Showing papers in "Pharmacological Reviews in 1980"

Presynaptic regulation of the release of catecholamines.

Abstract: During norepinephrine release elecited by the arrival of nerve impulses, the neurotransmitter interacts with specific receptors (alpha1-, beta1-, beta2-adrenoceptors) located in the membrane of the postsynaptic cell to trigger the response of the effector organ. Until a few years ago, it was thought that the role of noradrenergic nerve terminals in neurotransmission is concerned exclusively with the synthesis, storage, release, and inactivation of norepinephrine and there were no indications that receptors might also be present in the presynaptic membrane. During the last decade, evidence has accumulated in favour of the view that, in addition to the classical postsynaptic adrenoceptors that mediate the responses of the effector organ, there are also receptors located on the noradrenergic nerve terminals. These presynaptic recptors are involved in the modulation of the calcium-dependent, action-potential-evoked release of norepinephrine in the peripheral as well as in the central nervous system. Presynaptic inhibitory alpha-adrenoceptors are involved in the regulation of the release of norepinephrine through a negative feedback mechanism mediated by the neuron's own transmitter. Alpha-Adrenoceptor agonists inhibit the release of norepinephrine during nerve stimulation, while alpha-adrenoceptor blocking agents enhance the stimulation-evoked release of the neurotransmitter. These results have been obtained both i vitro and in vivo. There are pharmacological differences between the postsynaptic alpha-adrenoceptors that mediate the response of the effector organ and the presynaptic inhibitory alpha-adrenoceptors that modulate the release of norepinephrine during nerve stimulation. The subclassification of alpha-adrenoceptors into alpha1- and alpha2-types is bases on differences in relative affinities for a range of alpha-adrenoceptor agoinst and antagonist durgs. The term alpha1-adrenceptor is used for a receptor that is preferentially stimulated by phenylephrine and blocked by prazosin, whereas alpha2-adrenoceptor is reserved for those preferentially stimulated by guanabenz or clonidine and blocked by rauwolscine or yohimbine. The presynaptic inhibitory alpha-adrenoceptors in the peripheral and in the central nervous system have the pharmacological characteristics of the alpha2-adrenoceptors. Presynaptic inhibiotry autoreceptors appear to be involved in the modulation of the release of dopamine and of epinephrine in the central nervous system. A short negative feedback mechanism similar to that for norepinephrine appears to regulate the stimulation-evoked release of dopamine and epinephrine in central neurons. In addition to presynaptic autoreceptors through which the transmitter can modulate its own release, a real mosaic of receptors in present on noradrenergic nerve endings...

Precursor control of neurotransmitter synthesis.

Abstract: Studies performed during the past decade have shown that the rates at which certain neurons produce and release their neurotransmitters can be affected by precursor availability, and thus by the changes in plasma composition that occur after ingestion of the precursors in purified form or as constituents of foods. Thus, tryptophan administration or a plasma ratio of tryptophan to other large neutral amino acids, thereby raising brain tryptophan levels, increasing the substrate saturation of tryptophan hydroxylase, and accelerating the synthesis and release of serotonin. Tyrosine administration or a high-protein meal similarly elevates brain tyrosine and can accelerate catecholamine synthesis in the CNS and sympathoadrenal cells, while the consumption of lecithin or choline increases brain choline levels and neuronal acetylcholine synthesis. The physiologic and biochemical mechanisms that must exist in order for nutrient consumption to affect neurotransmitte synthesis have been characterized and include: 1) the lack of significant feedback control of plasma levels of the precursor; 2) the lack of a real "bloodbrain barrier" for the precursor, i.e. the ability of the plasma level of the precursor to control its influx into, or efflux from, the CNS; 3) the existence of a low-affinity (and thus unsaturated) transport system mediating the flux of the precursor between blood and brain; 4) low-affinity kinetics for the enzyme that initiates the conversion of the precursor to the transmitter; and, 5) the lack of end-product inhibition of the enzyme, in vivo, by its ultimate product, the neurotransmitter. The extent to which neurotransmitter synthesis in any particular aminergic neuron happens to be affected by changes in the availability of its precursor probably varies directly with the neuron's firing frequency. This relationship allows precursor administration to produce selective physiologic effects by enhancing neurotransmitter release from some but not all of the neurons potentially capable of utilizing the precursor for this purpose. It also allows the investigator to predict when administering the precursor might be useful for amplifying a physiologic process, or for treating a pathologic state. (for example, tyrosine administration raises blood pressure in hypotensive rats, lowers it in hypertensive animals, and has little effect on blood pressure in normotensive animals; the elevation in blood pressure probably reflects enhanced catecholamine release from sympathoadrenal cells, while the reduction in hypertensive animals probably results from increased catecholamine release within the brain-stem.) Such predictions are now being tested clinically in many institution. Available evidence suggests that lecithin or cholie administration can diminish the frequency of abnormal movements in patients with tardive dyskinesia...