Biphasic actions of L‐DOPA on the release of endogenous noradrenaline and dopamine from rat hypothalamic slices

Abstract

Effects of L‐DOPA on the release of endogenous noradrenaline and dopamine from rat hypothalamic slices evoked by electrical field stimulation at 5 Hz were investigated in the absence and presence of p‐bromobenzyloxyamine (NSD‐1055), a DOPA‐decarboxylase inhibitor. In the absence of NSD‐1055, L‐DOPA produced a facilitation of impulse‐evoked release of noradrenaline at 0.1 μM but not at 1 and 10 μM, and had no effect on the spontaneous release. On the other hand, L‐DOPA 0.1 to 10 μM dose‐dependently increased the spontaneous release of dopamine and the highest concentration only increased the evoked release and tissue content of dopamine. In the presence of NSD‐1055 10 μM, the increase in the spontaneous release of dopamine was prevented and L‐DOPA produced biphasic regulatory effects on the evoked release of noradrenaline and dopamine, a facilitation at 0.1 μM and an inhibition at 1 μM. The facilitation was antagonized by (‐)‐propranolol 0.1 μM, but not by the (+)‐isomer, whereas the inhibition was antagonized by S‐sulpiride 1 nM, but not by the R‐isomer. In conclusion, L‐DOPA appears to produce biphasic actions on the release of endogenous noradrenaline and dopamine from rat hypothalamic slices, not through its conversion to dopamine but through presynaptic regulatory mechanisms, an inhibition via dopamine receptors at a micromolar concentration and a facilitation via β‐adrenoceptors at the lower concentration.

Nanomolar L-DOPA facilitates release of dopamine via presynaptic .BETA.-adrenoceptors: Comparative studies on the actions in striatal slices from control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-treated C57 black mice, an animal model for parkinson's disease.

“…This facilitation seems to be due to L-DOPA itself but not due to the conversion from L-DOPA to DA, since qualitatively similar facilitatory actions of L-DOPA were seen even in the presence of an AADC inhibitor in rat striatal and hypothalamic slices (7,9,10). Thus a primary action of L-DOPA appears to be the facilitation of the evoked release of DA via presynaptic ,8-adrenoceptors even in striatal slices from this animal model for Parkinson's disease.…”

“…In the course of studies on presynaptic regulatory mechanisms for the release of endogenous catecholamines from rat brain slices (12)(13)(14), we found that endogenous DOPA is released in response to depolarizing stimuli such as bipolar electrical field pulses, high K+ (8) and nicotine (11) from rat striatal slices in a transmitter-like manner. On the other hand, exogenously applied L-DOPA had, even under the inhibition of AADC, biphasic presynaptic regulatory actions on the release of noradrenaline and DA from rat hypothalamic and striatal slices via facilitatory Q-adrenoceptors and inhibitory DA-receptors (7,10). Especially, this facilitatory action of L-DOPA was seen at concentrations lower than those needed to produce the conversion to DA.…”

“…Pretreatment with (-)-propranolol hydrochloride (Imperial Chemical Industries) was initiated at the start of superfusion and continued throughout the experiments. DA in the superfusate sample was purified by the alumina adsorption method and measured by HPLC-ECD as described previously (7). After the experiments, the slices were homogenized in 0.5 ml of 0.1 N HC1O4, centrifuged, and 100-,u l aliquots of the supernatant were used for the determination of the tissue content of DA.…”

“…It is generally accepted that the actions of L-DOPA are mediated via its conversion to dopamine (DA) by L-aromatic amino acid decarboxylase (AADC) (2), and this conversion initiates the accumulation of DA in the striata of humans (3) and rats (4), displacement of 3H -DA (5) , and impulse-evoked release of 3H-DA (6) from rat brain slices. On the contrary, we have proposed that L-DOPA is an endogenous neuroactive substance (7)(8)(9)(10)(11). In the course of studies on presynaptic regulatory mechanisms for the release of endogenous catecholamines from rat brain slices (12)(13)(14), we found that endogenous DOPA is released in response to depolarizing stimuli such as bipolar electrical field pulses, high K+ (8) and nicotine (11) from rat striatal slices in a transmitter-like manner.…”

The Cardiovascular Actions of DOPA Mediated by the Gene Product of ocular albinism 1

“…However, this might not reflect the nature of OA1 in native cells because the possibility of a low expression of OA1 or other factors in such cell lines cannot be excluded. Indeed, nanomolar concentrations of DOPA can induce presynaptic regulation of impulse-evoked catecholamine release from brain slices (11,42). In in vivo experiments, DOPA at doses comparable to those of glutamate induces depressor and bradycardic response in the NTS of anesthetized rats (7,12).…”