title: Intracellular methamphetamine prevents the dopamine-induced enhancement of neuronal firing.
abstract: The dysregulation of the dopaminergic system is implicated in multiple neurological and neuropsychiatric disorders such as Parkinson disease and drug addiction. The primary target of psychostimulants such as amphetamine and methamphetamine is the dopamine transporter (DAT), the major regulator of extracellular dopamine levels in the brain. However, the behavioral and neurophysiological correlates of methamphetamine and amphetamine administration are unique from one another, thereby suggesting these two compounds impact dopaminergic neurotransmission differentially. We further examined the unique mechanisms by which amphetamine and methamphetamine regulate DAT function and dopamine neurotransmission; in the present study we examined the impact of extracellular and intracellular amphetamine and methamphetamine on the spontaneous firing of cultured midbrain dopaminergic neurons and isolated DAT-mediated current. In dopaminergic neurons the spontaneous firing rate was enhanced by extracellular application of amphetamine > dopamine > methamphetamine and was DAT-dependent. Amphetamine > methamphetamine similarly enhanced DAT-mediated inward current, which was sensitive to isosmotic substitution of Na(+) or Cl(-) ion. Although isosmotic substitution of extracellular Na(+) ions blocked amphetamine and methamphetamine-induced DAT-mediated inward current similarly, the removal of extracellular Cl(-) ions preferentially blocked amphetamine-induced inward current. The intracellular application of methamphetamine, but not amphetamine, prevented the dopamine-induced increase in the spontaneous firing of dopaminergic neurons and the corresponding DAT-mediated inward current. The results reveal a new mechanism for methamphetamine-induced dysregulation of dopaminergic neurons.
authors: From the Department of Neuroscience and Department of Psychiatry, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida 32611.
authors: Kaustuv
authors: K
authors: Saha
authors: From the Department of Neuroscience and Department of Psychiatry, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida 32611.
authors: Danielle
authors: D
authors: Sambo
authors: From the Department of Neuroscience and Department of Psychiatry, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida 32611.
authors: Ben D
authors: BD
authors: Richardson
authors: From the Department of Neuroscience and Department of Psychiatry, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida 32611.
authors: Landon M
authors: LM
authors: Lin
authors: From the Department of Neuroscience and Department of Psychiatry, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida 32611.
authors: Brittany
authors: B
authors: Butler
authors: From the Department of Neuroscience and Department of Psychiatry, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida 32611.
authors: Laura
authors: L
authors: Villarroel
authors: From the Department of Neuroscience and Department of Psychiatry, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida 32611 habibeh@ufl.edu.
authors: Habibeh
authors: H
authors: Khoshbouei
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000661:Amphetamine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008694:Methamphetamine / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008959:Models, Neurological; D018408:Patch-Clamp Techniques; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D008694:Methamphetamine; D000661:Amphetamine
keywords: Addiction; Amphetamine; Dopamine Transporter; Methamphetamine; Monoamine Transporter; Neurotransmitter Transport; Patch Clamp Electrophysiology