Presynaptic inhibition by dopamine receptor agonists of noradrenergic neurotransmission in the rabbit hypothalamus

In superfused rabbit hypothalamic slices prelabeled with ³Hnorepinephrine (NE) and in the presence of 10 μM cocaine, exposure to epinephrine (EPI) and NE reduced in a concentration-dependent manner the electrical stimulation-evoked release of ³HNE at 3Hz. The alpha adrenoceptor antagonist yohimbine (0.1 μM) shifted to the right the concentration effect curve for the inhibitory action of EPI on noradrenergic neurotransmission. Exposure to 1 μM of the dopamine (DA) receptor antagonist S-sulpiride, a concentration which by itself had no effect on ³HNE overflow, failed to antagonize this inhibitory action of EPI. Exposure to DA (0.01-1 μM) in the presence of cocaine (10 μM) failed to reduce the stimulation-evoked release of ³HNE from the rabbit hypothalamus. The DA agonists pergolide (0.03 μM) and apomorphine (1 μM) when tested in the absence of cocaine significantly reduced the stimulation-evoked release of ³HNE at 5Hz to 60 and 64% of control values, respectively. Exposure to 1♂ S-sulpiride or 0.01 μM S-butaclamol completely antagonized the inhibitory effects of pergolide and apomorphine on ³HNE overflow. The inhibitory action of DA receptor agonists remained unaffected or was even potentiated when the presynaptic alpha adrenoceptors were blocked with yohimbine (0.1 μM) or phentolamine (1 or 10 μM). In the presence of the neuronal uptake inhibitors cocaine (10 μM) or desipramine (0.1 or 1 μM), both pergolide (0.03 μM) and apomorphine (1 μM) failed to reduce the overflow of ³H-transmitter elicited by electrical stimulation at 5 Hz. These results suggest that presynaptic DA-like receptors are present on the noradrenergic nerve terminals of the rabbit hypothalamus and that they are different from the presynaptic inhibitory alpha adrenoceptors that regulate noradrenergic neurotransmission. The failure of DA to stimulate these receptors and of sulpiride or butaclamol to enhance NE release by themselves suggests that this mechanism is not operational under physiological conditions, but can be triggered by appropriate DA receptor agonist drugs. There seems to be an interaction between inhibition of neuronal uptake with cocaine or desipramine and presynaptic inhibitory DNA-like receptors which resemble the interaction observed between cocaine or desipramine and alpha-2 adrenoceptor agonists of the imidazoline-type like clonidine or oxymetazoline. Because inhibition of neuronal uptake of NE by drugs can interfere with the effects of some presynaptic release modulating receptors, it is important to select carefully the experimental conditions when studies on presynaptic modulation of noradrenergic neurotransmission are carried out.