Differential effects of phorbol ester on prefrontal cortex and striatal dopamine terminals: Dependence on rate and duration of stimulation

Compared to the nigrostriatal dopamine (DA) neurons, the mesocortical DA neurons projecting to the prefrontal cortex (PFC) are able to sustain higher levels of release when driven at high stimulation frequencies. The effect of a well known activator of protein kinase C (PKC), 4-β-phorbol-12,13-dibutyrate (PDBu), were compared on PFC and striatal DA terminals. DA release was monitored from slices of the rabbit PFC and striatum obtained from the same animal. The PKC activator, PDBu (30-1000 nM) enhanced the stimulation-evoked release (SER) of DA from PFC and striatum. The magnitude of the facilitation of DA release produced by PDBu was much greater from the PFC than from the striatum. In the striatum, PDBu produced a bell-shaped dose-response curve, i.e., 0.03 and 1 μM PDBu enhanced SER of DA by 25%, whereas 0.1 and 0.3 μM PDBu enhanced DA release by 60 and 100%, respectively (1 Hz, 120 pulses). In the PFC, 0.03 μM enhanced the SER of DA by 70% and 1 μM by 250% (1 Hz, 120 pulses). In addition, in the PFC, PDBu enhance the basal release of DA (+65% at 1 μM); this effect was not seen in the striatum. The inactive isomer, 4-α-phorbol-12,13-dibutyrate (0.03-1 μM) failed to increase the SER and the basal release of DA from PFC or striatum. The SER of DA was dependent on the rate and duration of stimulation. However, under all conditions of stimulation studied DA release from PFC was always greater than from the striatum. The facilitatory effects of the PKC activator, PDBu, on the SER of DA were reduced markedly by high stimulation rates and by longer stimulations. In the striatum, 0.1 μM PDBu enhanced the SER of DA by 60% at 1 Hz, 120 pulses, by 22% at 10 Hz, 120 pulses and by 2.4% at 10 Hz, 1200 pulses. In the PFC, 0.1 μM PDBu enhanced SER of DA by 167, 87 and 33% at 1 Hz (120 pulses), 10 Hz (120 pulses) and 10 Hz (1200 pulses), respectively. At low and high stimulation frequencies, PDBu-induced facilitation of DA release from PFC was always greater than from the striatum. In summary, the ability of the PFC DA terminals to sustain higher levels of release at rapid stimulation rates may be related to their PKC activity levels. PDBu produced different quantitative effects on PFC than on striatal DA terminals. The facilitation of DA release produced by PDBu was considerably reduced when the nerve terminals were depolarized at rapid rates. These results suggest that PKC-mediated facilitation of transmitter release is rate dependent and that PFC terminals may have greater PKC activity, probably as an adaptive response to their higher in vivo firing rates.