Operational characteristics of the inhibitory feedback mechanism for regulation of dopamine release via presynaptic receptors

The effects of dopamine (DA) antagonists and an agonist on the release of DA were studied at different rates and lengths of stimulation. Rabbit striatal slices were incubated in vitro with [3H]DA and then superfused with amine-free medium. Electrical stimulation produced a calcium-dependent increase in transmitter overflow. For stimulations at 0.3, 1, 3 or 10 Hz, highly significant positive correlations (r > 0.88, P < .001) were encountered between the total number of depolarizing pulses applied (from 30-360) and the percentage of tissue 3H released by stimulation. However, flat or negatively sloped frequency-release curves were obtained. The fractional release per pulse decreased when longer trains of stimulation were applied. Apomorphine (0.03 and 0.1 μM) inhibited transmitter release. The magnitude of this effect was inversely related to the rate and duration of stimulation. In fact, at 10 Hz (90 pulses) the inhibitory effect of 0.03 and 0.1 μM apomorphine was only one-third of that observed at 3 Hz. Haloperidol (0.03 and 0.3 μM) and sulpiride (1 μM) enhanced transmitter release; again, the magnitude of this effect was directly related to the frequency of stimulation. Both DA antagonists increased release only at 3 and 10 Hz, enhancing the slopes of the curves: log frequency of stimulation vs. transmitter release. With longer trains of stimulation (360 pulses vs. 30, 60 or 90 pulses), the effects of apomorphine and of the DA antagonists were considerably reduced. The present study supports the contention that the release of DA from neostriatal neurons is modulated by presynaptic dopaminergic receptors. Because of the operational characteristics of this feedback mechanism, the effects of DA agonist and antagonists on DA release greatly depend on the firing pattern of the neurons. Bursts of high frequency would favor the facilitatory actions of antagonists, whereas DA agonists would exert maximal inhibitory effects at lower firing rates. This work also indicates that studies on the sensitivity of agonists and antagonists on presynaptic dopaminergic receptors (receptor characterization) require a careful selection of the stimulation parameters.