title: Methamphetamine blunts Ca(2+) 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, 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.
authors: Instituto de Investigaciones Farmacológicas, Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina.
authors: Betina
authors: B
authors: González
authors: Laboratorio de Fisiología y Biología Molecular, Instituto de Fisiología, Biología Molecular y Neurociencias, Departamento de Fisiología, Biología Molecular y Celular 'Dr. Hector Maldonado' (DFBMC), Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina.
authors: Celeste
authors: C
authors: Rivero-Echeto
authors: Instituto de Investigaciones Farmacológicas, Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina.
authors: Javier A
authors: JA
authors: Muñiz
authors: Molecular Neuropsychiatry Research Branch, NIH/NIDA Intramural Research Program, Baltimore, MD, USA.
authors: Jean Lud
authors: JL
authors: Cadet
authors: Center for Translational Neuroscience, Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors: Edgar
authors: E
authors: García-Rill
authors: Laboratorio de Fisiología y Biología Molecular, Instituto de Fisiología, Biología Molecular y Neurociencias, Departamento de Fisiología, Biología Molecular y Celular 'Dr. Hector Maldonado' (DFBMC), Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina.
authors: Francisco J
authors: FJ
authors: Urbano
authors: Instituto de Investigaciones Farmacológicas, Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina.
authors: Verónica
authors: V
authors: Bisagno
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000235:genetics; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000235:genetics; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000187:drug effects / Q000235:genetics; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D018091:Receptors, AMPA / Q000187:drug effects / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050641:Receptors, Dopamine D5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D001552:Benzazepines; D002118:Calcium; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D020747:Calcium Channels, T-Type; D018765:Dopamine Uptake Inhibitors; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008694:Methamphetamine; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D012333:RNA, Messenger; D018091:Receptors, AMPA; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; D016194:Receptors, N-Methyl-D-Aspartate; C512066:CACNA2D1 protein, mouse; C500963:Cacna1b protein, mouse; C498197:Cacna1g protein, mouse; C504883:Cacna1h protein, mouse; C534770:Cacna1i protein, mouse; C121673:Gprin1 protein, mouse; C578666:Hcn1 protein, mouse; C578711:Hcn2 protein, mouse; C534628:SCH 23390
keywords: Dopamine receptors; glutamate; methamphetamine; prefrontal cortex; voltage-gated calcium channels