Cocaine and amphetamine antagonize the decrease of noradrenergic neurotransmission elicited by oxymetazoline but potentiate the inhibition by α-methylnorepinephrine in the perfused cat spleen

In the perfused cat spleen labeled with [³H]norepinephrine, exposure to the alpha adrenoceptor agonist, oxymetazoline (0.3 μM) or the neuron blocking agent, bretylium (10 μM) significantly inhibited the release of ³H-transmitter elicited by nerve stimulation (1 Hz during 5 min, 0.5 msec duration, supramaximal voltage). The alpha adrenoceptor blocking agent phentolamine (3 μM) increased the stimulation-evoked overflow of [³H]norepinephrine 4-fold and completely antagonized the inhibition of neurotransmission elicited by oxymetazoline. This concentration of phentolamine did not affect the inhibition of neurotransmission induced by bretylium, indicating that the site of action of the neuron blocking agent is not the presynaptic alpha adrenoceptor. Amphetamine (1 and 3 μM) increased the spontaneous outflow of radioactivity but did not modify by itself the overflow of [³H]norepinephrine elicited by nerve stimulation. The decrease of the stimulation-evoked release of [³H]-norepinephrine elicited by either oxymetazoline (0.3 μM) or bretylium (10 μM) was completely antagonized by amphetamine (1 μM). However, this concentration of amphetamine failed to modify the inhibition of neurotransmission induced by the dopamine receptor agonist, apomorphine (0.1 μM) or the muscarinic cholinoceptor agonist, carbachol (0.3 μM). The failure of amphetamine to antagonize the inhibition of neurotransmission elicited by the activation of presynaptic dopamine or muscarinic receptors excludes the possibility that the antagonism by amphetamine of the inhibition elicited by oxymetazoline is of a nonspecific nature. Inhibition of neuronal uptake with cocaine (29 μM) did not affect the stimulation-evoked overflow of ³H-transmitter, per se. This concentration of cocaine, like amphetamine, completely antagonized the inhibition of neurotransmission elicited by oxymetazoline. The catecholamine α-methylnorepinephrine (0.1 μM) significantly inhibited the stimulation evoked release of [³H]norepinephrine in the absence of neuronal uptake inhibitors, α-methylnorepinephrine (0.1 μM) did not modify the stimulation-evoked release of ³H-transmitter, under conditions in which the spontaneous outflow of radioactivity was significantly increased. When the metabolism of [³H]norepinephrine through monoamine oxidase was inhibited by adding 10 μM pargyline to the perfusion medium, the alpha adrenoceptor agonist oxymetazoline was as effective as in the controls in inhibiting [³H]norepinephrine overflow during nerve stimulation. Inhibition of neuronal uptake with cocaine or amphetamine selectively antagonized the presynaptic inhibitory effects of the alpha adrenoceptor agonist oxymetazoline which is an imidazoline derivative, whereas it potentiated that of α-methylnorepinephrine. Since oxymetazoline is a partial agonist, it may be acting as a competitive antagonist at presynaptic alpha adrenoceptors when the concentration of norepinephrine is increased by uptake inhibitors. Alternatively, it is possible that neuronal uptake inhibitors antagonize the effects of oxymetazoline on neurotransmission through an interaction at the recognition site for imidazolines in the presynaptic alpha receptor. Our results suggest that differences may exist between the recognition site for catecholamines and for imidazolines at the level of the presynaptic alpha-2 adrenoceptor. It is concluded that the comparison of the order of potencies for imidazolines and phenylethylamines or presynaptic alpha-2 adrenoceptors when neuronal uptake of norepinephrine is inhibited by drugs may need extensive re-evaluation.