A history of ethanol drinking increases locomotor stimulation and blunts enhancement of dendritic dopamine transmission by methamphetamine

Addict Biol. 2020 Jul;25(4):e12763. doi: 10.1111/adb.12763. Epub 2019 May 6.


Ethanol and psychostimulant use disorders exhibit comorbidity in humans and cross-sensitization in animal models, but the neurobiological underpinnings of this are not well understood. Ethanol acutely increases dopamine neuron excitability, and psychostimulants such as cocaine or methamphetamine increase extracellular dopamine through inhibition of uptake through the dopamine transporter (DAT) and/or vesicular monoamine transporter 2 (VMAT2). Psychostimulants also depress dopamine neuron activity by enhancing dendritic dopamine neurotransmission. Here, we show that mice with a previous history of ethanol drinking are more sensitive to the locomotor-stimulating effects of a high dose (5 mg/kg), but not lower doses (1 and 3 mg/kg) of methamphetamine or any tested dose of cocaine (3, 10, and 18 mg/kg), compared with water-drinking controls. We next investigated the impact of a history of ethanol drinking, in a separate group of mice, on methamphetamine- or cocaine-induced enhancement of dendritic dopamine transmission using whole-cell voltage clamp electrophysiology in mouse brain slices. Methamphetamine, applied at a concentration (10 μM) that affects both DAT and VMAT2, enhanced D2 receptor-mediated inhibitory postsynaptic currents (D2-IPSCs) in both groups, but this effect was blunted in mice with a history of ethanol drinking. As methamphetamine action at VMAT2 disrupts dopamine neurotransmission, these results may suggest enhanced action of methamphetamine at VMAT2. Furthermore, there were no differences in low-dose methamphetamine or cocaine-induced enhancement of D2-IPSCs, suggesting intact DAT function. Disruption of methamphetamine-induced enhancement of dendritic dopamine transmission would result in decreased inhibition of dopamine neurons, ultimately increasing downstream release and the behavioral effects of methamphetamine.

Keywords: VMAT2; cocaine; dendrodendritic; dopamine; ethanol; methamphetamine.

Publication types

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

MeSH terms

  • Alcoholism
  • Amphetamine-Related Disorders
  • Animals
  • Central Nervous System Depressants / pharmacology*
  • Central Nervous System Stimulants / pharmacology*
  • Cocaine / pharmacology
  • Cocaine-Related Disorders
  • Dendrites / drug effects
  • Dendrites / metabolism
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins / drug effects
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopamine Uptake Inhibitors / pharmacology
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / metabolism
  • Ethanol / pharmacology*
  • Inhibitory Postsynaptic Potentials / drug effects
  • Locomotion / drug effects*
  • Male
  • Methamphetamine / pharmacology*
  • Mice
  • Pars Compacta / drug effects
  • Pars Compacta / metabolism
  • Patch-Clamp Techniques
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / metabolism
  • Synaptic Transmission / drug effects
  • Vesicular Monoamine Transport Proteins / drug effects
  • Vesicular Monoamine Transport Proteins / metabolism


  • Central Nervous System Depressants
  • Central Nervous System Stimulants
  • DRD2 protein, mouse
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • Receptors, Dopamine D2
  • Slc18a2 protein, mouse
  • Vesicular Monoamine Transport Proteins
  • Ethanol
  • Methamphetamine
  • Cocaine
  • Dopamine