Modulation of receptor sensitivity and action potentials by transmitters in vertebrate neurones

The nicotinic cholinergic transmission causing generation of the fast EPSP in bullfrog sympathetic ganglia is modulated by the action of transmitters or hormones other than ACh. In general, a synaptic transmission appears to be modulated in a variety of ways by the action of many kinds of transmitters or hormones in the vertebrate neural system. There are at least four different types of modulatory actions of these endogenous substances on a synaptic transmission; namely, 1) modulation of the amount of the transmitter released from presynaptic neurones, 2) modulation of the sensitivity of the receptors of postsynaptic neurones, 3) modulation of the resting membrane potential or conductance of postsynaptic neurones, 3) modulation of the resting membrane potential or conductance of postsynaptic neurones, and 4) modulation of the configuration of the action potential of postsynaptic neurones. In the present review, the experimental evidence supporting the modulatory actions of endogenous substances on the receptor sensitivity and the action potential of postsynaptic neurones was reviewed. The mechanisms underlying these two types of modulatory actions were also briefly discussed.     

Glutamate is a fast excitatory transmitter at some buccal neuromuscular synapses in Aplysia.

Studies of the modulation of synaptic transmission in buccal muscle of Aplysia were limited because the conventional fast transmitter used by a number of large buccal motor neurons was unknown. Most of the identified buccal motor neurons are cholinergic because they synthesize acetylcholine (ACh) and their excitatory junction potentials (EJPs) are blocked by the cholinergic antagonist hexamethonium. However, three large identified motor neurons (B3, B6, and B38) do not synthesize ACh and their EJPs are not inhibited by hexamethonium. To identify the fast excitatory transmitter used by these noncholinergic motor neurons, we surveyed putative transmitters for their ability to evoke contractions. Of the noncholinergic transmitters tested, glutamate was the most effective at evoking contractions. The pharmacology of the putative glutamate receptor is different from previously characterized glutamate receptors in that glutamate agonists and antagonists previously used to classify glutamate receptors had little effect in this system. In addition, glutamate itself was the most effective agent tested at reducing EJPs evoked by the noncholinergic motor neurons presumably by desensitizing glutamate receptors. Finally, immunocytology using an antiserum raised to conjugated glutamate in parallel with intracellular fills indicated that the varicose axons of these motor neurons were glutamate-immunoreactive. Taken together, these results indicate that the fast transmitter used by the noncholinergic neurons is almost certainly glutamate itself. This information should help us understand the role of transmitters and cotransmitters in the generation of feeding behaviors in Aplysia.     

大鼠实验性甲状旁腺功能减退的研究——Ⅱ.脑的某些神经生化改变

本文测定了电烫去除双侧甲状旁腺(PTX、甲旁减)大鼠脑内与主要神经递质功能有关的酶活性及受体结合活性的改变,并与老龄大鼠进行了比较。结果表明,PTX鼠和老龄鼠脑纹状体腺苷酸环化酶(AC)活性明显降低,PTX鼠纹状体AC对外源性多巴胺(DA)的反应性明显下降,纹状体谷氨酸脱羧酶(GAD)活性明显下降。老龄鼠脑突触体膜对GABA?和DA_2受体的结合活性明显减小,PTX鼠与老龄鼠呈相似变化。提示长期钙代谢失调可导致脑的神经功能紊乱和老化。     

Hyperhidrosis and the sympatho-adrenal system.

Some disorders in which excessive sweating, hyperhidrosis, is a symptom are also characterized by increased sympatho-adrenal activity. Such disorders are hypotension, hypoglycemia, pheochromocytoma and hyperthyroidism. Sweat glands are controlled by a cholinergic innervation but can also be stimulated by adrenergic agents whose effects can be blocked by both alpha- and beta-receptor blocking drugs. An adrenergic innervation has also been demonstrated. There is evidence that the adrenergic component of sweating particularly secretion of the adrenal medulla, is responsible for the enhancement of sweating during exercise but not for the hyperhidrosis present in these disorders since sweating in these circumstances can be effectively blocked by cholinergic blocking compounds. Cutaneous vasoconstriction due to elevated plasma catecholamines reduces the rate of evaporation of sweat and allows sweat to accumulate on the skin. It is suggested that in the case of hypotension and insulin hypoglycemia sweating results from general sympathetic stimulation and that adrenal medullary hormones are not an essential component of the response. Hyperhidrosis in pheochromocytoma may be due to central activation of heat loss mechanisms resulting from the passage of plasma catecholamines across the blood-brain barrier combined with increased thermogenesis and cutaneous vasoconstriction. The hyperhidrosis of hyperthyroidism is probably due to increased thermogenesis.     

Critique of current views on receptors, and a new general theory of receptor location and action in vivo

The Davson-Danielli model of the cell membrane accounted for nearly all the space within it by suggesting that it was composed of structural proteins and lipids; this would leave virtually no space for the large number of enzymes, carriers, antigens, antibodies, and receptors for hormones, transmitters, drugs and toxins, generally believed to be present within the membranes. The sizes of many of the structural proteins, lipids, enzymes and receptors, have been measured by electron microscopic techniques, and are too large to be located within or next to the Robertson 'unit' membrane or the Singer-Nicolson membrane, without producing bulges; these are never seen by transmission electron microscopy, and rarely by freezing techniques. If they were present but unstained, gaps should appear in the membranes corresponding to the measured dimensions of these macromolecules; such gaps are not seen. It has been assumed that the substances react with receptors located only at the cell membrane, but, in the intact organism, they pass through many cellular phases before having any effect; one hundred and five phases in the passage from the blood to the brain are identified. It is suggested that the receptor is the sum total of all the reactions between the substances added and each of the phase reacting to a differing degree. Experiments which could assess the relative validity of the currently accepted and new ones proposed are listed.     

Prostanoids synthesis in lymphocyte subpopulations by adrenergic and cholinergic receptor stimulation.

The release of eicosanoids (PGE2 and TXB2) as a consequence of specific neurotransmitter receptor agonist stimulation is described herein. The differential expression of beta adrenergic and muscarinic cholinergic receptors on sets and subsets of lymphocytes was first identified. Saturation assays with a specific radioligand for beta adrenergic receptors (3H-DHA) showed that B-, T-, T-helper (Th) and T-suppressor/cytotoxic (Ts/c) lymphocyte enriched populations all displayed beta adrenergic receptors. In contrast, when a specific radioligand for muscarinic cholinergic receptors (3H-QNB) was used, B-lymphocytes showed a lack of high-affinity muscarinic cholinergic receptors, while T-lymphocytes expressed them. Ts/c murine lymphocytes had more muscarinic cholinergic receptors than did Th cells. Specific receptor stimulation by the agonist caused a release of different eicosanoids depending on the cell type. Isoproterenol, triggered the release of TXB2 by B and Th-cells, but had no effect on Ts/c-cells. On the other hand, the muscarinic cholinergic agonist, carbachol only induced the release of PGE2 by Ts/c-cells. These results suggest differences in the expression and function of neurotransmitter receptors in sets and subsets of murine lymphocytes regarding the release of eicosanoids.     

Autonomic nervous influence of the female guinea-pig urinary bladder during the oestrus cycle

The mammalian urinary bladder receives dual innervation. The excitatory innervation is considered to be partly cholinergic and partly mediated via NANC-receptors. Several (co-)transmitters have been suggested. The adrenergic inhibitory innervation is mediated via α- and β-receptors. Female sex hormones could change autonomic influence of urogenital organs. It was considered to be of interest to characterize the spontaneous and nerve stimulation-induced muscular activity in the urinary bladder of the female guinea-pig during the oestrus cycle. Both the spontaneous activity and nerve-induced activity varied according to the hormonal status of the animal. An α-adrenergic inhibitory influence was identified. It was further confirmed that the excitatory innervation could not be blocked by the cholinergic antagonist scopolamine, while α-β-methylene ATP partly inhibited nerve stimulation-induced smooth muscle response, most prominent at cycle day 6. Indomethacin did not impair spontaneous activity or nerve stimulation-induced activity. Nitric oxide reduced nerve stimulation-induced responses on cycle day 12. Imperative urinary bladder contractions are reported to diminish after oestrogen use and in the female a hormonal effect of the nervous influence on the urinary bladder smooth muscle is suggested.     

Immunostaining of cholinergic pontomesencephalic neurons for alpha 1 versus alpha 2 adrenergic receptors suggests different sleep-wake state activities and roles

Cholinergic neurons of the pontomesencephalic tegmentum play a critical role in paradoxical sleep, when, according to single unit recording of 'possibly' cholinergic neurons, they fire maximally. The profile of activity of the cholinergic neurons may be determined by noradrenergic locus coeruleus neurons that are active during waking and silent during paradoxical sleep. Indeed, a permissive role of the noradrenergic neurons in paradoxical sleep has been proposed based upon an inhibitory action of noradrenaline through alpha(2) adrenergic receptors on the cholinergic cells. Yet some 'possibly' cholinergic neurons are purportedly maximally active during waking and excited by noradrenaline through alpha(1) receptors. In the present study, we examined by fluorescent dual-immunostaining in the laterodorsal and pedunculopontine tegmental nuclei of the rat whether choline acetyltransferase-immunopositive neurons are stained for alpha(2A) or alpha(1A) adrenergic receptors. For comparison, we examined immunostaining for these receptors on tyrosine hydroxylase-immunopositive locus coeruleus neurons, which are known to bear alpha(2A) autoreceptors. Whereas virtually all the noradrenergic neurons were labeled for the alpha(2A) and none for the alpha(1A), approximately half the cholinergic neurons were labeled for the alpha(2A) and one third for the alpha(1A) adrenergic receptors in adjacent sections. These results suggest that different groups of cholinergic neurons bear alpha(2) versus alpha(1) adrenergic receptors and would accordingly have different sleep-wake state activities and roles. The alpha(2)-bearing group would be inhibited by noradrenaline during waking to become disinhibited and maximally active while promoting paradoxical sleep, whereas the alpha(1)-bearing group would be excited by noradrenaline during waking to become maximally active while promoting features of that state.     

Neuromodulatory transmitter systems in the cortex and their role in cortical plasticity

Cortical neuromodulatory transmitter systems refer to those classical neurotransmitters such as acetylcholine and monoamines, which share a number of common features. For instance, their centers are located in subcortical regions and send long projection axons to innervate the cortex. The same transmitter can either excite or inhibit cortical neurons depending on the composition of postsynaptic transmitter receptor subtypes. The overall functions of these transmitters are believed to serve as chemical bases of arousal, attention and motivation. The anatomy and physiology of neuromodulatory transmitter systems and their innervations in the cerebral cortex have been well characterized. In addition, ample evidence is available indicating that neuromodulatory transmitters also play roles in development and plasticity of the cortex. In this article, the anatomical organization and physiological function of each of the following neuromodulatory transmitters, acetylcholine, noradrenaline, serotonin, dopamine, and histamine, in the cortex will be described. The involvement of these transmitters in cortical plasticity will then be discussed. Available data suggest that neuromodulatory transmitters can modulate the excitability of cortical neurons, enhance the signal-to-noise ratio of cortical responses, and modify the threshold for activity-dependent synaptic modifications. Synaptic transmissions of these neuromodulatory transmitters are mediated via numerous subtype receptors, which are linked to multiple signal transduction mechanisms. Among the neuromodulatory transmitter receptor subtypes, cholinergic M(1), noradrenergic beta(1) and serotonergic 5-HT(2C) receptors appear to be more important than other receptor subtypes for cortical plasticity. In general, the contribution of neuromodulatory transmitter systems to cortical plasticity may be made through a facilitation of NMDA receptor-gated processes.     

Studies of the hemopoietic microenvironment. VIII andrenergic and cholinergic innervation of the murine spleen

Neurohistochemical techniques were used to confirm morphologically the distribution of adrenergic and cholinergic nerves to the splenic microvasculature. The results form the basis of this report. Using these methods, adrenergic innervation was observed only in the adventitia of arteries and arterioles. No cholinergic innervation was found in this site. No adrenergic or cholinergic innervation could be demonstrated to the channels of the red pulp, venules or veins. These data provided morphological evidence that in the murine spleen only splenic arteries and arterioles are innervated; and these have only an adrenergic innervation.     

Social-emotional and behavioral adjustment in children with Williams-Beuren syndrome

The recent literature on the involvement of cholinergic muscarinic mechanisms and adrenergic/cholinergic balance in affective disorders is reviewed and integrated with the older literature. There is strong evidence supporting the presence of exaggerated responses (behavioral, neuro-endocrine, sleep) to cholinergic agents in affective disorder patients relative to normal controls and certain other psychiatric patients. There is also some, albeit less, conclusive evidence that these exaggerated responses may occur in euthymic individuals with a history of affective disorders, or in children at risk for development of affective disorders. Despite these promising results, suggesting a role for acetylcholine in the genetics of the affective disorders, further work in biochemistry and genetics is needed to link specific muscarinic receptors or other cholinergic variables to affective illness. © 1994 Wiley-Liss, Inc.     

Studies of the hemopoietic microenvironment. VIII. Andrenergic and cholinergic innervation of the murine spleen.

Neurohistochemical techniques were used to confirm morphologically the distribution of adrenergic and cholinergic nerves to the splenic microvasculature. The results form the basis of this report. Using these methods, adrenergic innervation was observed only in the adventitia of arteries and arterioles. No cholinergic innervation was found in this site. No adrenergic or cholinergic innervation could be demonstrated to the channels of the red pulp, venules or veins. These data provided morphological evidence that in the murine spleen only splenic arteries and arterioles are innervated; and these have only an adrenergic innervation.     

Adrenergic and cholinergic effects on the heart, the lung and the spleen of the African lungfish, Protopterus aethiopicus

Effects of adrenergic and cholinergic drugs were studied on isolated preparations from the heart, the lung and the spleen of the African lungfish. In addition, a nerve-lung preparation was employed for the study of the autonomic nervous control of the lung. Falck-Hillarp fluorescent histochemistry was used in the search for adrenergic neurons in the sympathetic chain and tissues. The Protopterus lung received a cholinergic excitatory innervation via the pulmonary branches of the vagi. The presence of parasympathetic ganglia in the lung tissue is indicated. Adrenergic drugs, when producing a response, either contracted or relaxed lung strips. Spleen strips were contracted by cholinergic drugs acting on muscarinic receptors and, to a lesser extent, by adrenergic drugs. A strong negative inotropic effect was produced by carcachol on paced atrial but not ventricular strips, while adrenaline increased the contraction force in ventricular but not atrial strips. The sympathetic ganglion cells did not contain enough catecholamines to give off any visible fluorescence, nor was it possible to show any adrenergic nerve terminals in the tissues studied. It is concluded that the adrenergic control in the lungfish is mainly due to circulating catecholamines, rather than adrenergic nerve fibres, since concentrations of catecholamines in protopterus plasma are high enough to affect the spleen, lung and ventricle.     

Heightened cholinergic responsiveness in IgE-producing rabbits

Atopic humans express an array of autonomic nervous system abnormalities. An animal model of IgE-mediated allergy was herein employed to determine if the induction of an IgE antibody response would affect autonomic responsiveness. Rabbits were immunized so as to selectively produce IgE antibodies, and their pupillary miotic and mydriatic responses to cholinergic and alpha adrenergic stimuli, respectively, were determined. IgE-producing rabbits exhibited hyperresponsiveness to cholinergic but not alpha adrenergic stimulation, a pattern resembling that seen in nonasthmatic atopic humans. Repeated sublethal anaphylactic episodes induced in three IgE-producing rabbits did not affect the pattern of autonomic responsiveness when compared to controls challenged with saline, despite clear evidence of increased plasma histamine levels immediately after antigen challenges in the IgE group. This study indicates that elicitation of an IgE antibody response is associated with the concomitant development of cholinergic hyper-responsiveness.     

Augmented amylase release from rat parotid gland slices,in vitro

Using a continuous amylase assay the effect of simultaneous stimulation of adrenergic and cholinergic receptors on amylase release by perfused rat parotid slices was investigated. Super imposing adrenergic stimulation (isoprenaline) on continual submaximal cholinergic stimulation (acetyl--methylcholine) resulted in an augmented amylase release compared with the sum of the two separate effects. This could also be shown with continual adrenergic stimulation with cholinergic stimulation superimposed on this. Possible explanations of this effect are discussed with particular respect to the role of Ca⁺⁺.     

Effects of some autonomic drugs on duodenal smooth muscle.

Longitudinal muscle strips (LMS) and circular muscle strips (CMS), 2 mm wide and 1.5--2 cm long, from opossum duodenum were exposed to some autonomic agonists. The cholinergic agonists, acetylcholine, carbachol, methacholine, and bethanechol stimulated only tonic contractions in LMS and tonic followed by phasic contractions in CMS. These effects were abolished by atropine 10(-6) M. The ED50S of all cholinergic agonists for LMS were significantly lower than for CMS. Norepinephrine caused initial contraction (abolished by phenoxybenzamine, 10(-4) M), followed by relaxation (abolished by propranolol, 10(-5) M), and isopropylnorepinephrine caused relaxation (abolished by propranolol, 10(-5) M) in both layers. There were no differences in relative potencies for adrenergic agonists between the layers. Tetrodotoxin did not affect the response to adrenergic agonists. Thus, the potency of cholinergic agonists is greater in longitudinal than in circular muscle, and the layers respond differently to cholinergic agonists. The alpha-adrenergic receptors mediate contraction and beta-adrenergic receptors mediate relaxation on the duodenal smooth muscle.     

Activation of cholinergic and adrenergic receptors increases the concentration of extracellular adenosine in the cerebral cortex of unanesthetized rat

Adenosine is an inhibitory neuromodulator in the CNS. For extracellular adenosine to play a physiological role in the brain, it must be present at effective concentrations. Acetylcholine and noradrenaline are known to play an important role in modulating the activity of cortical neurons, and they might have a role also in the release of adenosine in the cerebral cortex in vivo. We examined whether activation of cholinergic and adrenergic receptors affects extracellular adenosine levels in the cerebral cortex of unanesthetized rats using in vivo microdialysis. All drugs were administered locally within the cortex by reverse dialysis. Both acetylcholine and the acetylcholinesterase inhibitor neostigmine increased extracellular adenosine levels, and the effect of neostigmine was blocked by the nicotinic receptor antagonist mecamylamine. Both nicotine and the nicotinic receptor agonist epibatidine increased the concentration of extracellular adenosine. Activation of muscarinic receptors using the nonselective agonist oxotremorine and a selective M1 receptor agonist also increased extracellular adenosine levels. Noradrenaline and the noradrenergic reuptake inhibitor desipramine increased extracellular adenosine levels. The alpha(1)-adrenergic receptor agonist phenylephrine and the beta-adrenergic agonist isoproterenol increased extracellular adenosine levels, whereas the alpha(2)-adrenergic receptor agonist clonidine did not have an effect.These findings indicate that activation of specific cholinergic and adrenergic receptors can increase extracellular levels of adenosine in the cortex, and suggest that cholinergic and adrenergic receptor-mediated regulation of adenosine levels may represent a mechanism for controlling the excitability of cortical neurons.     

Sympathetic sprouting in visual cortex stimulated by cholinergic denervation rescues expression of two forms of long-term depression at layer 2/3 synapses

Cholinergic innervation of hippocampus and cortex is required for some forms of learning and memory. Several reports have shown that activation of muscarinic m1 receptors induces a long-term depression (mLTD) at glutamate synapses in hippocampus and in several areas of cortex, including perirhinal and visual cortices. This plasticity likely contributes to cognitive function dependent upon the cholinergic system. In rodent models, degeneration of hippocampal cholinergic innervation following lesion of the medial septum stimulates sprouting of adrenergic sympathetic axons, originating from the superior cervical ganglia (SCG), into denervated hippocampal subfields. We previously reported that this adrenergic sympathetic sprouting occurs simultaneously with a reappearance of cholinergic fibers in hippocampus and rescue of mLTD at CA3-CA1 synapses. Because cholinergic neurons throughout basal forebrain degenerate in aging and Alzheimer's disease, it is critical to determine if this compensatory sprouting occurs in other regions impacted by cholinergic cell loss. To this end, we investigated whether lesion of the nucleus basalis magnocellularis (NbM) to cholinergically denervate cortex stimulates adrenergic sympathetic sprouting and the accompanying increase in cholinergic innervation. Further, we assessed whether the presence of sprouting positively correlates with the ability of glutamate synapses in acute visual cortex slices to express mLTD and low frequency stimulation induced LTD (LFS LTD), another cholinergic dependent form of plasticity in visual cortex. We found that both mLTD and LFS LTD are absent in animals when NbM lesion is combined with bilateral removal of the SCG to prevent possible compensatory sprouting. In contrast, when the SCG remain intact to permit sprouting in animals with NbM lesion, cholinergic fiber density is increased concurrently with adrenergic sympathetic sprouting, and mLTD and LFS LTD are preserved. Our findings suggest that autonomic compensation for central cholinergic degeneration is not specific to hippocampus, but is a general repair mechanism occurring in other brain regions important for normal cognitive function.     

The effect of amphetamine and tyramine on the guinea-pig urinary bladder

Tyramine and amphetamine cause a contraction of muscle strips from the urinary bladder of the guinea-pig. This response was found to be due to an action directly on the smooth muscle and did not involve those receptors described as adrenergic (alpha or beta), cholinergic (muscarinic or nicotinic) or those for histamine or 5-hydroxytryptamine.     

Pharmacological evidence that alpha 1-adrenoceptors mediate metamorphosis of the Pacific oyster, Crassostrea gigas

Oyster larvae can be induced to metamorphose by exposure to the natural vertebrate adrenergic agonists, epinephrine and norepinephrine. The larval receptors mediating this induction were pharmacologically characterized by testing the ability of a variety of adrenergic agonists and selected structural analogs of epinephrine and norepinephrine to induce oyster metamorphosis, and by testing the ability of various adrenergic antagonists to block the induction of metamorphosis by epinephrine. Oyster metamorphosis can be induced by vertebrate adrenergic agonists with relative potencies: cirazoline greater than epinephrine greater than phenylephrine greater than or equal to norepinephrine greater than alpha-methylnorepinephrine greater than isoproterenol much greater than methoxamine = clonidine. Other structural analogs of epinephrine and norepinephrine, including dopamine and octopamine, were ineffective at inducing metamorphosis. Induction of metamorphosis by epinephrine can be blocked by vertebrate adrenergic antagonists with relative potencies: chlorpromazine greater than or equal to prazosin greater than phentolamine greater than WB4101 greater than propranolol greater than yohimbine greater than metoprolol. These data demonstrate that receptors similar to vertebrate-type alpha 1-adrenoceptors mediate oyster metamorphosis. This is the first evidence for alpha 1-adrenoceptors in molluscs, and provides an important clue to the control of the complex process of molluscan metamorphosis and to the evolution of vertebrate adrenergic receptors.