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

Addict Biol. 2016 May;21(3):589-602. doi: 10.1111/adb.12249. Epub 2015 Apr 14.

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, 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.

Keywords: Dopamine receptors; glutamate; methamphetamine; prefrontal cortex; voltage-gated calcium channels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzazepines / pharmacology
  • Calcium / metabolism*
  • Calcium Channels / drug effects
  • Calcium Channels / genetics
  • Calcium Channels, N-Type / drug effects
  • Calcium Channels, N-Type / genetics
  • Calcium Channels, T-Type / drug effects
  • Calcium Channels, T-Type / genetics
  • Dopamine Uptake Inhibitors / pharmacology*
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / drug effects
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / genetics
  • Male
  • Methamphetamine / pharmacology*
  • Mice
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / genetics
  • Potassium Channels / drug effects
  • Potassium Channels / genetics
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism
  • Pyramidal Cells / drug effects*
  • Pyramidal Cells / metabolism
  • RNA, Messenger / drug effects*
  • RNA, Messenger / metabolism
  • Receptors, AMPA / drug effects
  • Receptors, AMPA / genetics
  • Receptors, Dopamine D1 / antagonists & inhibitors
  • Receptors, Dopamine D1 / metabolism*
  • Receptors, Dopamine D5 / antagonists & inhibitors
  • Receptors, Dopamine D5 / metabolism*
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Synaptic Transmission / drug effects*

Substances

  • Benzazepines
  • CACNA2D1 protein, mouse
  • Cacna1b protein, mouse
  • Cacna1g protein, mouse
  • Cacna1h protein, mouse
  • Cacna1i protein, mouse
  • Calcium Channels
  • Calcium Channels, N-Type
  • Calcium Channels, T-Type
  • Dopamine Uptake Inhibitors
  • Gprin1 protein, mouse
  • Hcn1 protein, mouse
  • Hcn2 protein, mouse
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Nerve Tissue Proteins
  • Potassium Channels
  • RNA, Messenger
  • Receptors, AMPA
  • Receptors, Dopamine D1
  • Receptors, N-Methyl-D-Aspartate
  • SCH 23390
  • voltage-dependent calcium channel (P-Q type)
  • Receptors, Dopamine D5
  • Methamphetamine
  • Calcium
  • glutamate receptor ionotropic, AMPA 1