The brain and the immune system are the two major adaptive systems of the body During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome

The Sympathetic Nerve—An Integrative Interface between Two Supersystems: The Brain and the Immune System

Hippocampus plays a crucial role in important brain functions (e.g. memory, learning) thus in the past two decades this brain region became a major objective of neuroscience research. During this period large number of anatomical, neurochemical and electrophysiological data have been accumulated. While excellent reviews have been published on the anatomy and electrophysiology of hippocampal formation, the neurochemistry of this area has not been thoroughly surveyed. Therefore the aim of this review is to summarize the neurochemical and pharmacological data on the release of the major neurotransmitters found in the hippocampal region: glutamate (GLU), gamma-amino butyric acid (GABA), acetylcholine (ACh), noradrenaline (NA) and serotonin (5-HT). In addition, this review analyzes the synaptic and nonsynaptic interactions between hippocampal neuronal elements and overviews how auto- and heteroreceptors are involved in the presynaptic modulation of transmitter release. The presented data clearly show that transmitters released from axon terminals without synaptic contact play an important role in the fine tuning of communication between neurons within a neuronal circuit.

Neurochemistry and pharmacology of the major hippocampal transmitter systems: synaptic and nonsynaptic interactions

Modulation of lipopolysaccharide-induced tumor necrosis factor-α production by selective α- and β-adrenergic drugs in mice

It has long been known that the release of neurotransmitters and hormones requires the presence of extracellular Ca2+ (del Castillo and Katz, 1954; Douglas, 1968). According to the classical "calcium hypothesis," the release of neurotransmitters is trigsered pnmanly by the depolarization-evoked rapid Ca2' entry into the nerve terminals (Katz and Miledi, 1967, 1969, 1970; Llinas and Nicholson, 1975). Direct measurement of the intracellular Ca2+ concentration with calcium-sensitive dyes (Llinas et al., 1972; Llinas and Nicholson, 1975) and fluorescent calcium indicators (Tsien, 1980; Tsien et al., 1982) proved that a rise in intracellular free Ca2+ concentration ([Ca2+]i) was associated with secretory processes. In addition to the unequivocal evidence for the role of Ca2+ in stimulus-secretion coupling, in recent years numerous publications have appeared in the literature describing the neurotransmitter release that occurs in the absence of external Ca2+. These experimental data strongly suggest the existence of a release process in which external Ca2+ does not play any role. Three a priori possibilities for neurotransmitter release that is independent of external Ca2+ speculatively exist: a. The neurotransmitter release might be entirely independent of external Ca2+ but triggered by Ca2+ mobilized from intracellular Ca2+ pools. A certain pattern of depolarization might release Ca2+ from the mitochondria, endoplasmic reticulum, etc., which could activate the release process without requiring Ca" entry from the extracellular medium. b. There might be a truly Ca2+-independent neurotransmitter release that might otherwise have the same mechanism as exocytosis triggered by Ca2+ entry. c. There might be a release process working independently of external Ca2+ that is distinct from the one called Ca2+-dependent exocytosis. These are not simply theoretical considerations; experimental evidence is available for transmitter release by any of these possible mechanisms. The present review is addressed specifically to the characteristics, conditions, and possible functional importance of external Ca2+-independent release of different transmitters. This article is not dealing with the hormone-sensitive external Ca2+ independent secretions mediated by inositol trisphosphate and guanine nucleotidebinding proteins, which have been extensively reviewed elsewhere (Berridge and Irvine, 1984; Hirasawa and Nishizuka, 1985; Nishizuka, 1986; Knight et al., 1989).

External Ca2+‐Independent Release of Neurotransmitters

Beyond direct synaptic communication, neurons are able to talk to each other without making synapses. They are able to send chemical messages by means of diffusion to target cells via the extracellular space, provided that the target neurons are equipped with high-affinity receptors. While synaptic transmission is responsible for the ‘what’ of brain function, the ‘how’ of brain function (mood, attention, level of arousal, general excitability, etc.) is mainly controlled non-synaptically using the extracellular space as communication channel. It is principally the ‘how’ that can be modulated by medicine. In this paper, we discuss different forms of non-synaptic transmission, localized spillover of synaptic transmitters, local presynaptic modulation and tonic influence of ambient transmitter levels on the activity of vast neuronal populations. We consider different aspects of non-synaptic transmission, such as synaptic–extrasynaptic receptor trafficking, neuron–glia communication and retrograde signalling. We review structural and functional aspects of non-synaptic transmission, including (i) anatomical arrangement of non-synaptic release sites, receptors and transporters, (ii) intravesicular, intra- and extracellular concentrations of neurotransmitters, as well as the spatiotemporal pattern of transmitter diffusion. We propose that an effective general strategy for efficient pharmacological intervention could include the identification of specific non-synaptic targets and the subsequent development of selective pharmacological tools to influence them.

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Non-synaptic receptors and transporters involved in brain functions and targets of drug treatment

The selectivity and specificity of CH-38083 [7,8-(methylenedioxi)-14-alpha-hydroxyalloberbane HCl], a berbane derivative for alpha adrenoceptors has been studied and compared with yohimbine and idazoxan in peripheral tissues and in the central nervous system. In isolated tissue experiments CH-38083 was a competitive antagonist at presynaptic alpha-2 adrenoceptors on the axon terminals of the rat vas deferens (pA2 against xylazine = 8.17 +/- 0.06) and of the longitudinal muscle strip of guinea pig ileum (pA2 against xylazine = 8.07 +/- 0.20). As far as its postsynaptic alpha-2 adrenoceptor antagonistic activity is concerned its affinity in rat vas deferens (pA2 = 4.95 +/- 0.11) against l-phenylephrine and in rabbit pulmonary artery (pA2 = 5.38 +/- 0.33 against l-norepinephrine) was markedly less than that displayed for presynaptic sites. From pA2 values obtained in rat vas deferens the calculated alpha-1/alpha-2 adrenoceptor selectivity ratios for yohimbine, idazoxan and CH-38083 were 4.7, 117.5 and 1659, respectively. CH-38083 failed to show any affinity for histamine and muscarinic receptors and it even potentiated the effect of serotonin on atropinized longitudinal muscle strip of guinea pig ileum. It enhanced the release of [3H]norepinephrine from electrically stimulated mouse vas deferens loaded previously with labeled [3H]norepinephrine. In binding studies carried out in rat brain membrane preparations using [3H]prazosin and [3H]idazoxan, the selectivity ratios (Ki alpha-1/Ki alpha-2) proved to be 32.5, 289.5 and 1368 for yohimbine, idazoxan and CH-38083, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

CH-38083, a selective, potent antagonist of alpha-2 adrenoceptors.

Ca2+-dependent release of [3H] noradrenaline ([3H] NA) evoked by electrical stimulation of the isolated mouse vas deferens was subject to negative feedback modulation by idazoxan an alpha 2-adrenoceptor blocking agent. Both the resting release and that evoked by 1-phenylephrine proved to be Ca0-independent and unaffected by idazoxan. Ouabain-evoked release of [3H] acetylcholine from the myenteric plexus of ileal longitudinal muscle strips in the presence of eserine was not affected by atropine, but that evoked by electrical stimulation was enhanced. Since the release of NA or ACh by 1-phenylephrine and ouabain respectively is mainly of cytoplasmic origin, it is concluded that the release of transmitter from the cytoplasm is not subject to negative feedback modulation.

Bernath S

Papers

CH-38083, a selective, potent antagonist of alpha-2 adrenoceptors.

Transmitter release from the cytoplasm is of physiological importance but not subject to presynaptic modulation.