Inhibition of dopamine release via presynaptic D2 receptors: Time course and functional characteristics in vivo

Most neurotransmitters inhibit their own release through autoreceptors. How ever, the physiological functions of these presynaptic inhibitions are stil l poorly understood, in part because their time course and functional chara cteristics have not been described in vivo. Dopamine inhibits its own relea se through D2 autoreceptors. Here, the part played by autoinhibition in the relationship between impulse flow and dopamine release was studied in vivo in real time. Dopamine release was evoked in the striatum of anesthetized mice by electrical stimulation of the medial forebrain bundle and was conti nuously monitored by amperometry using carbon fiber electrodes. Control exp eriments performed in mice lacking D2 receptors showed no autoinhibition of dopamine release. In wild-type mice, stimulation at 100 Hz with two to six pulses linearly inhibited further release, whereas single pulses were inef ficient. Dopaminergic neurons exhibit two discharge patterns: single spikes forming a tonic activity below 4 Hz and bursts of two to six action potent ials at 15 Hz. Stimulation mimicking one burst (four pulses at 15 Hz) promo ted extracellular dopamine accumulation and thus inhibited further dopamine release. This autoinhibition was maximal between 150 and 300 msec after st imulation and disappeared within 600 msec. This delayed and prolonged time course is not reflected in extracellular DA availability and thus probably attributable to mechanisms downstream from autoreceptor stimulation. Thus, in physiological conditions, autoinhibition has two important roles. First, it contributes to the attenuation of extracellular dopamine during bursts. Second, autoinhibition elicited by one burst transiently attenuates furthe r dopamine release elicited by tonic activity.