the beneficial effects of Modafnil might be related to differential effects on DA/glutamate in the mPFC.