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

Abstract

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

Effects of methamphetamine on locomotor activity and thalamic gene expression in leptin-deficient obese mice

“…Five hundred nanograms of RNA were treated with DNAseI (Deoxiribonuclease I) and reverse-transcribed in a 20 µL reaction using M-MLV reverse transcriptase and random hexameres. For quantitative real-time PCR (qPCR) primer sets were designed for the specific amplification of murine Cacna1a, Cacna1g, Cacna1i, Hcn2, Gria1, Grin1, and Gapdh as a housekeeping control gene [17]. Each sample was assayed in duplicate using 4 pmol of each primer, 1× SYBR Green Master Mix, and 2–20 ng of cDNA in a total volume of 13 µL.…”

“…Our group has described multiple METH-mediated alterations in mouse cortical and sub-cortical areas [13–16], including changes in mRNA levels of membrane receptors and voltage-gated ion channels in medial prefrontal neurons [17]. Repeated exposure to cocaine, a psychostimulant that can also increase DA neurotransmission, enhanced low threshold T-type calcium channel protein levels in mouse somatosensory thalamus neurons [18].…”

Do specific NMDA receptor subunits act as gateways for addictive behaviors?

“…Cortical regions are critical for expression of many forms of behaviors, and cortical NMDAR adaptations are likely to profoundly influence the expression of addiction. In this regard, repeated methamphetamine exposure decreases GluN2B levels in the mPFC (Lominac et al ) (see also Gonzalez et al ). Furthermore, both extended and brief cocaine self‐administration decrease mPFC GluN1 and GluN2B levels and tyrosine phosphorylation of GluN2B, which is required for surface expression of GluN2Bs (McGinty et al ).…”

Methamphetamine self-administration modulates glutamate neurophysiology

“…Synaptic physiology data from meth-experienced rats are scarce, but it has been reported that experimenter delivered meth (1 mg/kg, 7days) decreases calcium currents and excitatory transmission in the mPFC four days after drug treatment (González et al 2015). Additionally, a sensitizing regimen of amphetamine increases AMPA/NMDA ratios and frequency and amplitude of miniature excitatory postsynaptic currents (mEPSc) in the shell of the nucleus accumbens (Jedynak et al 2016).…”