Methamphetamine blunts Ca(2+) currents and excitatory synaptic transmission through D1/5 receptor-mediated mechanisms in the mouse medial prefrontal cortex.

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, 1 mg/kg) depressed voltage-dependent calcium currents (ICa ) and increased hyperpolarization-activated cation current (IH ) amplitude and the paired-pulse ratio of evoked excitatory postsynaptic currents (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 (1) voltage-gated calcium channels P/Q-type Cacna1a (Cav 2.1), N-type Cacna1b (Cav 2.2), T-type Cav 3.1 Cacna1g, Cav 3.2 Cacna1h, Cav 3.3 Cacna1i and the auxiliary 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 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 PFC functional alterations that could lead to PFC impairments observed in METH-addicted individuals.

Differential effects of environment-induced changes in body temperature on modafinil's actions against methamphetamine-induced striatal toxicity in mice.

Methamphetamine (METH) exposure can produce hyperthermia that might lead to toxicity and death. Modafinil is a wake-promoting compound that is also been prescribed off-label to treat METH dependence. Modafinil has shown neuroprotective properties against METH harmful effects in animal models. The goal of the present study was to test if the prevention of hyperthermia might play a role on the neuroprotective actions of modafinil against METH toxicity using various ambient temperatures. METH was administered to female C57BL/6 mice in a binge regimen: 4 × 5 mg/kg, 2 h apart; modafinil (90 mg/kg) was injected twice, 1 h before first and fourth METH injections. Drugs were given at cold ambient temperature (14 °C) or hot ambient temperature (29 °C). Body temperature was measured during treatments. Brains were dissected out 6 days after treatments and processed for tyrosine hydroxylase (TH), dopamine transporter (DAT), GFAP and c-Fos immunohistochemistry. Exposure to hot ambient temperature exacerbated METH toxicity evidenced by striatal reductions in TH and DAT and increased GFAP immmunoreactivity. Modafinil counteracted reductions in TH and DAT, but failed to block astroglial activation. At both ambient temperatures tested modafinil did induce increments in GFAP, but the magnitude was significantly lower than the one induced by METH. Both drugs induced increases in c-Fos positive nuclei; modafinil did not block this effect. Our results suggest that protective effects of modafinil against METH-induced neurotoxicity may be dependent, in part, to its hypothermic effects. Nevertheless, modafinil maintained some protective properties on METH-induced alterations in the striatum at different ambient temperatures.