Methamphetamine blunts Ca2+ currents and excitatory synaptic transmission through D1/5 receptor-mediated mechanisms in the mouse medial prefrontal cortex.

GONZALEZ, B.; RIVERO-ECHETO, C.; MUÑIZ, J.A.; CADET, J.L.; GARCIA-RILL, E.; URBANO, F.J.; BISAGNO, V.

ADDICTION BIOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2015

1355-6215

Psychostimulant addiction is associated with dysfunctions in frontal cortex. Previous data demonstrated that repeatedexposure to methamphetamine (METH) can alter prefrontal cortex (PFC)-dependent functions. Here, we show thatwithdrawal from repetitive non-contingent METH administration (7 days, 1 mg/kg) depressed voltage-dependentcalcium currents (ICa) and increased hyperpolarization-activated cation current (IH) amplitude and the paired-pulseratio of evoked excitatory postsynaptic currents (EPSCs) in deep-layer pyramidal mPFC neurons. Most of these effectswere blocked by systemic co-administration of the D1/D5 receptor antagonist SCH23390 (0.5 and 0.05 mg/kg). In vitroMETH (i.e. bath-applied to slices from naïve-treated animals) was able to emulate its systemic effects on ICa and evokedEPSCs paired-pulse ratio.We also provide evidence of altered mRNA expression of (1) voltage-gated calcium channelsP/Q-type Cacna1a (Cav2.1), N-type Cacna1b (Cav2.2), T-type Cav3.1 Cacna1g, Cav3.2 Cacna1h, Cav3.3 Cacna1i and theauxiliary subunit Cacna2d1 (α2δ1); (2) hyperpolarization-activated cyclic nucleotide-gated channels Hcn1 and Hcn2;and (3) glutamate receptors subunits AMPA-type Gria1,NMDA-type Grin1 and metabotropic Grm1 in the mouse mPFCafter repeatedMETHtreatment. Moreover,we showthat some of these changes inmRNAexpressionwere sensitive D1/5receptor blockade. Altogether, these altered mechanisms affecting synaptic physiology and transcriptional regulationmay underlie PFC functional alterations that could lead to PFC impairments observed in METH-addicted individuals.