Physiological and behavioral effects of amphetamine in BACE1(-/-) mice

Genes Brain Behav. 2015 Jun;14(5):411-8. doi: 10.1111/gbb.12222. Epub 2015 May 21.

Abstract

β-Site APP-cleaving Enzyme 1 (BACE1) is a protease that has been linked to schizophrenia, a severe mental illness that is potentially characterized by enhanced dopamine (DA) release in the striatum. Here, we used acute amphetamine administration to stimulate neuronal activity and investigated the neurophysiological and locomotor-activity response in BACE1-deficient (BACE1(-/-) ) mice. We measured locomotor activity at baseline and after treatment with amphetamine (3.2 and 10 mg/kg). While baseline locomotor activity did not vary between groups, BACE1(-/-) mice exhibited reduced sensitivity to the locomotor-enhancing effects of amphetamine. Using high-performance liquid chromatography (HPLC) to measure DA and DA metabolites in the striatum, we found no significant differences in BACE1(-/-) compared with wild-type mice. To determine if DA neuron excitability is altered in BACE1(-/-) mice, we performed patch-clamp electrophysiology in putative DA neurons from brain slices that contained the substantia nigra. Pacemaker firing rate was slightly increased in slices from BACE1(-/-) mice. We next measured G protein-coupled potassium currents produced by activation of D2 autoreceptors, which strongly inhibit firing of these neurons. The maximal amplitude and decay times of D2 autoreceptor currents were not altered in BACE1(-/-) mice, indicating no change in D2 autoreceptor-sensitivity and DA transporter-mediated reuptake. However, amphetamine (30 µm)-induced potassium currents produced by efflux of DA were enhanced in BACE1(-/-) mice, perhaps indicating increased vesicular DA content in the midbrain. This suggests a plausible mechanism to explain the decreased sensitivity to amphetamine-induced locomotion, and provides evidence that decreased availability of BACE1 can produce persistent adaptations in the dopaminergic system.

Keywords: Amphetamine; BACE1; dopamine; schizophrenia; striatum.

Publication types

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

MeSH terms

  • Action Potentials*
  • Amphetamine / pharmacology*
  • Amyloid Precursor Protein Secretases / genetics*
  • Animals
  • Aspartic Acid Endopeptidases / genetics*
  • Corpus Striatum / cytology
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / physiology
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
  • Locomotion*
  • Male
  • Mice
  • Mice, Inbred C57BL

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Amphetamine
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse