Mathematical modelling and quantification of the autoinhibitory feedback control of noradrenaline release in brain slices (original) (raw)
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Estimation of endogenous noradrenaline release in rat brain in vivo using [3H]RX 821002
Synapse, 2005
Noradrenaline plays an important role in many normal brain functions, e.g., attention, memory, and emotion. Dysfunction in the noradrenergic system is thought to lead to a number of abnormal brain conditions. The lack of suitable in vivo tracers to monitor noradrenaline release, levels, and regulation has hampered our fully understanding the roles that it plays in the brain. Presented here are data showing that the in vivo binding of the ␣ 2 -adrenoceptor antagonist [ 3 H]RX 821002 is sensitive to endogenous noradrenaline. Elevation of extracellular noradrenaline, using three different pharmacological challenges in rat, led to a reduction in the binding potential (BP) of [ 3 H]RX 821002 when compared with vehicle controls. The challenges used were i.p. administration of D-amphetamine, the imidazoline 2 binding site-selective ligand BU224, and L-deprenyl. Of the cortical regions measured, the reduction in BP reached significance in the anterior cingulate cortex for all of these pharmacological challenges. These initial observations in rat indicate that labelling of the ␣ 2 -adrenoceptors with RX 821002 can be used to estimate changes in extracellular noradrenaline concentration in the cortex. This has the potential to enable the investigation of the role that noradrenaline plays both in the normal and abnormal brain and, if the ligand can be radiolabelled with a suitable positron-emitting isotope at high specific radioactivity, it could be an invaluable PET tracer. Synapse 55:126 -132, 2005.
Regulation of Noradrenaline Release From Rat Brain Tissue Chops by alpha2-Adrenoceptors
ProQuest Dissertations & Theses,, 1989
Page 1.4 Cyclic AMP in various rat brain regions 1.5 Regulation of cAMP in intact brain slices 1.5.1 Adenylate cyclase 1.5.2 Receptor-mediated cAMP formation 1.5.2.1 a-and p-Adrenergic agents (Noradrenaline) 1.5.2.2 Adenosine 34 1.5.3 Forskolin stimulation of adenylate cyclase 35 1.5.4 Effect of depolarization on cAMP formation 36 1.5.5 Ca^+/Calmodulin regulation of neuronal cAMP levels 37 1.6 Modulation of voltage-sensitive ion channels by 38 guanine nucleotide regulatory proteins (G-proteins) 1.6.1 Modulation of ion channels by Ca^+ mobilizing 39 receptors possibly mediated via unknown G-proteins 1.6.2 Modulation of ion channels by intracellular messengers 40 1.7 Aim of project 43 2 MATERIALS AND METHODS 1.2 Materials 2.2 Dissection of rat brain 2.3 Preparation of tissue chops 2.4 HEPES buffered salines 2.5 HPLC-ED Assay of endogenous catecholamines from rat 47 brain regions 2.6 Uptake of [^h ]NA into occipital cortex tissue chops 48 2.7 Determination of [^h ]NA release 2.7.1 Calculation of [^HlNA release 2.8 cAMP assay 2.9 Preparation of Dowex 50 and alumina columns for adenylate cyclase assay 2.9.1 Supplies 2.9.2 Packing Dowex 50 columns 55-V-Page 2.9.3 Packing alumina columns 55 2.9.4 Column recycling 55 2.10 cAMP purification 56 2.11 Preparation of a dual-label quency curve by external 56 standard method 2.12 Scintillation counting 56 2.13 Protein estimation 57 2.14 Statistical Evaluation 59 3 RESULTS 3.1 Preliminary Studies 60 3.1.1 NA and DA content in the occipital cortex (O.C.) and 60 hypothalamus of rat brain 3.1.2 Effect of desipramine (DMI) on the uptake of [2H ]NA 60 in O.C. tissue chops 3.1.3 K+-stimulated Ca2+-dependent release of [2h]na 62 from O.C. and hypothalamic tissue chops 3.1.4 Time course of the effect of clonidine on the release 62 of [2H]NA from O.C. tissue chops 3.1.5 Effect of pretreatment of tissue chops with clonidine 66 on K+-evoked release of [2h]NA from O.C. tissue chops 3.1.6 Effect of clonidine on 40mM, 30mM and 20mM K+-evoked 66 release of [2H]NA from O.C. tissue chops 3.2 cC2~Adrenergic regulation of [2H]NA release 71 3.2.1 a 2-Adrenergic modulation of K+-evoked release of 72 [2H]NA from O.C. and hypothalamic tissue chops 3.2.2 The effect of yohimbine on the inhibition of [2H]NA 75 release from O.C. and hypothalamic tissue chops by OC2~a(3rener9 ic agonists 3.2.3 Effect of preincubation with forskolin on K+-evoked 75 release of [2H]NA from O.C. tissue chops 3.2.4 Effect of db-cAMP, forskolin and PDE-inhibitors (IBMX 80 and RO20-1724) on a2~a<3renergic agonist modulation of K+-evoked release of [3h ]NA from O.C. tissue chops 3.2.5 Influence of db-cAMP and forskolin in the presence of IBMX on clonidine inhibitory response of K+-evoked release of [ ] N A from hypothalamic tissue chops 3.2.6 Effects of adenosine and N^-cyclohexyl-adenosine (CHA) on the release of [^H]NA from O.C. tissue chops 3.2.7 Effects of PDE-inhibitors, IBMX and RO20-1724 on the adenosine inhibitory response of [^H]NA release from O.C. tissue chops 3.2.8 Effect of adenosine A^ antagonist, CPDPX on adenosine inhibitory response of K+-evoked release of [ ] N A from O.C. tissue chops 3.2.9 NA and adenosine modulation of K+-evoked release of [ ] N A from O.C. tissue chops 3.3 Regulation of cAMP formation in O.C. tissue chops 3.3.1 Stimulation of cAMP formation by forskolin, NA and isoprenaline in the absence or presence of IBMX and RO20-1724 3.3.1.1 Effects of a-and ^-adrenergic antagonists on NA or isoprenaline stimulation of cAMP formation 3.3.1.2 Stimulation of cAMP formation by adenosine in the absence or presence of IBMX and RO20-1724 3.3.1.3 Effects of aand ^-adrenergic antagonists on adenosine combined with NA stimulation of cAMP formation 3.3.1.4 Influence of forskolin on NA, isoprenaline and adenosine stimulation of cAMP formation 3.3.2 K+ stimulation of cAMP formation in the absence or presence of IBMX, RO20-1724 or DMI 3.3.2.1 Influence of forskolin on K+ stimulation of cAMP formation 3.3.3 Effect' of a 2~adrenergic agonist in the presence of various cAMP stimulating agents 3.
Brain Research, 2001
The present study was undertaken to investigate and compare the properties of noradrenaline release in the locus coeruleus (LC) and prefrontal cortex (PFC). For that aim the dual-probe microdialysis technique was applied for simultaneous detection of noradrenaline levels in the LC and PFC in conscious rats. Calcium omission in the LC decreased noradrenaline levels in the LC, but increased its levels in the PFC. Novelty increased noradrenaline levels in both structures. Infusion of the a-adrenoceptor agonist clonidine decreased 2 extracellular noradrenaline in the LC as well as in the PFC. Infusion of the a-adrenoceptor antagonist BRL44408, or the 2A a-adrenoceptor agonist cirazoline into the LC or PFC caused a similar dose-dependent increase in both structures. When BRL44408 or 1 cirazoline were infused into the LC, few effects were seen in the PFC. Infusion of the 5-HT-receptor agonist flesinoxan into the LC or 1A the PFC decreased the release of noradrenaline in both structures. When flesinoxan was infused into the LC, no effects were seen in the PFC. When the GABA antagonist bicuculline was applied to the LC, noradrenaline increased in the LC as well as in the PFC. It is A concluded that the release of noradrenaline from somatodendritic sites and nerve terminals responded in a similar manner to presynaptic receptor modulation. The possible existence of dendritic noradrenaline release is discussed.
Changes in Plasma Noradrenaline Concentration as a Measure of Release Rate
British Journal of Pharmacology, 1978
A method is described for repeated sampling of plasma noradrenaline (NA) in freely moving rats. Na concentration does not change during the day or after adrenalectomy. 2 Exogenous NA has a half-life of 1.5 min; drugs which block neuronal and extra-neuronal uptake lengthen this' to 6.3 min. 3 Swim-stress leads to a steep rise followed by a rapid decline in plasma NA concentration. 4 This method of plasma NA sampling can serve as a measure of both steady and rapid changes in 'release rate over long periods of time.
Brain Research, 1994
Mlcrodlalysls was used to determine extracellular levels of both noradrenahne and xts metabohtes m several brain regions of rats under basal conditions and m response to drugs selective for the cc 2-adrenoceptor to study regional differences in the regulation of noradrenaline overflow. Basal overflow of noradrenaline was about 1.3 fmol/min in frontoparletal cortex, amygdala and hippocampus and in the medial prefrontal cortex 2 4 fmol/min was measured, whereas the overflow of the noradrenaline metabolites 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol was 10-fold higher. After correction for recovery and membrane length no regional differences in the basal overflow of noradrenallne (NA) were found. There were, however, regional differences in the drug-induced effects: locally applied moxonidine decreased extracellular noradrenahne stronger in the frontoparietal cortex than in the medial prefrontal cortex. The increase m noradrenaline overflow caused by idazoxan (10 -4 M) was stronger in frontoparietal cortex than in amygdala and hippocampus. The metabohtes were also generally decreased by moxonldine and increased by ldazoxan, although less markedly The present study shows that the regulation of noradrenahne overflow by the presynaptic cc 2-autoreceptor was stronger in cortncal regions than in amygdala and hlppocampus In those latter regions the uptake mechanism probably plays a relatively more important role in the regulation of noradrenaline overflow
Endogenous noradrenaline impairs the prostaglandin-induced inhibition of noradrenaline release
Naunyn-Schmiedeberg's Archives of Pharmacology, 1989
The effects ofprostaglandin E2 (PGE2) on electrically evoked noradrenaline release in rat brain cortex were studied under conditions under which autoinhibition of release was avoided. When stimulation was carried out with 36 pulses at 3 Hz, 1 ~tmol/1 pGE2, produced about 50% inhibition of release. In the presence of the e2-adrenoceptor antagonist yohimbine (1 gmol/1) the effect of PGE2 was markedly increased. When release was elicited by 3 pulses/ 100 Hz the period of stimulation was too short to permit development of autoinhibition by released noradrenaline. Then the concentration-response-curve for PGE2 was very similar to that obtained under the above conditions (36 pulses/3 Hz, in the presence of yohimbine). These data suggest that both the e2-adrenoceptor and the PGE2-receptor are linked to a common pathway. Since indometacin (10 gmol/1) did not enhance evoked transmitter release, an influence of endogenous PG's on in vitro release of noradrenaline from rat brain cortex slices can be excluded.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1990
Slices and synaptosomes from human cerebral cortex (which had to be removed to reach deeply located tumours) and, for comparison, synaptosomes from guinea-pig and rat cerebral cortex were preincubated with [3H]5-hydroxytryptamine and superfused with physiological salt solution containing an inhibitor of 5-hydroxytryptamine uptake. The effects of alpha-adrenoceptor agonists and antagonists on the electrically (slices) or potassium-evoked (synaptosomes) tritium overflow were studied. In human cerebral cortical slices, the electrically-evoked [3H] overflow was inhibited by noradrenaline (pIC25 value: 6.35); the non-selective alpha-adrenoceptor antagonist phentolamine, at a concentration of 0.32 mumol/l, strongly antagonized the inhibitory effect of noradrenaline (apparent pA2 value: 8.19) but did not affect the evoked overflow by itself. In synaptosomes from humans, guinea-pigs and rats, noradrenaline also inhibited the K(+)-evoked [3H] overflow in a concentration dependent manner; the alpha 2-adrenoceptor clonidine (1 mumol/l), but not the alpha 1-adrenoceptor agonist methoxamine (1 mumol/l), mimicked the effects of noradrenaline; the effect of noradrenaline (0.3 mumol/l) was abolished by the alpha 2-adrenoceptor antagonist idazoxan (0.5 mumol/l), but not by the alpha 1-adrenoceptor antagonist prazosin (1 mumol/l). It is concluded that release-inhibiting adrenoceptors of the alpha 2-subtype exist on 5-hydroxytryptamine terminals innervating the cerebral cortex in human and guinea-pig brain.
Journal of Neurochemistry, 1991
Noradrenaline (NA) and the a2-adrenergic agonists clonidine, BHT-920, and UK 14304-1 8 inhibit potassiumevoked release of [3H]NA from rat occipital cortex tissue chops with similar potencies. NA (M) was most effective as up to 85% inhibition could be observed compared with 75%, 55%, and 35% for UK 14304-18, clonidine, and BHT-920, respectively, all at I 0-5 M. Potassium-evoked release was enhanced by both forskolin (M) and 1 Wdibutyryl cyclic AMP. Pretreatment of tissue chops with 1 mM dibutyryl cyclic AMP in the presence of 3-isobutyl-l-methylxanthine partially reversed the a2-adrenergic agonist inhibition of NA release. No reversal of inhibition was observed following pretreatment with M forskolin. The effects of clonidine, BHT-920, UK-14308-18, and NA on cyclic AMP formation stimulated by (a) forskolin, (b) isoprenaline, (c) adenosine, (d) potassium, and (e) NA were examined. Only cAMP formation stimulated by NA was inhibited by these cu2-adrenergic agonists. These results suggest that only a small fraction of adenylate cyclase in rat occipital cortex is coupled to a2-adrenergic receptors. These results are discussed in relation to recent findings that several a2-adrenergic receptor subtypes occur, not all of which are coupled to the inhibition of adenylate cyclase, and that a2-adrenergic receptors inhibit NA release in rat occipital cortex by a mechanism that does not involve decreasing cyclic AMP levels.