1158 - PREFRONTAL CORTEX HYPOFUNCTION AFTER REPEATED METHAMPHETAMINE IN MICE: ROLE OF DOPAMINE 1/5 RECEPTORS

GONZALEZ B; RIVERO ECHETO MC; MUÑIZ JA; CADET JL; GARCIA-RILL E; URBANO FJ; BISAGNO V

RIO DE JANEIRO

Congreso; IBRO 2015 9th World Congress; 2015

IBRO

Chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans and animal models. We have previously demonstrated that METH sub-chronic administration in mice induces deficits on visual memory retention through a mechanism that involves blunted novelty-induced ERK signaling in the medial prefrontal cortex (mPFC). In the present study we evaluated different components of mPFC circuitry in METH-treated and control mice (1 mg/Kg, daily for 7 days, evaluated after a 4-day withdraw period), by analyzing total Ca2+ current (ICa) density and excitatory synaptic transmission (whole-cell patch clamp in slices) as well as the mRNA expression of voltage-gated Ca2+ channels (VGCC) and glutamate receptor subunits (qPCR). We found a reduction in ICa density in mPFC layer V pyramidal neurons in mice treated repeatedly with METH compared to controls. Repeated METH also increased paired-pulse ratio of evoked excitatory post-synaptic currents (EPSCs) compared to controls, suggesting reduced presynaptic release probability of glutamate onto layer V pyramidal mPFC neurons. These effects on ICa and evoked EPSCs were blocked by systemic co-administration of the D1/5 receptor antagonist SCH23390 (0.5 and 0.05 mg/kg, ½ hr before METH). We have also analyzed VGCC mRNA expression and found that repeated METH caused an increase in high voltage P/Q type Cacna1a (Cav2.1) and N type Cacna1b (Cav2.2) as well as in low voltage T type Cacna1g (Cav3.1), Cacna1h (Cav3.2) and Cacna1i (Cav3.3) subunits. Glutamate receptor subunits mRNA expression AMPA Gria1, NMDA Grin1 and metabotropic Grm1 were also increased in repeated METH-treated animals compared to controls. Some of these changes in mRNA expression within the mPFC were sensitive to D1/5 receptor blockade. Changes found in VGCC and glutamate subunits mRNA expression might represent compensatory changes induced by profound alterations elicited by METH on calcium currents and glutamate transmission in the mPFC. Altogether these altered mechanisms affecting synaptic physiology and transcriptional regulation may underlie prefrontal functional alterations that could lead to PFC hypofunction observed in METH-addicted individuals.Acknowledgements: This work was supported by grants from FONCYT-ANPCyT PICT-2012-1769 and UBACYT 2014-2017 #20120130101305BA (to Dr. Urbano) and PICT-2012-0924 (to Dr. Bisagno). We are also grateful to NIH award R01 NS020246, and to core facilities of the Center for Translational Neuroscience supported by NIH award P20 GM103425 (to Dr. Garcia-Rill).