Basal Norepinephrine Release Research Articles

Impact of age on modulation of norepinephrine release from sympathetic nerves in the rat superior mesentery artery

There is an age-related increase in stimulation-evoked fractional norepinephrine release in tail arteries of Fischer 344 rats from 6–20 months of age. Previous studies have ruled out changes in the function of uptake and subsequent metabolism mechanisms, or feedback by prejunctional α 2-adrenoceptors. The tail artery is important in thermoregulation, and there is the possibility that the previously observed increase in sympathetic nerve activity is due to age-related changes in thermoregulation as opposed to a fundamental age-related change in the regulation of sympathetic nerves. Thus, we measured stimulation-evoked norepinephrine release in another blood vessel model, the superior mesentery artery using HPLC with electrochemical detection. In this study fractional norepinephrine release was measured under three separate conditions, drug free Krebs'; in the presence of deoxycorticosterone and cocaine; in the presence of deoxycorticosterone and cocaine and the α 2-adrenergic receptor antagonist, idazoxan. The most significant finding was that fractional norepinephrine release in mesentery arteries from 20-month-old animals was higher as compared to 6 months regardless of treatment condition. Furthermore, the elevation in norepinephrine release cannot be accounted for by changes in norepinephrine content, uptake and subsequent metabolism mechanisms or changes in basal norepinephrine release. These data from the mesentery artery model confirm and support our previous work in the rat tail artery model. In addition, the data from this study suggest the possibility that there are common mechanisms underlying the age-related increase in peripheral sympathetic nerve activity.

A new GABA-A receptor subtype coupled with Ca++/Cl- synporter modulates aminergic release from rat brain neuron terminals.

The aim of the present study was to give a better characterization of GABA receptors that modulate aminergic release. GABA or muscimol (15 microM) increased basal noradrenaline (3H-NA) release but reduced the following K+-evoked 3H-NA release in the synaptosomes from rat cerebellar cortex. Bicuculline and picrotoxin counteracted these two effects. The same GABA modulation resulted to operate also on dopaminergic and serotoninergic neuron terminals. The increased basal noradrenaline release resulted to be both calcium and chloride dependent and associated with an increased entry of 45Ca++ into the synaptosomes. We therefore advance the hypothesis of an involvement of a Cl-/Ca++ synporter system coupled to the receptor. Baclofen also reduced the K+-evoked 3H-NA release, but did not increase basal 3H-NA release; moreover, the interaction of baclofen G with GABA-B receptors resulted to be associated with the inhibition of 45Ca++ entry into synaptosomes. GABA-B receptors resulted to be present also on serotoninergic but not on dopaminergic neuron terminals. The GABA-C receptor agonist cis-4-aminocrotonic acid (CACA) did not influence either basal or K+-evoked 3H-NA release. These results point to a new type of GABA functional role through a different A-family receptor subtype, coupled with calcium influx in aminergic neuron terminals, modulating aminergic release.

Mechanism of peripheral noradrenergic stimulation by clozapine

In a canine model of diabetes enhanced ventricular vulnerability (VFT) has been associated with reduced myocardial myoinositol and increased release of norepinephrine (NE). To assess the role of the polyol, a dietary supplement of myoinositol was fed for 1 year to a diabetic group. Diabetes was induced with alloxan, 30 mg/kg. Controls (Group 1) were compared with diabetics without (Group 2) and with the inositol supplement (Group 3). After 1 year the animals were anesthetized to assess VFT. Basal heart rate and arterial pressure were comparable. The VFT in Group 1 was 43 ± 2.6 ma, 26.7 ± 2.8 ma in Group 2 (P < 0.02) and 39 ± 3.5 ma in Group 3 (P < 0.02 vs. Group 2). Since the cardiac sympathetic system may promote arrhythmogenesis, the release of NE into the coronary sinus (CS) has been determined. To assess basal NE release serial arterial (A) and (CS) samples were taken at 5 min intervals for 20 min during infusion of 3H-NE. There was no significant difference between the diabetic groups in the level of arterial NE (HPLC). The mean for NEA-CS was higher in Group 2 (−228 ± 33 pg/ml) compared to normals (−75 ± 19 P < 0.02). In Group 3 the mean NE in the coronary venous effluent was −33 ± 9 pg/ml, significantly less than Group 2. Infusion of 3H-NE was attended by significantly higher 3H-NEcslevels in Group 2. While dihydroxyphenylglycol (DHPG) was increased, 3H DHPG was not, suggesting that an impaired uptake mechanism contributed to the increased NEcs. Thus, myoinositol feeding of the diabetic animals was associated with normalization of myocardial vulnerability and NE metabolism.

Cholinergic Control of Catecholamine Release in the Eel

The perifused posterior cardinal vein of the American eel (Anguilla rostrata) releases spontaneously dopamine (DA), norepinephrine (NE), and epinephrine (E). NE and E are secreted by innervated chromaffin cells, while DA is most likely released from a component of the vascular wall. Stimulation with acetylcholine strongly enhances the release of DA and E, and to a lesser degree the release of NE. Nicotine stimulates the release of all three catecholamines. Muscarine reduces the basal release of NE. Muscarine does not prevent nicotinic stimulation of NE and E release, but abolishes the nicotine effect on DA release. The muscarinic antagonist atropine stimulates the release of NE, but not of DA and E. The β-adrenergic receptor antagonist propranolol suppresses the acetylcholine-stimulated release of NE and E, and reduces the DA response. From these findings, it appears that (1) nicotinic receptors regulate NE and E secretion from the chromaffin cells, (2) muscarinic receptors inhibit basal NE release, and (3) acetylcholine-stimulated release of NE and E requires the interaction with adrenergic receptors. On the other hand, DA release involves both nicotinic and adrenergic receptors, while the reduction of nicotine-stimulated (but not basal) DA release involves muscarinic receptors.

Noradrenergic Influences on Prefrontal Cortical Cognitive Function: Opposing Actions at Postjunctional α1 Versus α2-Adrenergic Receptors

Publisher Summary This chapter summarizes that postsynaptic α1 and α2 receptors may have opposing roles in the prefrontal cortex (PFC), as they do in the thalamus regulating arousal and in the hypothalamus regulating ingestive behavior. Research in rodents and primates indicates that norepinephrine (NE) has beneficial effects on PFC function through actions at postsynaptic, α2 receptors in the PFC but has detrimental actions through α1-receptor mechanisms. Preliminary data comparing the binding of [3H]NE to recombinant human α-adrenoceptors suggests that NE has higher affinity for the α2A subtype than for either the α1A or α1D subtypes. NE improves PFC working memory function at α2A receptors localized postsynaptic to NE terminals in the PFC. α2A Agonists are now being tested as potential cognitive enhancers in disorders with prominent PFC dysfunction, such as attention deficit hyperactivity disorder. Recent results from open trials suggest that α2A agonists can improve PFC function in humans, as they do in animal models. In contrast to the beneficial effects of α2 agonists, recent evidence indicates that NE impairs spatial working memory function through α1 -receptor mechanisms. Thus, α2 mechanisms may predominate when basal NE release is moderate and PFC function is optimal, while α1 mechanisms may predominate under conditions of higher levels of NE release, contributing to PFC cognitive impairment. These results suggest that PFC cognitive impairment induced by α1-receptor stimulation results from excessive PI turnover that can be countered by lithium pretreatment. These results may have clinical relevance to mania, a disorder commonly treated with lithium medication.

Release of [3H]-noradrenaline from rat hippocampal synaptosomes by nicotine: mediation by different nicotinic receptor subtypes from striatal [3H]-dopamine release.

1. The aim of the present experiment was to characterize nicotine-evoked [3H]-noradrenaline ([3H]-NA) release from rat superfused hippocampal synaptosomes, using striatal [3H]-dopamine release for comparison. 2. (-)-Nicotine, cytisine, DMPP and acetylcholine (ACh) (with esterase inhibitor and muscarinic receptor blocker) increased NA release in a concentration-dependent manner (EC50 6.5 microM, 8.2 microM, 9.3 microM, and 27 microM, respectively) with similar efficacy. 3. Nicotine released striatal dopamine more potently than hippocampal NA (EC50 0.16 microM vs. 6.5 microM). (+)-Anatoxin-a also increased dopamine more potently than NA (EC50 0.05 microM vs. 0.39 microM), and maximal effects were similar to those of nicotine. Isoarecolone (10-320 microM) released dopamine more effectively than NA but a maximal effect was not reached. (-)-Lobeline (10-320 microM) evoked dopamine release, but the effect was large and delayed with respect to nicotine; NA release was not increased but rather depressed at high concentrations of lobeline. High K+ (10 mM) released and NA to similar extents. 4. Addition of the 5-hydroxytryptamine (5-HT) reuptake blocker, citalopram (1 microM) to hippocampal synaptosomes affected neither basal NA release nor nicotine-evoked release. 5. The nicotinic antagonist, mecamylamine (10 microM), virtually abolished NA and dopamine release evoked by high concentrations of nicotine, ACh, cytisine, isoarecolone, and anatoxin-a. Although NA release evoked by DMPP (100 microM) was entirely mecamylamine-sensitive, DMPP-evoked dopamine release was only partially blocked. Dopamine release evoked by lobeline (320 microM) was completely mecamylamine-insensitive. 6. The nicotinic antagonists dihydro-beta-erythroidine and methyllycaconitine inhibited nicotine-evoked dopamine release approximately 30 fold more potently than NA release. In contrast, the antagonist chlorisondamine, displayed a reverse sensitivity, whereas trimetaphan and mecamylamine did not preferentially block either response. None of these antagonists, given at a high concentration, significantly altered release evoked by high K+. 7. Blockade of nicotine-evoked transmitter release by methyllycaconitine and dihydro-beta-erythroidine was surmounted by a high concentration of nicotine (100 microM), but blockade by mecamylamine, chlorisondamine, and trimetaphan was insurmountable. 8. Nicotine-evoked NA release was unaffected by tetrodotoxin, whereas veratridine-evoked NA release was virtually abolished. 9. We conclude that presynaptic nicotinic receptors associated with striatal dopamine and hippocampal NA terminals differ pharmacologically. In situ hybridization studies suggest that nigrostriatal dopaminergic neurones express mainly alpha 4, alpha 5, and beta 2 nicotinic cholinoceptor subunits, whereas hippocampal-projecting noradrenaline (NA) neurones express alpha 3, beta 2 and beta 4 subunits. Pharmacological comparisons of recombinant receptors suggest that release of hippocampal NA may be modulated by receptors containing alpha 3 and beta 4 subunits.

Nitric oxide inhibits the release of norepinephrine and dopamine from the medial basal hypothalamus of the rat.

Previous research indicates that norepinephrine and dopamine stimulate release of luteinizing hormone (LH)-releasing hormone (LHRH), which then reaches the adenohypophysis via the hypophyseal portal vessels to release LH. Norepinephrine exerts its effect via alpha 1-adrenergic receptors, which stimulate the release of nitric oxide (NO) from nitricoxidergic (NOergic) neurons in the medial basal hypothalamus (MBH). The NO activates guanylate cyclase and cyclooxygenase, thereby inducing release of LHRH into the hypophyseal portal vessels. We tested the hypothesis that these two catecholamines modulate NO release by local feedback. MBH explants were incubated in the presence of sodium nitroprusside (NP), a releaser of NO, and the effect on release of catecholamines was determined. NP inhibited release of norepinephrine. Basal release was increased by incubation of the tissue with the NO scavenger hemoglobin (20 micrograms/ml). Hemoglobin also blocked the inhibitory effect of NP. In the presence of high-potassium (40 mM) medium to depolarize cell membranes, norepinephrine release was increased by a factor of 3, and this was significantly inhibited by NP. Hemoglobin again produced a further increase in norepinephrine release and also blocked the action of NP. When constitutive NO synthase was inhibited by the competitive inhibitor NG-monomethyl-L-arginine (NMMA) at 300 microM, basal release of norepinephrine was increased, as was potassium-evoked release, and this was associated in the latter instance with a decrease in tissue concentration, presumably because synthesis did not keep up with the increased release in the presence of NMMA. The results were very similar with dopamine, except that reduction of potassium-evoked dopamine release by NP was not significant. However, the increase following incubation with hemoglobin was significant, and hemoglobin, when incubated with NP, caused a significant elevation in dopamine release above that with NP alone. In this case, NP increased tissue concentration of dopamine along with inhibiting release, suggesting that synthesis continued, thereby raising the tissue concentration in the face of diminished release. When the tissue was incubated with NP plus hemoglobin, which caused an increase in release above that obtained with NP alone, the tissue concentration decreased significantly compared with that in the absence of hemoglobin, indicating that, with increased release, release exceeded synthesis, causing a fall in tissue concentration. When NO synthase was blocked by NMMA, the release of dopamine, under either basal or potassium-evoked conditions, was increased. Again, in the latter instance the tissue concentration declined significantly, presumably because synthesis did not match release. Therefore, the results were very similar with both catecholamines and indicate that NO acts to suppress release of both amines. Since both catecholamines activate the release of LHRH, the inhibition of their release by NO serves as an ultra-short-loop negative feedback by which NO inhibits the release of the catecholamines, thereby reducing the activation of the NOergic neurons and decreasing the release of LHRH. This may be an important means for terminating the pulses of release of LHRH, which generate the pulsatile release of LH that stimulates gonadal function in both male and female mammals.

Intracerebroventricular administration of neuropeptide Y inhibits release of noradrenaline in the hypothalamic paraventricular nucleus caused by manual restraint in the rat through an opioid system.

Intracerebroventricular injection of 1.5 micrograms neuropeptide Y (NPY) had no effect on basal release of noradrenaline (NA) in the hypothalamic paraventricular nucleus (PVN), measured by intracerebral microdialysis in the rat. However, it blocked the increase in NA release caused by manual restraint but not that by tail-pinch, and the effect was blocked by naloxone (1.0 mg/kg body weight). Thus, NPY attenuates NA release in the PVN by a painless stressor, such as manual restraint, through an opioid system.

Idazoxan-induced reductions in cortical glucose use are accompanied by an increase in noradrenaline release: Complementary [ 14C]2-deoxyglucose and microdialysis studies

The autoradiographic [ 14C]2-deoxyglucose procedure was used to map function-related alterations in local cerebral glucose use following acute administration of the α 2-adrenoceptor antagonist, idazoxan (0.3–3 mg kg −1 s.c.). The most prominent feature of the results obtained was the significant reduction in glucose use in certain locus coeruleus projection areas. Thus, in various cortical, hippocampal and thalamic regions, as well as structures involved in auditory and visual function, idazoxan administration was associated with a 13–20% decrease in glucose use. In a complementary microdialysis study, the effect of idazoxan on extracellular noradrenaline levels in the frontal cortex of rats, manipulated in the same fashion as during the [ 14C]2-deoxyglucose procedure (i.e. following the application of surgery and partial restraint), was examined. Both surgery and restraint were associated with a modest but significant increase in basal noradrenaline release ( + 31% and + 26%, respectively). Subsequent administration of idazoxan (3 mg kg −1 s.c.) evoked a further increase in noradrenaline release, the magnitude of which was the same as that observed following its administration to freely-moving rats (+ 113%). These combined data suggest that idazoxan-induced reductions in cerebral glucose use, at least in the frontal cortex, may occur as a consequence of the increase in noradrenaline release. In addition, it appears that surgery and partial restraint do not alter α 2-adrenoceptor tone in the frontal cortex.

Learned helplessness: In vivo biogenic amine release in hypothalamus

Learned helplessness (LH) is a behavioral depression caused by inescapable stress that models some aspects of human depression. We are developing a neuronal map of learned helplessness, which involves multiple neurotransmitters in several limbic regions. In frontal cortex, dopamine (DA), serotonin (5-HT), and GABA modulate the development and maintenance of LH, while in hippocampus interactions between GABA and norepinephrine (NE) play the major role. In hypothalamus, other investigators have reported decreased 5-HT uptake into synaptosomes and decreased basal and K+-stimulated 5-HT release from tissue slices of LH rats, as well as decreased paroxetine and unchanged [3-receptor binding. We have now applied in vivo microdialysis to measuring DA, NE, and 5-HT simultaneously in hypothalamus or caudate of conscious, freely moving rats in a LH paradigm. Rats received 100 trials of inescapable tailshock stress, and after testing for LH, microdialysis probes were implanted into either caudate or lateral hypothalamus. One day later, perfusion was maintained with Ringer's solution until a stable baseline was obtained, then switched to high K +. In caudate, no differences were found in DA or 5-HT among any of the three experimental groups--LH, non-helpless (NH), or unstressed tested controls (TC). In hypothalamus, no differences were observed among experimental groups for DA or 5-HT; however, NE showed significantly higher levels of basal release in LH rats, compared to NH or TC. Interestingly, NH rats had significantly higher K+-stimulated NE release compared to the other two groups. For all the stressed rats, there was a significant positive correlation between shuttlebox escape latencies and basal NE release. These data suggest that the caudate may not be involved in the biogenic amine neurochemistry of LH, and that in the lateral hypothalamus, NE mechanisms predominate in this animal model of depression.

Overflow of endogenous norepinephrine from PVH nucleus of DOCA-salt hypertensive rats.

Previous studies from this laboratory demonstrated that there was enhanced basal and evoked (K+ depolarization) overflow of endogenous norepinephrine (NE) into the perfusate of a push-pull cannula placed in the paraventricular nucleus of the hypothalamus (PVH) of conscious freely moving spontaneously hypertensive rat (SHR) compared with Wistar-Kyoto (WKY) or Sprague-Dawley (SD) rats. The present study was carried out to determine whether results obtained with SHR were specific to this genetic model of hypertension by examining NE release in deoxycorticosterone acetate (DOCA)-salt hypertension. DOCA-salt hypertension was produced in 8-wk-old uninephrectomized SD rats by administering a 50-mg DOCA Silastic pellet subcutaneously 7 days postnephrectomy and providing 0.9% NaCl + 0.2% KCl drinking solution at libitum for 3 wk. Sham-implanted animals received normal tap water. Blood pressure was similar to that of 8- to 10-wk-old SHR. Basal release of NE as well as release after K+ added to the push-pull cannula or sodium nitroprusside or phenylphrine administered intravenously was determined. It was observed that there was no difference in basal overflow or after K+ administration in DOCA-salt hypertensive rats compared with sham animals. Similarly, the increase in NE overflow due to sodium nitroprusside or the decrease due to phenylphrine was similar between DOCA-salt rats or sham controls. This was in sharp contrast to what was observed in SHR: basal or K(+)-evoked release was significantly greater in SHR than WKY, SD, DOCA-salt, or DOCA-sham controls. It is concluded that central noradrenergic activity involving the PVH is not altered in DOCA-salt hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Prejunctional facilitatory α1‐adrenoceptors in the rat urinary bladder

1. The effect of activation of alpha 1-adrenoceptors on acetylcholine (ACh) release and neurally evoked contractile responses induced by electrical field stimulation was investigated in smooth muscle strips from the rat urinary bladder. 2. Neurogenic contractions were facilitated by the alpha 1-adrenoceptor agonists, phenylephrine (PE) (2-128 microM) and methoxamine (2-128 microM) in a dose-dependent manner. These agents also increased small amplitude spontaneous contractions of bladder strips and in 10% of strips increased basal tone. However, contractions elicited by exogenous ACh (1-10 microM) were not affected by alpha 1-agonists. 3. The magnitude of the PE facilitation was higher at lower frequencies (1-5 Hz) or at submaximal intensities of stimulation and at lower Ca2+ concentrations (0.5-1 mM). The selective alpha 1-adrenoceptor antagonist, terazosin (TRZ) (0.05-1 microM), competitively inhibited (pA2 value: 8.6) the PE facilitation of the neurally evoked contractions but not the PE induced increase of spontaneous contractions. 4. [3H]-noradrenaline (NA) and [14C]-ACh release evoked by electrical field stimulation were increased (140% and 173%, respectively) by 2 microM PE. TRZ (0.05-0.1 microM) blocked the PE facilitation of ACh release but not the facilitation of NA release. TRZ alone did not alter the release of ACh or NA nor the amplitude of the neurogenic contractions. 5. PE (2 microM) did not alter the basal release of ACh but did increase (by 180%) the basal release of NA. Desipramine (2 microM) blocked this effect of PE and also the PE-facilitation of evoked ACh and NA release. 6. It is concluded that cholinergic terminals in the rat urinary bladder exhibit alpha 1-adrenoceptors which can facilitate the release of transmitter. However, under the conditions of our experiments it appears that cholinergic transmission is not modulated by alpha 1 adrenergic mechanisms. Further studies are necessary to determine whether these receptors can be activated by endogenous noradrenaline released within the bladder.

Opioid peptide inhibition of endogenous norepinephrine release from the A2 noradrenergic cell group in vitro.

We investigated the potential influence of opioid and melanotropic peptides on endogenous norepinephrine (NE) release from the A2 noradrenergic cell group of rats using a static, fixed-volume incubation procedure. Norepinephrine release from slices of caudal dorsomedial medulla (CDMM) was evoked by high potassium concentrations (20 and 60 mM) in a Ca(2+)-dependent and dose-related manner. Treatment with the potent melanotropin agonist [Nle4,D-Phe7] alpha-MSH(NDP-MSH) had no effect on K(+)-induced NE release. In contrast, human beta-endorphin1-31 significantly reduced K(+)-stimulated NE release, but not in the presence of naloxone. The highly-selective mu-opioid agonist [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO) also significantly reduced evoked NE release. The inhibitory effect of DAMGO was completely blocked by naloxone. Naloxone alone did not alter evoked NE release. The inhibitory effect of DAMGO was not enhanced by reducing the stimulatory concentration of K+. None of the peptides tested influenced basal NE release. These data indicate that melanotropin receptors do not regulate NE release in CDMM. In contrast, the opioid peptides DAMGO and beta-endorphin inhibit K(+)-stimulated release of endogenous NE. These data suggest a role for mu-opioid receptors in controlling NE release from A2 noradrenergic neurons.

Subtype-specificity of the presynaptic α 2-adrenoceptors modulating hippocampal norepinephrine release in rat

In vivo brain microdialysis and high-performance liquid chromatography with electrochemical detection were used to study the effect of different selective α 2-antagonists on hippocampal norepinephrine (NE) release in freely moving awake rat. Systemic administration (0.5 mg/kg i.p.) of either the α 2AD-antagonist BRL 44408 or the α- 2BC-antagonist ARC 239 did not significantly change the basal release of NE. At a higher dose (5 mg/kg i.p.) ARC 239 was still ineffective, whereas BRL 44408 caused a significant increase of the extracellular level of NE. Similar results were obtained from in vitro perfusion experiments. Rat hippocampal slices were loaded with [ 3H]NE and the electrical stimulation-evoked release of [ 3H]NE was determined. The α 2-antagonists were applied in a concentration range of 10 −8 to 10 −6 M. ARC 239 was ineffective, whereas BRL 44408 significantly increased the electrically induced release of [ 3H]NE. In agreement with the data of microdialysis and perfusion experiments. BRL 44408 displaced [ 3H]yohimbine from hippocampal and cortical membranes of rat brain with high affinity whereas ARC 239 was less effective. The p K i values of eight different α 2-adrenergic compounds showed a very good correlation ( r = 0.98, slope = 1.11 P < 0.0001) in hippocampus and frontal cortex where the α 2-adrenoceptors have been characterized as α 2D-subtype. Our data indicate that hippocampal NE release in rat is regulated by α 2D-adrenoceptors, a species variation of the human α 2A-subtype.

Regionally specific changes in extracellular noradrenaline following chronic idazoxan as revealed by in vivo microdialysis.

The selective alpha 2-adrenoceptor antagonist idazoxan was administered chronically (0.8 mg/kg per h) to rats for a period of 10 days via osmotic minipumps. On day 11, 24 h after removal of the pumps, the rats were anaesthetised and microdialysis probes were implanted into either the frontal cortex or hippocampus. Basal noradrenaline release in the frontal cortex was significantly elevated compared with the saline control group. Each animal was then challenged with idazoxan (10 mg/kg s.c.). Inhibition of presynaptic alpha 2-adrenoceptors resulted in a significant increase in noradrenaline release in the saline control group. However, animals treated chronically with idazoxan, showed a markedly attenuated response to the single dose idazoxan challenge in the frontal cortex. No significant change in either basal release or in response to idazoxan challenge was observed in the hippocampus in the chronic idazoxan-treated animals as compared with the chronic saline control group. Chronic idazoxan administration results in selective enhancement of noradrenaline release in the frontal cortex but not in the hippocampus. This would be consistent with a down-regulation of presynaptic alpha 2-adrenoceptors with the subsequent loss of presynaptic noradrenergic negative feedback inhibition.

Influence of dietary myoinositol on myocardial vulnerability and norepinephrine release in a diabetic animal model

In a canine model of diabetes enhanced ventricular vulnerability (VFT) has been associated with reduced myocardial myoinositol and increased release of norepinephrine (NE). To assess the role of the polyol, a dietary supplement of myoinositol was fed for 1 year to a diabetic group. Diabetes was induced with alloxan, 30 mg/kg. Controls (Group 1) were compared with diabetics without (Group 2) and with the inositol supplement (Group 3). After 1 year the animals were anesthetized to assess VFT. Basal heart rate and arterial pressure were comparable. The VFT in Group 1 was 43 ± 2.6 ma, 26.7 ± 2.8 ma in Group 2 ( P < 0.02) and 39 ± 3.5 ma in Group 3 ( P < 0.02 vs. Group 2). Since the cardiac sympathetic system may promote arrhythmogenesis, the release of NE into the coronary sinus (CS) has been determined. To assess basal NE release serial arterial (A) and (CS) samples were taken at 5 min intervals for 20 min during infusion of 3H-NE. There was no significant difference between the diabetic groups in the level of arterial NE (HPLC). The mean for NE A-CS was higher in Group 2 (−228 ± 33 pg/ml) compared to normals (−75 ± 19 P < 0.02). In Group 3 the mean NE in the coronary venous effluent was −33 ± 9 pg/ml, significantly less than Group 2. Infusion of 3H-NE was attended by significantly higher 3H-NE cslevels in Group 2. While dihydroxyphenylglycol (DHPG) was increased, 3H DHPG was not, suggesting that an impaired uptake mechanism contributed to the increased NE cs. Thus, myoinositol feeding of the diabetic animals was associated with normalization of myocardial vulnerability and NE metabolism.

Learned helplessness and in vivo hippocampal norepinephrine release

Hippocampal norepinephrine release was measured using in vivo microdialysis in rats before and after exposure to inescapable tail shock stress and after testing for learned helplessness. Rats that did not develop learned helplessness after stress had higher basal norepinephrine release after stress than rats developing learned helplessness or than control rats. After the shuttlebox test for learned helplessness, K +-stimulated norepinephrine release was lower in learned helpless than in nonhelpless or control rats. These results confirm an important role for the hippocampal noradrenergic system in differential behavioral responses to stress.

Aging prolongs the stress-induced release of noradrenaline in rat hypothalamus

A stress-induced increase in noradrenaline (NA) release was measured by intracerebral microdialysis in the hypothalamic paraventricular nucleus of freely moving Wistar-Kyoto rats at three different ages (6, 18 and 24 months). NA levels in 20-min dialysate samples were measured by high-performance liquid chromatography with electrochemical detection. Microdialysis sampling was done at the baseline during a 20-min immobilization stress and for the next 100 min. Basal NA release was not significantly different in the three age groups. The immobilization stress increased NA levels (247, 197 and 234% of the baseline for the 6-, 18- and 24-month animals, respectively) which was not significantly different in the three groups. In the two younger groups NA returned to the baseline in the first sample after the end of the stress ( t = 40 min) whereas in the 24-month group it remained significantly higher for longer (until t = 60 min). Stress-induced release of hypothalamic NA thus appears to be prolonged in old rats.

Lack of glucocorticoids sustains the stress-induced release of noradrenaline in the anterior hypothalamus.

The release of endogenous noradrenaline in the anterior hypothalamus was studied with microdialysis perfusion in freely moving rats that were subjected to immobilization stress. Experiments were carried out in sham-adrenalectomized and adrenalectomized rats that were first given drinking water containing corticosterone for 5 days following surgery and then switched to a corticosterone-free diet the day before stress application. One group of these adrenalectomized animals was injected with dexamethasone. Basal release of noradrenaline collected in 20-min fractions was similar in the three groups of animals and averaged 24 fmol. The recovery of the probe was about 10%. In sham-adrenalectomized rats application of 20-min immobilization stress increased noradrenaline release to 310% of baseline in the sample collected during stress application. A significant increase (+ 175% of baseline) was still observed in the next 20-min sample. Subsequent values were all identical to baseline. In adrenalectomized rats lacking exogenous corticosterone the stress-induced release of noradrenaline was prolonged with noradrenaline levels remaining elevated for 2 h after the onset of stress. The total noradrenaline release during this entire period was about 2.5 times higher in adrenalectomized than in sham-operated rats. However, the maximal increase during the period of immobilization was not significantly affected. Treatment with dexamethasone prevented the prolonged increase in noradrenaline release but did not affect the increase during the period of stress. While glucocorticoids do not appear to affect the increased release of NA in the anterior hypothalamus during the period of stress, they act to limit the duration of this activation after the application of stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of acute and chronic electroconvulsive shock on noradrenaline release in the rat hippocampus and frontal cortex.

1. Changes in the extracellular content of endogenous noradrenaline (NA) in frontal cortex and hippocampus were determined by in vivo microdialysis following acute and chronic electroconvulsive shock (ECS) in rats anaesthetized with chloral hydrate. 2. Basal release of NA in the frontal cortex (4.9 +/- 0.3 pg/sample) did not differ significantly from that in the hippocampus (4.6 +/- 0.2 pg/sample). 3. A single ECS resulted in an increase of NA release in the hippocampus (21.1 +/- 1.3 pg/sample) and in the frontal cortex (11.6 +/- 1.2 pg/sample). In both brain regions extracellular NA had returned to basal values within 30 min. 4. Animals were treated chronically with ECS (once per day for seven days). Twenty-four h later (day 8), basal release of NA into dialysis samples from the frontal cortex was significantly increased (50%) as compared to chronic sham controls. Basal release in the hippocampus was not significantly different from the sham controls. In the chronic ECS animals the increase in NA released in both brain areas following an ECS on day 8 did not differ from either the chronic sham controls or from animals given acute ECS. 5. Animals were challenged 24 h after eight ECS or sham control treatments (once per day) with the alpha 2-adrenoceptor antagonist, idazoxan (10 mg kg-1, s.c.). Idazoxan increased NA release in the hippocampus in both groups. There was no difference in the magnitude of the response in ECS- and in sham-treated rats.In the frontal cortex, idazoxan increased the extracellular NA content in the chronic sham controls, but the response to idazoxan was significantly attenuated in the chronic ECS animals.6. Chronic but not acute ECS was found to elicit a sustained (>24 h) increase in the release of NA in the frontal cortex, but not in the hippocampus. The idazoxan data suggest that the increase may be due to a downregulation of presynaptic alpha2-adrenoceptors in the frontal cortex. The difference in response of these two brain regions to chronic ECS is discussed in terms of differences in the regulation of extracellular NA content by uptake and autoreceptor activation.