Activity Of Noradrenergic Neurons Research Articles

Temporal expression of estrogen receptor α in the hypothalamus and medulla oblongata during fasting: a role of noradrenergic neurons

Fasting-induced LH suppression is augmented by estrogen in female rats. We investigated the temporal changes in the number of estrogen receptor alpha (ERalpha)-immunoreactive (ir) cells in various brain regions in ovariectomized rats fasted for 6, 24, 30, and 48 h, commencing at 1300 h. We also determined the anatomical relationship of ERalpha immunoreactivity and dopamine-beta-hydroxylase (DBH) neurons in the A2 region of the nucleus of the solitary tract (NTS) and the paraventricular nucleus (PVN). The number of ERalpha-ir cells significantly increased after 30 h from the onset of fasting in the PVN and NTS compared with the unfasted controls and was sustained until 48 h. In the A2 region of 48-h fasted rats, 46.75% DBH-ir cells expressed ERalpha, and this was significantly higher than in unfasted controls (8.16% DBH-ir cells expressed ERalpha). In the PVN, most ERalpha-ir neurons were juxtaposed with DBH-ir varicosities. These results suggest that ERalpha is expressed in specific brain regions at a defined time from the onset of fasting. In addition, the anatomical relationship of noradrenergic and ERalpha-ir neurons in the A2 region and PVN may suggest a role for estrogen in increasing the activity of noradrenergic neurons in the A2 region and enhancing sensitivity of the PVN to noradrenergic input arising from the lower brainstem and thereby augmenting the suppression of LH secretion during fasting.

Activation of neurons of zone A5 of the rat brain upon hypoxic and thermonociceptive stimulation and switching off of the central respiratory generator

We recorded spike activity of noradrenergic neurons of zone A5 (n = 89) in the brain of anesthetized rats under conditions of hypoxic stimulation (breathing with pure N2, 10 sec), thermonociceptive stimulation (tail-flick test), and reversible hypothermal blocking of the central respiratory activity. Hypoxic stimulation of peripheral O2-sensitive chemoreceptors considerably increased the discharge frequency in all the examined neurons and induced tachypnea and a hypotensive reaction. Sixty-nine (77.5%) neurons of the studied group were tested using nociceptive stimulation (thermal stimulation of the tail); such stimulation resulted in a multifold increase in their discharge frequency. This was accompanied by tachypnea and a hypertensive response. Thus, we first demonstrated the role of nociception in the control of activity of noradrenergic neurons in zone A5 and the role of nociceptive afferent signals in the modulation of functions of the respiratory and cardiovascular systems mediated by neurons of the above zone. Under conditions of blocking of the central respiratory activity, we examined 36 (40.4%) neurons of zone A5 and first observed the effect of strong activation of a significant proportion of these cells upon switching off of respiration. This fact shows that there is an activating “respiratory” drive on neurons of zone A5 (probably, from the side of an expiratory neuronal population of the respiratory center) and allows us to hypothesize on the genesis of “respiratory” modulation of these cells. The activity of 16 (18.0%) cells was recorded under conditions of consecutive applications of the above stimuli; all the neurons were activated by the respective afferent influences. The simultaneously induced effects of hypoxic and nociceptive stimulations on the activity of neurons of zone A5 were additive. Thus, we first obtained proofs in favor of the multimodality of noradrenergic neurons of the above zone. This feature is a significant factor providing integrative interaction between the respiratory and cardiovascular systems and the system of nociception.

Electrophysiological and neurochemical characterization of the effect of repeated treatment with milnacipran on the rat serotonergic and noradrenergic systems

The present study was undertaken to elucidate the effects of repeated treatment with milnacipran, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor (SNRI), on the synaptic plasticity in the hippocampal CA1 field, focusing on the interaction between the serotonergic and noradrenergic system. Repeated treatment with milnacipran (30 mg/kg, i.p. after 30 mg/kg, p.o. x 14 days) completely restored the suppression of the long-term potentiation (LTP) induced by single milnacipran treatment (30 mg/kg, i.p.). Single and repeated milnacipran increased to a similar extent extracellular NA in the hippocampus. Single milnacipran increased extracellular 5-HT and this effect tended to be enhanced by repeated treatment. The restoration of LTP and facilitation of the 5-HT level were not shown after repeated treatment with a selective 5-HT reuptake inhibitor (SSRI) fluvoxamine (30 mg/kg, p.o. x 14 days). These results suggest that milnacipran-induced restoration of LTP suppression is responsible for the enhancement of 5-HT neurotransmission, which appears to be associated with noradrenergic neuronal activity. In addition, the 5-HT1A receptor agonist tandospirone-induced suppression of LTP was completely blocked by repeated treatment with milnacipran, indicating the possibility that this reversal effect is due to the functional changes in postsynaptic 5-HT1A receptors. Taken together, the present data suggest that the interaction between the serotonergic and noradrenergic mechanism play an important role in the modulation of synaptic plasticity caused by repeated treatment with milnacipran, which may be implicated in the therapeutic effects of SNRI on psychiatric disorders.

Cannabinoids modulate spontaneous neuronal activity and evoked inhibition of locus coeruleus noradrenergic neurons

The noradrenergic pathway arising from the locus coeruleus (LC) is involved in the regulation of attention, arousal, cognitive processes and sleep. These physiological activities are affected by Cannabis exposure - both in humans and laboratory animals. In addition, exogenous cannabinoids, as well as pharmacological and genetic manipulation of the endocannabinoid system, are known to influence emotional states (e.g. anxiety) for which a contributory role of the LC-noradrenergic system has long been postulated. However, whether cannabinoid administration would affect the LC neuronal activity in vivo is still unknown. To this end, single-unit extracellular recordings were performed from LC noradrenergic cells in anaesthetized rats. Intravenous injection of both the synthetic cannabinoid agonist, WIN55212-2, and the main psychoactive principle of Cannabis, Delta9-tetrahydrocannabinol, dose-dependently increased the firing rate of LC noradrenergic neurons, with WIN55212-2 being the most efficacious. Similar results were obtained by the administration of these drugs into a lateral ventricle. Cannabinoid-induced stimulation of LC noradrenergic neuronal activity was counteracted by SR141716A, a cannabinoid receptor antagonist/reverse agonist, which by itself slightly reduced LC discharge rate. Moreover, WIN55212-2 suppressed the inhibition of noradrenergic cells produced by stimulation of the major gamma-aminobutyric acid (GABA)ergic afferent to the LC, the nucleus prepositus hypoglossi. Altogether, these findings suggest the involvement of noradrenergic pathways in some consequences of Cannabis intake (e.g. cognitive and attention deficits, anxiety reactions), as well as a role for cannabinoid receptors in basic brain activities sustaining arousal and emotional states.

On the Origin of Cortical Dopamine: Is it a Co-Transmitter in Noradrenergic Neurons?

Dopamine (DA) and noradrenaline (NA) in the prefrontal cortex (PFC) modulate superior cognitive functions, and are involved in the aetiology of depressive and psychotic symptoms. Moreover, microdialysis studies in rats have shown how pharmacological treatments that induce modifications of extracellular NA in the medial PFC (mPFC), also produce parallel changes in extracellular DA.To explain the coupling of NA and DA changes, this article reviews the evidence supporting the hypothesis that extracellular DA in the cerebral cortex originates not only from dopaminergic terminals but also from noradrenergic ones, where it acts both as precursor for NA and as a co-transmitter.Accordingly, extracellular DA concentration in the occipital, parietal and cerebellar cortex was found to be much higher than expected in view of the scarce dopaminergic innervation in these areas.Systemic administration or intra-cortical perfusion of alpha(2)-adrenoceptor agonists and antagonists, consistent with their action on noradrenergic neuronal activity, produced concomitant changes not only in extracellular NA but also in DA in the mPFC, occipital and parietal cortex.Chemical modulation of the locus coeruleus by locally applied carbachol, kainate, NMDA or clonidine modified both NA and DA in the mPFC.Electrical stimulation of the locus coeruleus led to an increased efflux of both NA and DA in mPFC, parietal and occipital cortex, while in the striatum, NA efflux alone was enhanced.Atypical antipsychotics, such as clozapine and olanzapine, or antidepressants, including mirtazapine and mianserine, have been found to increase both NA and DA throughout the cerebral cortex, likely through blockade of alpha(2)-adrenoceptors. On the other hand, drugs selectively acting on dopaminergic transmission produced modest changes in extracellular DA in mPFC, and had no effect on the occipital or parietal cortex.Acute administration of morphine did not increase DA levels in the PFC (where NA is diminished), in contrast with augmented dopaminergic neuronal activity; moreover, during morphine withdrawal both DA and NA levels increased, in spite of a diminished dopaminergic activity, both increases being antagonised by clonidine but not quinpirole administration.Extensive 6-hydroxy dopamine lesion of the ventral tegmental area (VTA) decreases below 95% of control both intra- and extracellular DA and DOPAC in the nucleus accumbens, but only partially or not significantly in the mPFC and parietal cortex.The above evidence points to a common origin for NA and DA in the cerebral cortex and suggests the possible utility of noradrenergic system modulation as a target for drugs with potential clinical efficacy on cognitive functions.

Systemic effect of cannabinoids on the spontaneous firing rate of locus coeruleus neurons in rats

Previous reports have described modulation of noradrenergic activity by cannabinoid receptors. The aim of the present research was to examine the effect of two synthetic cannabinoid CB 1/CB 2 receptor agonists, R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)-methyl]pyrrolol-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone (WIN 55212-2) and (−)- cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]- trans-4-(3-hydroxypropyl) cyclohexanol (CP 55940), on the spontaneous activity of locus coeruleus noradrenergic neurons by single-unit extracellular recordings in vivo and in vitro. In anaesthetized rats, intravenous administrations of WIN 55212-2 (31.3–500 μg/kg) or CP 55940 (31.3–500 μg/kg) increased the firing rate of locus coeruleus neurons in a dose-dependent manner. The stimulatory effect of WIN 55212-2 was blocked by pretreatment with the cannabinoid CB 1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3-carboxamide (SR 141716A; 2 mg/kg). Paradoxically, local administration of WIN 55212-2 (8.3–31.3 pmol) into the locus coeruleus and intracerebroventricular injections of WIN 55212–2 (10–20 μg) or CP 55940 (20–40 μg) failed to change the spontaneous firing rate of locus coeruleus neurons. Likewise, in rat brain slice preparations perfusion with WIN 55212-2 (10 μM) or CP 55940 (10–30 μM) did not specifically affect the spontaneous firing rate of locus coeruleus cells. Therefore, we conclude that synthetic cannabinoids increase the spontaneous firing activity of noradrenergic neurons in the rat locus coeruleus through cannabinoid CB 1 receptors. This stimulation appears to be indirectly induced via a receptor mechanism probably located at the peripheral level.

Activation of A1 and A2 noradrenergic neurons in response to running in the rat

Since running accompanied with blood lactate accumulation stimulates the release of adrenocorticotropic hormone (ACTH), running above the lactate threshold (LT) acts as stress (running stress). To examine whether A1/A2 noradrenergic neurons that project to the hypothalamus activate under running stress, c-Fos immunohistochemistry was used to compare the effects of running with or without stress response on A1/A2 noradrenergic neurons. Blood lactate and plasma ACTH concentrations significantly increased in the running stress group, but not in the running without stress response and control groups, confirming different physiological impacts between different intensity of running with or without stress. Running stress markedly increased c-Fos accumulation in the A1/A2 noradrenergic neurons. Running without stress response also induced a significant increase in c-Fos expression in the A1/A2 noradrenergic neurons, and the percentage of the increase was smaller than that of running stress. The extent of c-Fos expression in the A1/A2 noradrenergic neurons correlates with exercise intensity, signifying that this neuronal activation is running speed-dependent. We thus suggest that A1/A2 noradrenergic neurons are activated in response to not only running stress, but also to other physiological running, enhanced by non-stressful running. These findings will be helpful in studies of specific neurocircuits and in identifying their functions in response to running at different intensities.

Network reset: a simplified overarching theory of locus coeruleus noradrenaline function

Unraveling the functional role of neuromodulatory systems has been a major challenge for cognitive neuroscience, giving rise to theories ranging from a simple role in vigilance to complex models concerning decision making, prediction errors or unexpected uncertainty. A new, simplified and overarching theory of noradrenaline function is inspired by an invertebrate model: neuromodulators in crustacea abruptly interrupt activity in neural networks and reorganize the elements into new functional networks determining the behavioral output. Analogously in mammals, phasic activation of noradrenergic neurons of the locus coeruleus in time with cognitive shifts could provoke or facilitate dynamic reorganization of target neural networks, permitting rapid behavioral adaptation to changing environmental imperatives. Detailed analysis and discussion of extensive electrophysiological data from the locus coeruleus of rats and monkeys in controlled behavioral situations is provided here to support this view. This simplified 'new look' at locus coeruleus noradrenaline function redirects the challenge of understanding neuromodulatory systems towards their target networks, particularly to the dynamics of their interactions and how they organize adaptive behavior.

Effect of number of tailshocks on learned helplessness and activation of serotonergic and noradrenergic neurons in the rat

Adult male albino rats were exposed to varying numbers of tailshocks (0, 10, 50 or 100). The following day, their escape latencies in a shuttlebox were measured in order to estimate the degree of learned helplessness (LH) produced by the varying number of shocks. Only the groups exposed to 50 or 100 shocks displayed evidence of LH. In a parallel experiment, c-fos activation was used to determine the degree of activation of raphe serotonergic neurons (FosIR + 5-HT) and locus coeruleus (LC) noradrenergic neurons (FosIR + TH) produced by the same shock conditions. Compared to unhandled cage controls, all shock groups (0 shocks was a restrained group) significantly activated both raphe and LC neurons. The 50 and 100 shock groups had significantly higher degrees of activation of serotonergic neurons in the rostral raphe groups and the LC than the 0 and 10 shock groups. These data are consistent with the hypothesis that activation of rostral raphe serotonergic neurons and LC noradrenergic neurons beyond a certain threshold may be critical for the development of LH. The relevance of these results for elucidating the neural bases of psychopathology is discussed.

Activation of presynaptic GABA A receptors increases spontaneous glutamate release onto noradrenergic neurons of the rat locus coeruleus

In order to further explore how GABA can modulate the excitability of noradrenergic neurons of the locus coeruleus (LC), we investigated the presence of GABA A receptors on glutamatergic nerve terminals and the functional consequences of their activation. We used mechanically dissociated immature rat LC neurons with adherent nerve terminals and patch-clamp recordings of spontaneous excitatory postsynaptic currents. Activation of presynaptic GABA A receptors by muscimol facilitated spontaneous glutamate release by activating tetrodotoxin-sensitive Na + channels and high-threshold Ca 2+ channels. Bumetanide (10 μM), a potent blocker of Na +–K +–Cl − cotransporter, diminished the muscimol-induced facilitatory action of glutamate release. Our results indicate that the Na +–K +–Cl − cotransporter accumulates Cl − inside the nerve terminals so that activation of presynaptic GABA A receptors causes depolarization. This GABA A-receptor-mediated modulation of spontaneous glutamatergic transmission is another mechanism by which GABA and its analogues can regulate the excitability and activity of noradrenergic neurons in the LC.

Effects of Bemitil on the Activity of Noradrenergic and Serotonergic Brainstem Neurons and on EEG of Awake Cats

In experiments on five awake cats, we studied the effects of bemitil, a drug possessing psychostimulatory, antidepressive, and actoprotector properties (peroral introduction, 50 mg/kg), on the activity of neurons of the aminergic cerebral systems. Eleven noradrenergic (NA-ergic) neurons of the locus coeruleus (LC) and 11 serotonergic (ST-ergic) neurons of the nuclei raphe (NR) were examined. A control experimental series was carried out on 8 NA-ergic neurons of the LC and 8 ST-ergic neurons of the NR. Bemitil was found to exert opposite effects on the impulse activity of NA-ergic and ST-ergic brainstem neurons; it suppressed impulsation of LC neurons and increased the spiking frequency of NR neurons within certain time intervals after its introduction. Analysis of EEG showed that bemitil decreased the spectral power of the delta and theta activities, which was accompanied by behavioral relaxation.

Emotional arousal and enhanced amygdala activity: New evidence for the old perseveration-consolidation hypothesis

Emotional arousal and enhanced amygdala activity: New evidence for the old perseveration-consolidation hypothesis

Activation of noradrenergic locus coeruleus neurons by clozapine and haloperidol: involvement of glutamatergic mechanisms

The major brain noradrenergic nucleus locus coeruleus (LC) has long been thought to be involved in states of alertness and cognitive processes. These functional characteristics make this nucleus interesting with regard to the signs of schizophrenia, especially the negative symptoms of the disease. In the present in-vivo electrophysiological study we analyse a putative interaction between endogenous kynurenic acid (KYNA) and the antipsychotic drugs clozapine and haloperidol on noradrenergic LC neurons. Previous studies have shown that systemically administered antipsychotic drugs increase the neuronal activity of LC noradrenaline (NA) neurons. In line with these findings, our results show that clozapine (1.25-10 mg/kg i.v.) and haloperidol (0.05-0.08 mg/kg i.v.) increased the firing rate of LC NA neurons in anaesthetized rats. Pretreatment with PNU 156561A (40 mg/kg i.v., 3 h), a potent inhibitor of kynurenine 3-hydroxylase, produced a 2-fold increase in rat brain KYNA levels. This treatment prevented the increase in firing rate of LC NA neurons induced by haloperidol (0.05-0.08 mg/kg i.v.) and clozapine in high doses (2.5-10 mg/kg i.v.). However, the excitatory action of the lowest dose of clozapine (1.25 mg/kg i.v.) was not abolished by elevated levels of brain KYNA. Furthermore, pretreatment with L-701,324 (4 mg/kg i.v.) a selective antagonist at the glycine site of the NMDA receptor prevented the excitatory effects of both clozapine and haloperidol. The present results suggest that the excitation of LC NA neurons by haloperidol and clozapine involves a glutamatergic component.

Neuropharmacological profiles of antagonists of group II metabotropic glutamate receptors

Glutamatergic abnormalities play roles in several psychiatric disorders. Glutamate acts at two classes of receptors, ionotropic and metabotropic glutamate receptors (mGluR), the latter is classified into three group, based on receptor homology and signaling mechanisms. Among them, recent pharmacological and histochemical studies suggest that the group II mGluR (mGluR2 and mGluR3) plays crucial roles in the control of emotional states. We previously reported that MGS0039, a selective group II mGluR antagonist, exhibited dose-dependent antidepressant-like effects in some animal models. However, the mechanism by which group II mGluR antagonists exhibit such effects is still unclear. In the present two studies, we examined neuropharmacological effects of group II mGluR antagonists on monoaminergic neurons. In an electrophysiological study, MGS0039 dose-dependently and significantly increased the firing rate of dorsal raphe nucleus (DRN) serotonergic neurons. LY341495, another group II mGluR antagonist, also increased DRN serotonergic neural activity significantly. Consistent with the findings of this electrophysiological study, MGS0039 significantly increased extracellular level of serotonin in rat medial prefrontal cortex in a microdialysis study. In contrast, MGS0039 had no effect on the activity of locus coeruleus noradrenergic neurons. These findings suggest that modulation of serotonergic neuron might be, at least in part, responsible for the antidepressant-like effects of group II mGluR antagonists.

Patterns of neuronal activation in the rat brain and spinal cord in response to increasing durations of restraint stress

By most accounts the psychological stressor restraint produces a distinct pattern of neuronal activation in the brain. However, some evidence is incongruous with this pattern, leading us to propose that the restraint-induced pattern in the central nervous system might depend on the duration of restraint used. We therefore determined the pattern of neuronal activation (as indicated by the presence of Fos protein) seen in the paraventricular nucleus (PVN), bed nucleus of the stria terminalis, amygdala, locus coeruleus, nucleus tractus solitarius (NTS), ventrolateral medulla (VLM) and thoracic spinal cord of the rat in response to 0, 15, 30 or 60 min periods of restraint. We found that although a number of cell groups displayed a linear increase in activity with increasing durations of restraint (e.g. hypothalamic corticotrophin-releasing factor (CRF) cells, medial amygdala neurons and sympathetic preganglionic neurons of the thoracic spinal cord), a number of cell groups did not. For example, in the central amygdala restraint produced both a decrease in CRF cell activity and an increase in non-CRF cell activity. In the locus coeruleus, noradrenergic neurons did not display Fos in response to 15 min of restraint, but were significantly activated by 30 or 60 min restraint. After 30 or 60 min restraint a greater degree of activation of more rostral A1 noradrenergic neurons was observed compared with the pattern of A1 noradrenergic neurons in response to 15 min restraint. The results of this study demonstrate that restraint stress duration determines the amount and the pattern of neuronal activation seen in response to this psychological stressor.

Involvement of the Noradrenergic System in Performance on a Continuous Task Requiring Effortful Attention

To determine the effects of noradrenergic neuronal activity on performance in continuous tasks requiring effortful attention, the performance of 23 male students in the Uchida-Kraepelin test (UKT) was examined. The UKT requires continuous arithmetic addition of single-digit figures for 25 min. The relationship of performance with saliva levels of 3-methoxy-4-hydroxyphenylglycol (sMHPG) was analyzed. Saliva samples were taken before, during and after test performance, and sMHPG levels determined by gas chromatography-mass spectrometry. There was no significant change in mean sMHPG as a result of test performance. However, when initial effort was calculated, defined as number of items completed during the 1st min subtracted from the average completed per minute in the 1st and the 2nd halves (blocks) of the test, significant correlations with sMHPG (p = 0.0002 for the 1st block and p < 0.0001 for the 2nd block) were found. Thus the data indicate that noradrenergic neuronal activity affects the performance on continuous tasks requiring effortful attention.

Chronic very low dose naltrexone administration attenuates opioid withdrawal expression

Background Different regimens of agonist and antagonist drugs have been used in opioid withdrawal management, with variable results. We examined whether administering extremely small quantities of opiate antagonists in the presence of opiate agonist drugs reduces withdrawal expression. Methods Forty-one male Sprague-Dawley rats were implanted with morphine or placebo pellets for eight days. Starting on day 3, some rats received naltrexone in their drinking water (5 mg/L), or unadulterated water. On day 8, rats were injected with saline or naltrexone (100 mg/kg) and evaluated for behavioral signs of withdrawal. Next, sections through the locus coeruleus (LC) and nucleus of the solitary tract (NTS), brainstem areas exhibiting cellular activation following opiate withdrawal, were processed for c-Fos to detect early gene expression. Finally, the same nuclei were examined for protein kinase A regulatory subunit II (PKA) and phosphorylated cyclic adenosine monophosphate response element binding protein (pCREB), using Western blot analysis. Results Withdrawal was attenuated and c-Fos, PKA, and pCREB expression was decreased in the NTS and LC of rats receiving chronic very low doses of naltrexone. Conclusions Reduction of withdrawal upon chronic very low naltrexone administration may be due in part to decreased activation of brainstem noradrenergic neurons in morphine dependent rats.

Cataplexy-Active Neurons in the Hypothalamus: Implications for the Role of Histamine in Sleep and Waking Behavior

Noradrenergic, serotonergic, and histaminergic neurons are continuously active during waking, reduce discharge during NREM sleep, and cease discharge during REM sleep. Cataplexy, a symptom associated with narcolepsy, is a waking state in which muscle tone is lost, as it is in REM sleep, while environmental awareness continues, as in alert waking. In prior work, we reported that, during cataplexy, noradrenergic neurons cease discharge, and serotonergic neurons greatly reduce activity. We now report that, in contrast to these other monoaminergic “REM-off” cell groups, histamine neurons are active in cataplexy at a level similar to or greater than that in quiet waking. We hypothesize that the activity of histamine cells is linked to the maintenance of waking, in contrast to activity in noradrenergic and serotonergic neurons, which is more tightly coupled to the maintenance of muscle tone in waking and its loss in REM sleep and cataplexy.

Expression of connexins during development and following manipulation of afferent input in the rat locus coeruleus

Synchronous activity of locus coeruleus (LC) neurons during early postnatal development is regulated, in part, by electrotonic coupling. Connexin (Cx) proteins that make up gap junction channels are localized to both neurons and glia in the LC during this period. In adult rats, however, synchrony exists only under certain experimental conditions. The expression of Cx proteins was examined using western blot analysis at several developmental time points. Immunoblot analysis revealed little to no expression of Cx26 while Cx32, Cx43 and Cx36 were present at all time points examined. A progressive increase in Cx43 was identified from the first postnatal week through adulthood. Immunocytochemical detection of Cx36 and Cx43 in adult LC showed that Cx36 was associated with neuronal processes while Cx43 was localized to glia. In adult LC, in vitro intracellular recordings combined with neurobiotin injections confirmed the presence of gap junctional communication albeit to a lesser extent than in early postnatal periods. The degree to which synaptic inputs to LC neurons impact on Cx protein expression was also evaluated. Samples of the LC from rats that received an electrolytic lesion of the amygdala were processed for western blot analysis of Cx36 and Cx43. The predominantly neuronal Cx36 exhibited an increase in expression while the glial Cx43 was unchanged. The present results indicate that, despite subtype-specific changes during development, several Cx proteins are expressed in the adult LC. In addition, manipulating afferent input to the LC, in adult rats, results in increases in neuronal Cx protein levels but not in glial Cx levels suggesting that altering synaptic inputs to the LC may alter synchronous activity in noradrenergic neurons.

Changes of central norepinephrine, beta-endorphin, LEU-enkephalin, peripheral arginine-vasopressin, and angiotensin II levels in acute and chronic phases of sino-aortic denervation in rats.

We and others have demonstrated that impaired arterial baroreceptor reflex (ABR) function is one of the major causes of hypertension-associated end organ damage. The goal of this study was to clarify the potential neuro-humoral mechanisms responsible for impaired ABR-induced end organ damage. The sino-aortic denervated (SAD) rat was used as an animal model of ABR dysfunction. One-week SAD rats were characterized by hypertension, tachycardia, increased norepinephrine content, and decreased beta-endorphin and leu-enkephalin content in hypothalamus and medulla oblongata, and increased plasma levels of arginine-vasopressin. In 18-week SAD rats, the 24-hour average arterial pressure, heart rate, beta-endorphin, and leu-enkephalin content in hypothalamus and medulla oblongata and plasma levels of arginine-vasopressin and angiotensin II were not different from those measured in ABR-intact rats. However, blood pressure variability and angiotensin II content in kidney and left ventricle increased. When exposed to chronic stress, exaggerated changes in arterial pressure, blood pressure variability, the levels of central norepinephrine, beta-endorphin and leu-enkephalin, plasma arginine-vasopressin and angiotensin II, and tissue angiotensin II were found in 18-week SAD rats. These data indicate that a long-term impairment of ABR leads to chronic activation of central noradrenergic neurons and tissue renin-angiotensin system, and that stress induces exaggerated responses of neuro-humoral factors and hemodynamics in SAD rats. Thus, if the present results hold true for humans, one can expect abnormal neurotransmitter/neuromodulator responses to environmental insults in patients with impaired ABR function.