Presynaptic receptors for dopamine, histamine and serotonin that are located on dopaminergic, histaminergic and sertonergic axon terminals, respectively, function as autoreceptors. Presynaptic receptors also occur as heteroreceptors on other axon terminals. Auto- and heteroreceptors mainly affect Ca(2+) -dependent exocytosis from the receptor-bearing nerve ending. Some additionally subserve other presynaptic functions.Presynaptic dopamine, histamine and serotonin receptors are involved in various (patho)physiological conditions. Examples are the following:Dopamine autoreceptors play a role in Parkinson's disease, schizophrenia and drug addiction. Dopamine heteroreceptors affecting the release of acetylcholine and of amino acid neurotransmitters in the basal ganglia are also relevant for Parkinson's disease. Peripheral dopamine heteroreceptors on postganglionic sympathetic terminals influence heart rate and vascular resistance through modulation of noradrenaline release. Blockade of histamine autoreceptors increases histamine synthesis and release and may support higher CNS functions such as arousal, cognition and learning. Peripheral histamine heteroreceptors on C fiber and on postganglionic sympathetic fiber terminals diminish neuropeptide and noradrenaline release, respectively. Both inhibititory effects are beneficial in myocardial ischemia. The inhibition of neuropeptide release also explains the antimigraine effects of some agonists of presynaptic histamine receptors. Upregulation of presynaptic serotonin autoreceptors is probably involved in the pathogenesis of major depression. Correspondingly, antidepressant treatments can be linked with a reduced density of 5-HT autoreceptors. 5-HT Heteroreceptor activation diminishes acetylcholine and GABA release and may therefore increase anxiety. In the periphery, presynaptic 5-HT heteroreceptor agonists shorten migraine attacks by inhibition of the release of neuropeptides from trigeminal afferents, apart from their constrictive action on meningeal vessels.

Presynaptic receptors for dopamine, histamine, and serotonin.

Purinergic modulation of glutamate release under ischemic-like conditions in the hippocampus.

Adenosine is arguably the most potent and widespread presynaptic modulator in the CNS, yet adenosine receptor signal transduction pathways remain unresolved. Here, we demonstrate a novel mechanism in which adenosine A1 receptor stimulation leads to p38 mitogen-activated protein kinase (MAPK) activation and contributes to the inhibition of synaptic transmission. Western blot analysis indicated that selective A1 receptor activation [with N6-cyclopentyladenosine (CPA)] resulted in rapid increases in phosphorylated p38 (phospho-p38) MAPK immunoreactivity in membrane fractions, and decreases in phospho-p38 MAPK in cytosolic fractions. Immunoprecipitation with a phospho-p38 MAPK antibody revealed constitutive association of this phosphoprotein with adenosine A1 receptors. Phospho-p38 MAPK activation by A1 receptor stimulation induced translocation of PP2a (protein phosphatase 2a) to the membrane. We then examined the actions of p38 MAPK activation in A1 receptor-mediated synaptic inhibition. Excitatory postsynaptic field potentials evoked in area CA1 of the rat hippocampus markedly decreased in response to adenosine (10 microM), the A1 receptor agonist CPA (40 nM), or a 5 min exposure to hypoxia. These inhibitory responses were mediated by A1 receptor activation because the selective antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine) (100 nM) prevented them. In agreement with the biochemical analysis, the selective p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole] (25 microM) blocked the inhibitory actions of A1 receptor activation, whereas both the inactive analog SB202474 [4-ethyl-2-(p-methoxyphenyl)-5-(4'-pyridyl)-1H-imidazole] (25 microM) and the ERK 1/2 (extracellular signal-regulated kinase 1/2) MAPK inhibitor PD98059 [2'-amino-3'-methoxyflavone] (50 microM) were ineffective. In contrast, the p38 MAPK inhibitors did not inhibit GABA(B)-mediated synaptic depression. These data suggest A1 receptor-mediated p38 MAPK activation is a crucial step underlying the presynaptic inhibitory effect of adenosine on CA3-CA1 synaptic transmission.

p38 Mitogen-Activated Protein Kinase Contributes to Adenosine A1 Receptor-Mediated Synaptic Depression in Area CA1 of the Rat Hippocampus

Electrical high-frequency stimulation (HFS) is applied in many brain areas to treat various clinical syndromes. The nearly identical constellation of stimulation parameters raises the question of a unique mechanism of action of this therapeutic option. The identification of a single HFS mechanism may help to optimize the HFS technology by targeting this single mechanism. Experimentally, only axonal membranes are targets of HFS, but not other membranes of neurons or glial cells. Within all HFS target regions, axons of excitatory glutamatergic and inhibitory GABAergic neurons are present and play roles in all clinical syndromes treated successfully with HFS. Therefore, glutamatergic or GABAergic fibres are likely candidates as mediators of a unique HFS mode of action. The selective involvement of another neuronal fibre type (e.g. monoaminergic, cholinergic, etc.) in the HFS mode of action is highly unlikely since the regional and syndromal dissimilarity of the clinical HFS applications precludes the assumption of such a fibre type as primary HFS site of action. Our recent experimental finding that HFS of human neocortical slices induces the action potential-mediated release of GABA, but not of glutamate, simplifies the possibilities to explain the HFS mode of action, as the explanation now may concentrate on GABAergic axons only. Thus, we are analysing, on the basis of the pathophysiological grounds of the various syndromes treated with deep brain stimulation, whether a selective GABA release is a collective explanation of the mode of action of HFS. We suggest that selective GABA release indeed may needfully and sufficiently explain efficacy and side effects of HFS.

Selective GABA release as a mechanistic basis of high-frequency stimulation used for the treatment of neuropsychiatric diseases.

Signalling through adenosineand adenine-nucleotide-gated receptors (purinoceptors) regulates a vast array of physiological processes in the central nervous system, including synaptic transmission. The research presented here describes a role for mitogen-activated protein kinases ( M A P K s ) in mediating molecular signalling cascades initiated by activation of purinoceptors in the hippocampus. In particular, it is proposed that M A P K activation is a requirement for purinoceptor-mediated presynaptic inhibition of neurotransmission. The three primary findings presented here are: 1) P 2 X 7 receptors are localized on mossy fiber terminals where they function to inhibit mossy fiber-CA3 synaptic transmission in a pathway requiring p38 M A P K activation; 2) Adenosine A i receptors exist in a complex with p38 M A P K in which A i receptors activate p38 M A P K to decrease Schaffer-collateral-CAl synaptic transmission; and 3) Sequential activation of C-Jun N-terminal kinase ( INK) following p38 M A P K activation is also required for A i receptor-mediated synaptic depression. Immunocytochemistry was used to demonstrate that P 2 X 7 receptors are abundant on presynaptic terminals of mossy fiber synapses in the rat hippocampus. Western blotting was used to show increases in the phosphorylation state of p38 M A P K and J N K following A i receptor stimulation in the C A 1 region. Coimmunoprecipitation showed that A i receptors are physically associated with p38 M A P K and J N K in the hippocampus. Synaptic function was assessed using field excitatory postsynaptic potentials (fEPSPs) evoked in stratum lucidum in the C A 3 region or in stratum radiatum in the C A 1 region of rat hippocampal slices. Selective stimulation of P 2 X 7 receptors with the agonist B z A T P potently decreased mossy fiber-CA3 synaptic depression and this was blocked by the P 2 X 7 antagonist oxidized-ATP, but not by the

Purinergic modulation of neurotransmission

A model of electrically evoked release of glutamate from rat hippocampus was developed and used to detect possible changes induced by lesions of hippocampal afferences Neuronal glutamate in hippocampal slices was labelled by preincubation with [3H]glutamine The slices were then superfused with physiological medium in the presence of the glutamate uptake inhibitor L-transpyrrolidine-2,4-dicarboxylic acid (100 microM or 3 microM) and stimulated twice electrically (S1, S2: 240 pulses, 3 Hz, 2 ms, 26-30 mA); various drugs were added before S2 In order to determine the basal and evoked outflow of [3H]glutamate only, the mixture of 3H-labelled compounds (glutamine, glutamate and GABA) was separated by ion exchange chromatography in superfusate fractions and slices The electrically evoked overflow of [3H]glutamate was largely Ca2+-dependent and tetrodotoxin-sensitive and hence represented action potential-induced exocytotic release of [3H]glutamate Evoked [3H]glutamate release was significantly increased by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 01 microM), suggesting the presence of endogenous inhibitory adenosine, and reduced by the A1 receptor agonist N6-cyclopentyladenosine (1 microM, antagonized by DPCPX, 01 microM) There was no evidence for a cholinergic, serotonergic, or adrenergic modulation of the evoked release of [3H]glutamate: the corresponding selective agonists (or antagonists) were ineffective After aspirative lesions of the septohippocampal pathways the hippocampal noradrenaline content was markedly increased, whereas cholinergic and serotonergic markers were reduced The evoked release of [3H]glutamate in hippocampal slices of lesioned rats was significantly increased by a mechanism which still has to be determined, but which is not related to alterations in A1 receptor function It is concluded that the present model was able to detect lesion-induced differences in electrically evoked release of [3H]glutamate, but the relationship of these differences to changes of noradrenergic, cholinergic or serotonergic hippocampal innervations remains to be established

Electrically evoked release of glutamate in rat hippocampal slices: effects of various drugs and fimbria-fornix lesions.

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Electrically evoked release of glutamate in rat hippocampal slices: effects of various drugs and fimbria-fornix lesions.