Frequency-dependent effects of neuronal uptake inhibitors on the autoreceptor-mediated modulation of dopamine and acetylcholine release from the rabbit striatum

The effects of four structurally unrelated neuronal uptake inhibitors (NUI) on the spontaneous efflux and on the electrically evoked overflow of [3H]dopamine (DA) and [14C]acetylcholine (ACh) in rabbit striatal slices, were investigated. Benztropine (BZT), bupropion (BUP), cocaine (COC) and nomifensine (NOM) (each at 10 μM) reduced the evoked overflow of ACh in a frequency-dependent fashion, i.e., greater inhibition was seen at 3 than at 0.3 Hz. These effects were antagonized by 1 μM sulpiride, a DA receptor antagonist. The NUI had different effects on DA overflow. At 0.3 Hz, BZT and NOM increased DA overflow by 120 and 50%, respectively, whereas CUC reduced it by 30% and BUP had mo effect. At 3 Hz, BZT and NOM increased DA overflow by 30 and 3%, and COC and BUP inhibited it by 40 and 30%, respectively. However, in the presence of sulpiride, the NUI produced a large enhancement of the evoked overflow of DA. At 0.3 Hz, NOM (10 μM) produced a striking increase (3.5-fold) in DA overflow in the presence of 1 μM sulpiride. Under these conditions sulpiride completely abolished the inhibitory effect of NOM on ACh overflow. These findings indicate that the net effect of NUI on DA overflow depends on the balance of two factors: 1) degree of blockade of DA reuptake (which enhances overflow); and 2) degree of autoreceptor activation (which inhibits overflow). The efficient removal of the released DA by the neuronal uptake pump prevents autoreceptor activation at low frequencies and accounts for the small and variable facilitation of DA and ACh release reported with DA antagonists (in the absence of NUI). At 10 μM, BZT, BUP, COC and NOM produced a small increase in the spontaneus outflow of tritium, but only the latter three agents reduced that of 14C-products. The differences observed between BZT and the other NUI on the spontaneous and on the evoked overflow of DA and ACh were not related to its anticholinergic properties, inasmuch as atropine (1 μM) had no effect per se and it did not modify NOM effects on DA and ACh overflows (0.3 Hz, 120 pulses). Apomorphine (30 nM) inhibited the overflow of DA and ACh elicited by electrical stimulation. Greater inhibition was seen at 0.3 than at 3 Hz. Sulpiride enhanced DA and ACh overflow at 3 Hz, but not at 0.3 Hz. NOM (1, 3 and 10 μM) antagonized the inhibitory effects of apomorphine on DA and ACh overflow, in a concentration-dependent manner. In summary, these results indicate that changes in the synaptic concentration of DA modify the release of DA and ACh, and the responsivess of autoreceptors to DA agonists and antagonists. The high synaptic concentrations of DA obtained with NUI and/or high rates of stimulation reduce the release of DA and ACh, and antagonize apomorphine effects on DA and ACh release-modulatory receptors.