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Methamphetamine blunts Ca(2+) currents and excitatory synaptic transmission through D1/5 receptor-mediated mechanisms

Betina González1, Celeste Rivero-Echeto2, Javier A Muñiz1

  • 1Instituto de Investigaciones Farmacológicas, Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina.

Addiction Biology
|April 15, 2015
PubMed

Insights

Methamphetamine withdrawal impairs prefrontal cortex (PFC) neuron function by altering calcium and cation currents. These changes, linked to D1/D5 receptor activity, may contribute to addiction-related cognitive deficits.

Area of Science:

  • Neuroscience
  • Addiction Research
  • Molecular Biology

Background:

  • Psychostimulant addiction, particularly methamphetamine (METH) use, is linked to prefrontal cortex (PFC) dysfunction.
  • Previous research indicates METH alters PFC-dependent cognitive functions.

Purpose of the Study:

  • To investigate the effects of METH withdrawal on synaptic function and gene expression in mouse medial PFC (mPFC) neurons.
  • To explore the role of D1/D5 receptors in mediating these METH-induced changes.

Main Methods:

  • Electrophysiological recordings (calcium currents, hyperpolarization-activated currents, excitatory postsynaptic currents) in mPFC neurons from METH-withdrawn mice.
  • In vitro METH application to brain slices.
  • Quantitative analysis of mRNA expression for ion channels and receptors in the mPFC.

Main Results:

  • METH withdrawal decreased calcium currents (ICa) and increased hyperpolarization-activated cation currents (IH) in mPFC neurons.
  • Increased paired-pulse ratio of excitatory postsynaptic currents (EPSCs) was observed, suggesting altered presynaptic function.
  • Many observed effects were reversed by D1/D5 receptor antagonism and mimicked by in vitro METH application.
  • Altered mRNA expression of voltage-gated calcium channels, hyperpolarization-activated cyclic nucleotide-gated channels, and glutamate receptors was found, with some changes sensitive to D1/D5 blockade.

Conclusions:

  • METH withdrawal induces significant alterations in synaptic transmission and ion channel function within the mPFC.
  • D1/D5 receptor signaling plays a crucial role in mediating these neurophysiological and transcriptional changes.
  • These molecular and cellular alterations may underlie the cognitive impairments associated with METH addiction.
Keywords:
Dopamine receptorsglutamatemethamphetamineprefrontal cortexvoltage-gated calcium channels

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