Physiological and behavioral effects of amphetamine in BACE1(-/-) mice.
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.
Department of Psychiatry, University of Texas Health Science Center, San Antonio.
R Madelaine
RM
Paredes
Department of Psychiatry, University of Texas Health Science Center, San Antonio.
E
E
Piccart
Department of Psychiatry, University of Texas Health Science Center, San Antonio.
E
E
Navaira
Department of Psychiatry, University of Texas Health Science Center, San Antonio.
D
D
Cruz
Department of Psychiatry, University of Texas Health Science Center, San Antonio.
M A
MA
Javors
Department of Psychiatry, University of Texas Health Science Center, San Antonio.
W
W
Koek
Department of Psychiatry, University of Texas Health Science Center, San Antonio.
M J
MJ
Beckstead
Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.
C
C
Walss-Bass
D000200:Action Potentials; D000661:Amphetamine / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D008124:Locomotion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D050483:Dopamine Plasma Membrane Transport Proteins; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D000661:Amphetamine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
Amphetamine; BACE1; dopamine; schizophrenia; striatum