title: Methamphetamine self-administration in mice decreases GIRK channel-mediated currents in midbrain dopamine neurons.
abstract: BACKGROUND
  Methamphetamine is a psychomotor stimulant with abuse liability and a substrate for catecholamine uptake transporters. Acute methamphetamine elevates extracellular dopamine, which in the midbrain can activate D2 autoreceptors to increase a G-protein gated inwardly rectifying potassium (GIRK) conductance that inhibits dopamine neuron firing. These studies examined the neurophysiological consequences of methamphetamine self-administration on GIRK channel-mediated currents in dopaminergic neurons in the substantia nigra and ventral tegmental area.
  
  
  METHODS
  Male DBA/2J mice were trained to self-administer intravenous methamphetamine. A dose response was conducted as well as extinction and cue-induced reinstatement. In a second study, after at least 2 weeks of stable self-administration of methamphetamine, electrophysiological brain slice recordings were conducted on dopamine neurons from self-administering and control mice.
  
  
  RESULTS
  In the first experiment, ad libitum-fed, nonfood-trained mice exhibited a significant increase in intake and locomotion following self-administration as the concentration of methamphetamine per infusion was increased (0.0015-0.15mg/kg/infusion). Mice exhibited extinction in responding and cue-induced reinstatement. In the second experiment, dopamine cells in both the substantia nigra and ventral tegmental area from adult mice with a history of methamphetamine self-administration exhibited significantly smaller D2 and GABAB receptor-mediated currents compared with control mice, regardless of whether their daily self-administration sessions had been 1 or 4 hours. Interestingly, the effects of methamphetamine self-administration were not present when intracellular calcium was chelated by including BAPTA in the recording pipette.
  
  
  CONCLUSIONS
  Our results suggest that methamphetamine self-administration decreases GIRK channel-mediated currents in dopaminergic neurons and that this effect may be calcium dependent.
authors.affiliation: Department of Pharmaceutical Sciences, Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas (Dr Sharpe, L. Bettinger); Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (Dr Sharpe, E. Varela, and Dr Beckstead); Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, Texas (Dr Beckstead).
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Sharpe
authors.affiliation: Department of Pharmaceutical Sciences, Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas (Dr Sharpe, L. Bettinger); Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (Dr Sharpe, E. Varela, and Dr Beckstead); Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, Texas (Dr Beckstead).
authors.forename: Erika
authors.initials: E
authors.lastname: Varela
authors.affiliation: Department of Pharmaceutical Sciences, Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas (Dr Sharpe, L. Bettinger); Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (Dr Sharpe, E. Varela, and Dr Beckstead); Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, Texas (Dr Beckstead).
authors.forename: Lynne
authors.initials: L
authors.lastname: Bettinger
authors.affiliation: Department of Pharmaceutical Sciences, Feik School of Pharmacy, University of the Incarnate Word, San Antonio, Texas (Dr Sharpe, L. Bettinger); Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (Dr Sharpe, E. Varela, and Dr Beckstead); Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, Texas (Dr Beckstead). beckstead@uthscsa.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Beckstead
mesh_terms: D000818:Animals; D016739:Behavior, Addictive; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants; D003463:Cues; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005108:Extinction, Psychological / Q000187:drug effects; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology*; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects*; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D012055:Reinforcement Schedule; D012646:Self Administration / Q000523:psychology; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects
chemical_list: D000697:Central Nervous System Stimulants; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D008694:Methamphetamine
keywords: GIRK; dopamine; electrophysiology; methamphetamine; mouse; self-administration