The Sixth Gaddum Memorial Lecture, delivered by S.Z. Langer, discusses the presence of presynaptic receptors in noradrenergic nerve endings and their role in regulating neurotransmitter release. Sir John Gaddum's contributions to neurotransmission, including his work on cholinergic and noradrenergic systems, are highlighted. The lecture emphasizes the discovery of presynaptic α-adrenoceptors, which regulate noradrenaline release through a negative feedback mechanism. When noradrenaline reaches a threshold concentration in the synaptic cleft, it activates presynaptic α-adrenoceptors, inhibiting further release. This mechanism is present in both α- and β-adrenoceptor-mediated responses. Phenoxybenzamine, an α-adrenoceptor blocker, increases transmitter overflow by reducing uptake and metabolism. However, this effect is not solely due to the blockade of α-adrenoceptors but also involves other factors. The presence of presynaptic α-adrenoceptors is supported by experiments showing that α-adrenoceptor agonists inhibit transmitter release, and that presynaptic α-adrenoceptors are distinct from postsynaptic ones. Phenoxybenzamine is more potent in blocking postsynaptic α-adrenoceptors than presynaptic ones. The lecture also discusses presynaptic β-adrenoceptors, which mediate a positive feedback mechanism, increasing transmitter release at low frequencies of nerve stimulation. This mechanism is linked to increased cyclic AMP levels in nerve endings. The presence of various other presynaptic receptors, such as muscarinic, dopamine, opiate, prostaglandin, adenosine, angiotensin II, and nicotinic receptors, is also described. While some of these receptors may not have physiological roles, they can influence sympathetic neurotransmission when activated by agonists or their analogues. The lecture concludes that presynaptic α- and β-adrenoceptors play significant roles in regulating noradrenaline release, with α-adrenoceptors being particularly important under physiological conditions. These findings have implications for the development of drugs targeting presynaptic receptors in the treatment of hypertension and other neurological disorders.The Sixth Gaddum Memorial Lecture, delivered by S.Z. Langer, discusses the presence of presynaptic receptors in noradrenergic nerve endings and their role in regulating neurotransmitter release. Sir John Gaddum's contributions to neurotransmission, including his work on cholinergic and noradrenergic systems, are highlighted. The lecture emphasizes the discovery of presynaptic α-adrenoceptors, which regulate noradrenaline release through a negative feedback mechanism. When noradrenaline reaches a threshold concentration in the synaptic cleft, it activates presynaptic α-adrenoceptors, inhibiting further release. This mechanism is present in both α- and β-adrenoceptor-mediated responses. Phenoxybenzamine, an α-adrenoceptor blocker, increases transmitter overflow by reducing uptake and metabolism. However, this effect is not solely due to the blockade of α-adrenoceptors but also involves other factors. The presence of presynaptic α-adrenoceptors is supported by experiments showing that α-adrenoceptor agonists inhibit transmitter release, and that presynaptic α-adrenoceptors are distinct from postsynaptic ones. Phenoxybenzamine is more potent in blocking postsynaptic α-adrenoceptors than presynaptic ones. The lecture also discusses presynaptic β-adrenoceptors, which mediate a positive feedback mechanism, increasing transmitter release at low frequencies of nerve stimulation. This mechanism is linked to increased cyclic AMP levels in nerve endings. The presence of various other presynaptic receptors, such as muscarinic, dopamine, opiate, prostaglandin, adenosine, angiotensin II, and nicotinic receptors, is also described. While some of these receptors may not have physiological roles, they can influence sympathetic neurotransmission when activated by agonists or their analogues. The lecture concludes that presynaptic α- and β-adrenoceptors play significant roles in regulating noradrenaline release, with α-adrenoceptors being particularly important under physiological conditions. These findings have implications for the development of drugs targeting presynaptic receptors in the treatment of hypertension and other neurological disorders.