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 evo ked by electrical stimulation of the medial forebrain bundle. The amplitude of DA release per pulse was lower (7% in striatum and 21% in nucleus accum bens) than in wild-type mice. Inhibition of monoamine oxidases (MAOs) by pa rgyline, but not of catechol-O-methyltransferase (COMT) by tolcapone, slowe d down DA elimination in knockout mice. As DA half-life was two orders of m agnitude higher in these mice, the DA diffusion distance was 10-times highe r than in wild-types (100 and 10 mu m, respectively). In knockout mice, alp ha-methyl-p-tyrosine induced a much faster decline of DA release and halope ridol was less effective in potentiating DA release. Therefore, DA release was more dependent on DA synthesis than in normal animals but was less infl uenced by D2 autoregulation. Dopaminergic neurons exhibit two kinds of disc harge activity, i.e. single spikes and bursts of 2-6 action potentials. In wild-type mice, stimuli mimicking bursts evoked significant increases in ex tracellular DA over its basal level sustained by tonic activity. However, i n mice lacking the DAT, low frequency firing resulted in consistently high extracellular DA levels that could not be distinguished from DA levels achi eved by high frequency firing. Therefore, the burst firing activity cannot be specifically translated into phasic changes in extracellular DA. This de ficit might contribute to the difficulties of these mice in spatial cogniti ve function.