Release and elimination of dopamine in vivo in mice lacking the dopamine transporter: functional consequences.
In mice lacking the dopamine transporter (DAT), the amplitude of dopamine (DA) release and the kinetics of dopamine elimination were measured in vivo using carbon fibre electrodes combined with amperometry. DA release was evoked by electrical stimulation of the medial forebrain bundle. The amplitude of DA release per pulse was lower (7% in striatum and 21% in nucleus accumbens) than in wild-type mice. Inhibition of monoamine oxidases (MAOs) by pargyline, but not of catechol-O-methyltransferase (COMT) by tolcapone, slowed down DA elimination in knockout mice. As DA half-life was two orders of magnitude higher in these mice, the DA diffusion distance was 10-times higher than in wild-types (100 and 10 microm, respectively). In knockout mice, alpha-methyl-p-tyrosine induced a much faster decline of DA release and haloperidol was less effective in potentiating DA release. Therefore, DA release was more dependent on DA synthesis than in normal animals but was less influenced by D2 autoregulation. Dopaminergic neurons exhibit two kinds of discharge activity, i.e. single spikes and bursts of 2-6 action potentials. In wild-type mice, stimuli mimicking bursts evoked significant increases in extracellular DA over its basal level sustained by tonic activity. However, in mice lacking the DAT, low frequency firing resulted in consistently high extracellular DA levels that could not be distinguished from DA levels achieved by high frequency firing. Therefore, the burst firing activity cannot be specifically translated into phasic changes in extracellular DA. This deficit might contribute to the difficulties of these mice in spatial cognitive function.
Benoit-Marand
M
M
CNRS UMR 5541, Université Victor Segalen Bordeaux 2, France.
Jaber
M
M
Gonon
F
F
D000818:Animals; D017660:Autoreceptors / Q000502:physiology; D001577:Benzophenones / Q000494:pharmacology; D001923:Brain Chemistry / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics*; D065098:Catechol O-Methyltransferase Inhibitors; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D004558:Electric Stimulation; D004563:Electrochemistry; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008474:Medial Forebrain Bundle / Q000166:cytology / Q000502:physiology; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D009596:Nitrophenols; D009714:Nucleus Accumbens / Q000166:cytology / Q000502:physiology; D010293:Pargyline / Q000494:pharmacology; D000077867:Tolcapone
D017660:Autoreceptors; D001577:Benzophenones; D002352:Carrier Proteins; D065098:Catechol O-Methyltransferase Inhibitors; D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008996:Monoamine Oxidase Inhibitors; D009419:Nerve Tissue Proteins; D009596:Nitrophenols; C493215:Slc6a3 protein, mouse; D010293:Pargyline; D000077867:Tolcapone; D004298:Dopamine