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Hypotensive stress engages corticotropin-releasing factor (CRF) release within the rat locus coeruleus (LC), which activates LC neurones, initiating norepinephrine release in forebrain and activation of forebrain electroencephalographic activity. This study identified CRF afferents to the LC that are engaged during hypotensive stress. One of two potential CRF afferents, the central nucleus of the amygdala (CNA) or bed nucleus of the stria terminalis (BNST), was electrolytically lesioned and LC activation during hypotensive stress was quantified. Neither lesion altered LC spontaneous discharge rate or activation by intra-LC administered CRF. By contrast, LC activation by hypotensive stress was greatly attenuated in CNA-lesioned, but not BNST-lesioned, rats. Hypotensive stress-induced changes in transcriptional activation were immunohistochemically identified in CRF neurones that were retrogradely labelled from the LC region. c-fos immunoreactivity was prevalent in the paraventricular nucleus of the hypothalamus (PVN), CNA and BNST. However, only the PVN contained a substantial number of neurones that were doubly immunolabelled for CRF and c-fos, and few of these were retrogradely labelled from the LC. By contrast, immunoreactivity for the phosporylated form of cyclic AMP response-element binding protein (PCREB) was prevalent in CRF neurones in the CNA and BNST. Moreover, approximately one-third of the PCREB-expressing CRF neurones in the CNA were retrogradely labelled from the LC. These electrophysiological and anatomical findings implicate the CNA as a primary source of CRF that activates the LC during hypotensive stress. Additionally, CREB phosphorylation, rather than c-fos induction, is associated with hypotensive activation of CRF-CNA neurones that project to the LC.

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The locus coeruleus (LC)-noradrenergic system, which has been implicated in arousal and attention, is activated by visceral stimuli such as colon and bladder distension. Neurons of Barrington's nucleus (the pontine micturition center) have been identified which project to both the LC and preganglionic column of the lumbosacral spinal cord. Thus, Barrington's nucleus is positioned to coordinate brain noradrenergic activity with pelvic visceral functions. The aim of this study was to determine whether LC activation by colonic distension was mediated by projections from Barrington's nucleus to the LC in the rat. Lesions of Barrington's nucleus were performed unilaterally by local injection of ibotenic acid (microg/microl, 90 nl) 10 days prior to recording: (i) ipsilateral spontaneous LC discharge rate; (ii) LC responses to colonic distension; and (iii) LC responses to sciatic nerve stimulation. In some rats LC activation by hypotensive challenge was also examined. Lesions of Barrington's nucleus significantly reduced LC activation by colon distension from a magnitude of 26.6+/-6% increase in discharge rate (n=8) to 6.9+/-3% (n=6), while having no effect on basal LC discharge rate. In contrast, LC responses to sciatic nerve stimulation were not altered in rats with lesions of Barrington's nucleus and LC neurons were still activated by hypotensive challenge. These results support the hypothesis that Barrington's nucleus selectively relays input from pelvic visceral afferents to the LC. This may serve as a limb in a circuit designed to coordinate central and peripheral responses to pelvic visceral stimuli.

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Endogenous opioids target noradrenergic locus ceruleus (LC) neurons and potently inhibit LC activity. Nonetheless, it has been difficult to demonstrate functional regulation of the LC-noradrenergic system by endogenous opioids because of the lack of effect of opiate antagonists. The present findings provide evidence that endogenous opioids regulate LC neuronal activity during the termination of a stressor. LC neuronal discharge was recorded from halothane-anesthetized rats before, during, and after hypotensive stress elicited by intravenous nitroprusside infusion. In naive rats, mean arterial blood pressure was temporally correlated with LC activity such that hypotension was associated with increased LC discharge and a return to the normotensive state was associated with a decrease in LC discharge below pre-stress values. After microinfusion of an antagonist of the stress neuropeptide corticotropin-releasing factor (CRF) into the LC, the increase in LC discharge associated with hypotension was prevented, whereas LC inhibition associated with termination of the challenge occurred at an earlier time and was of a greater magnitude. In contrast, microinfusion of naloxone into the LC completely abolished LC inhibition associated with termination of the stressor. Naloxone microinfusion did not prevent LC inhibition associated with hypertension produced by intravenous vasopressin administration, suggesting that endogenous opioids may be selectively engaged during the termination of hypotensive stress. These results provide evidence for a functional release of endogenous opioids within the LC. This action of endogenous opioids may serve to counterbalance excitatory effects of CRF on the LC-norepinephrine system, thereby limiting its activation by stress.

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Corticotropin-releasing factor (CRF) acts as a putative neurotransmitter in the locus ceruleus (LC) to mediate its activation by certain stressors. In this study, we quantified LC sensitivity to CRF 24 h after swim stress, at a time when behavioral depression that is sensitive to antidepressants is apparent. Rats were placed in a tank with 30 cm (swim stress) or 4 cm water and 24 h later, either behavior was monitored in a forced swim test or LC discharge was recorded. Swim stress rats were more immobile than control animals in the swim test. LC neurons of swim stress rats were sensitized to low doses of CRF (0.1-0.3 microgram i.c.v.) that were ineffective in control animals and were desensitized to higher doses. Swim stress selectively altered LC sensitivity to CRF because neither LC spontaneous discharge nor responses to other agents (e.g., carbachol, vasoactive intestinal peptide) were altered. Finally, the mechanism for sensitization was localized to the LC because neuronal activation by low doses of CRF was prevented by the intracerulear administration of a CRF antagonist. CRF dose-response curves were consistent with a two-site model with similar dissociation constants under control conditions but divergent dissociation constants after swim stress. The results suggest that swim stress (and perhaps other stressors) functionally alters CRF receptors that have an impact on LC activity. Stress-induced regulation of LC sensitivity to CRF may underlie behavioral aspects of stress-related psychiatric disorders.

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The serotonergic dorsal raphe nucleus is innervated by corticotropin-releasing factor (CRF) and expresses CRF receptors, suggesting that endogenous CRF impacts on this system. The present study characterized interactions between CRF and the dorsal raphe serotonin (5-HT) system. The effects of intracerebroventricularly (i.c.v.) administered CRF on microdialysate concentrations of 5-HT in the lateral striatum of freely moving rats were determined. CRF had biphasic effects, with 0.1 and 0.3 microgram decreasing, and 3.0 micrograms increasing 5-HT dialysate concentrations. i.c.v. administration of CRF inhibited neuronal activity of the majority of dorsal raphe neurons at both low (0.3 microgram) and high (3 micrograms) doses. Likewise, intraraphe administration of CRF (0.3 and 1.0 ng) had predominantly inhibitory effects on discharge rate. Together, these results suggest that CRF is positioned to regulate the function of the dorsal raphe serotonergic system via actions within the cell body region. This regulation may play a role in stress-related psychiatric disorders in which 5-HT has been implicated.

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The present study was designed to elucidate the neurotransmitters involved in activation of the noradrenergic nucleus, locus coeruleus, by distention of the distal colon. Locus coeruleus spontaneous discharge rate was recorded from halothane-anesthetized rats before, during and after distention of the colon produced by inflation of a balloon catheter with varying volumes of water. Locus coeruleus activation by colon distention was volume-dependent and reversible. Activation of cortical electroencephalographic activity was temporally correlated with locus coeruleus activation during colon distention and prolonged distention (greater than 2 min) resulted in tachyphalaxis to both locus coeruleus and cortical electroencephalographic activation. The corticotropin-releasing factor antagonist, DPheCRF(12-41), administered intracerebroventricularly (3 microg) or microinfused into the locus coeruleus (10 ng) significantly attenuated locus coeruleus activation produced by lower, but not higher magnitudes of colon distention, implicating corticotropin-releasing factor afferents to the locus coeruleus in this response. Consistent with this, prior exposure to 30 min of footshock stress, which desensitizes locus coeruleus neurons to corticotropin-releasing factor, produced a similar attenuation of locus coeruleus activation by low, but not high magnitudes of distention. Kynurenic acid, administered intracerebroventricularly (5 micromol), significantly antagonized locus coeruleus activation by all magnitudes of colon distention. However, this excitatory amino acid antagonist was ineffective when administered directly into the locus coeruleus (0.3 nmol). Together, these findings suggest that low magnitudes of colon distention activate the locus coeruleus-noradrenergic system via corticotropin-releasing factor release within the locus coeruleus and that excitatory amino acid neurotransmission at a site distal to the locus coeruleus is necessary for this response. Activation of the locus coeruleus-noradrenergic system during colon distention may serve as a cognitive limb of the peripheral parasympathetic response. This activation may also play a role in disorders characterized by comorbidity of colonic and psychiatric symptoms, such as irritable bowel syndrome.

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Corticotropin-releasing factor (CRF) administered intracerebroventricularly (i.c.v.) activates noradrenergic locus coeruleus (LC) neurons of halothane-anesthetized and unanesthetized rats. This study used a technique for microinfusing CRF into the LC from calibrated micropipettes to characterize and quantify the effects of locally administered CRF on LC discharge in halothane-anesthetized rats. CRF (3-100 ng) microinfusion into the LC increased discharge rate in a dose-dependent manner from 28 +/- 8 to 105 +/- 26% above preinfusion discharge rates. The CRF dose-response curve generated by local microinfusion was parallel to, and shifted approximately 200-fold to the left, of that generated by i.c.v. administration. Intracoerulear microinfusion of the CRF antagonist, [DPhe12,Nle(21,38),CalphaMeLeu37]r/hCRF(12-41), greatly attenuated LC activation produced by a maximally effective dose of i.c.v. administered CRF, suggesting that these effects are primarily due to actions within the LC. In rats in which both LC discharge rate and norepinephrine levels in prefrontal cortex were measured by in vivo microdialysis, CRF microinfused into the LC increased both endpoints. Finally, LC activation produced by CRF (60 ng) microinfusion into the LC was associated with cortical electroencephalographic activation. Taken together with previous anatomical and electrophysiological evidence for endogenous CRF interactions in the LC, our results support the hypothesis that CRF serves as an excitatory neurotransmitter in the LC, and suggest that its actions on LC neurons are translated to enhanced norepinephrine release and an impact on cortical targets.

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Spontaneous and stress-evoked discharge of locus coeruleus neurons were characterized in rats with a history of stress. Rats exposed to one or five daily 30-min sessions of footshock were anesthetized with halothane and surgically prepared for locus coeruleus single-unit recording immediately following the last session. Locus coeruleus spontaneous discharge rate and discharge evoked by sciatic nerve stimulation were comparable between acutely and repeatedly stressed rats and controls. In contrast, locus coeruleus activation produced by intracerebroventricular administration of corticotropin-releasing factor (3 micrograms) or by hypotensive challenge (which requires endogenous corticotropin-releasing factor release in the locus coeruleus) was greatly attenuated in acutely stressed rats. The corticotropin-releasing factor dose-response curve was shifted to the right in acutely stressed rats compared with controls. In repeatedly stressed rats, the effects of 3 micrograms corticotropin-releasing factor on locus coeruleus discharge were similarly diminished. Although the maximum effect produced by corticotropin-releasing factor was decreased in these rats, the dose-response curve was shifted to the left, indicative of sensitization. Hypotensive challenge, which was ineffective in acutely stressed rats, increased locus coeruleus discharge of repeatedly stressed rats by a similar magnitude as in matched controls. The return of locus coeruleus responsiveness to hypotension in repeatedly stressed rats may be related to the sensitization to corticotropin-releasing factor. Finally, the protocol of repeated stress did not alter the affinity or density of corticotropin-releasing factor receptors in either the frontal cortex or brainstem. Taken together, the results suggest that a history of stress alters corticotropin-releasing factor neurotransmission in the locus coeruleus at the postsynaptic level. However, these effects are not reflected by corticotropin-releasing factor binding kinetics in brainstem. Stress-induced changes in corticotropin-releasing factor neurotransmitter function in the locus coeruleus may play a role in certain symptoms of stress-related psychiatric disorders.

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The present study compared the effects of two analogs of corticotropin-releasing factor (CRF), [D-Phe12,Nle21,38, C alpha MeLeu37]CRF12-41 (D-PheCRF12-41) and alpha helical CRF9-41, as antagonists of CRF in in vivo and in vitro assays. In halothane-anesthetized rats, intracerebroventricular (i.c.v.) administration of both analogs inhibited the activation of locus coeruleus (LC) neuronal discharge produced by CRF (3.0 micrograms, i.c.v.). LC activation by hypotensive stress elicited by intravenous (i.v.) infusion of nitroprusside was antagonized by the same doses of the CRF antagonists that were effective in antagonizing CRF, suggesting that the receptors involved in LC activation by CRF and by hypotensive stress are similar. However, D-PheCRF12-41 was approximately 100 times more potent than alpha helical CRF9-41 when administered i.c.v. The IC50 values for D-PheCRF12-41 as an antagonist of CRF and of nitroprusside were 0.16 and 0.14 microgram, i.c.v., respectively. The IC50 values for alpha helical CRF9-41 as an antagonist of CRF and of nitroprusside were 18 and 27 micrograms, i.c.v., respectively. In contrast, D-PheCRF12-41 was only slightly more potent than alpha helical CRF9-41 in antagonizing CRF-stimulated cyclic AMP production in rat brain homogenates, with IC50s of 78 +/- 15 and 260 +/- 30 nM for D-PheCRF12-41 and alpha helical CRF9-41, respectively. Moreover, the antagonists had similar affinities for CRF binding sites in rat brain homogenates, with Kis of 15.5 +/- 4 nM and 10.3 +/- 6 nM for D-PheCRF12-41 and alpha helical CRF9-41, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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Hypersecretion of corticotropin-releasing factor (CRF), has been hypothesized to occur in depression. Because CRF may serve as a neurotransmitter in the locus coeruleus (LC), it was proposed that CRF hypersecretion in the LC is responsible for some characteristics of depression, and that antidepressants act by interfering with CRF neurotransmission in the LC. To test this hypothesis, the acute and chronic effects of four antidepressants and cocaine were characterized on LC spontaneous and sensory-evoked discharge, LC activation by a stressor that requires CRF release, and LC activation by exogenously administered CRF. None of the antidepressants or cocaine altered LC activation by intracerebroventricularly administered CRF (3.0 microgram) after chronic administration. However, chronic administration of desmethylimipramine and mianserin inhibited LC activation by a hypotensive stress that requires endogenous CRF release, suggesting that they decrease CRF release in the LC. Chronic administration of sertraline and phenelzine altered LC responses to repeated sciatic nerve stimulation in a manner opposite to the effect produced by CRF, suggesting that these drugs may functionally antagonize CRF actions in the LC. Cocaine did not appear to interfere with CRF actions in the LC. In conclusion, chronic administration of antidepressants may have the potential to interfere with CRF neurotransmission in the LC.

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The present study characterized and quantified the effects of systemically administered cocaine on spontaneous, sensory-evoked and stress-elicited activity of noradrenergic locus coeruleus (LC) neurons of anesthetized and unanesthetized rats. Cocaine (0.1-3.0 mg/kg, i.v.) decreased LC spontaneous discharge rate and discharge evoked by repeated sciatic nerve stimulation in halothane-anesthetized rats. In unanesthetized rats cocaine (0.3-10.0 mg/kg, i.v.) also decreased LC spontaneous discharge rate and LC discharge evoked by repeated auditory stimulation. However, analysis of variance revealed a statistically significant shift to the right in the cocaine dose-response curves for effects on tonic and evoked LC discharge in unanesthetized compared to anesthetized rats. Thus, cocaine was somewhat less potent in inhibiting tonic and evoked discharge of unanesthetized rats compared to anesthetized rats. In anesthetized rats cocaine (1.0 mg/kg) did not affect LC activation by intracerebroventricularly (i.c.v.) administered corticotropin-releasing factor (3.0 micrograms in 3.0 microliters) or by hemodynamic stress elicited by i.v. nitroprusside infusion. The present findings demonstrate that cocaine has similar effects on LC neurons of anesthetized and unanesthetized rats but that it is less potent in unanesthetized rats. These effects of cocaine at noradrenergic cell bodies acting in concert with its effects at noradrenergic terminals in LC target regions may be important in the overall action of cocaine on arousal and cortical information processing.

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The effects of hypotensive stress elicited by nitroprusside infusion on discharge activity of noradrenergic locus coeruleus (LC) neurons of unanesthetized rats were characterized. Nitroprusside (75 micrograms/30 microliters/min, 15 min IV infusion) decreased mean arterial pressure of unanesthetized rats by 50 +/- 2 mmHg (n = 5). Simultaneous recordings of LC spontaneous discharge revealed an increase in discharge rate (197 +/- 87%) that was associated with hypotension. A lower concentration of nitroprusside (10 micrograms/30 microliters/min) that decreased blood pressure of halothane-anesthetized rats by 55 +/- 2 mmHg was much less effective in producing hypotension and did not increase LC discharge when administered to unanesthetized rats. Prior administration of the CRF antagonist, alpha helical CRF9-41 (50 micrograms, ICV) greatly attenuated LC activation by nitroprusside. These findings demonstrate that LC activation elicited by nitroprusside is dependent on the magnitude of hypotension. The present results also demonstrate that nitroprusside is a less potent hemodynamic challenge in unanesthetized rats. Finally, LC activation associated with nitroprusside administration to unanesthetized rats is mediated to a large extent by CRF, confirming findings in anesthetized rats.

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The present study was designed to determine whether activation of locus coeruleus (LC) neurons by hemodynamic stress is mediated by local release of corticotropin-releasing factor (CRF) within the LC. The ability of local LC injection of the CRF antagonist, alpha helical CRF9-41, to prevent LC activation elicited by i.v. nitroprusside infusion was investigated in halothane-anesthetized rats. Nitroprusside infusion (10 micrograms/30 microliters/min for 15 min) consistently increased LC spontaneous discharge rate with the mean maximum increase of 32 +/- 5% (n = 8) occurring between 3 and 9 min after the initiation of the infusion. Prior local LC injection of alpha helical CRF9-41 (150 ng), but not of saline (150 nl), prevented LC activation by nitroprusside. Alpha helical CRF9-41 did not alter LC spontaneous discharge rate or LC discharge evoked by repeated sciatic nerve stimulation suggesting that the CRF antagonist selectively attenuates stress-elicited LC activation. In contrast to alpha helical CRF9-41, the excitatory amino acid antagonist, kynurenic acid, did not attenuated LC activation by nitroprusside at a dose (0.5 mumol in 5 microliters, i.c.v.) that prevented LC activation by sciatic nerve stimulation. Taken together, these findings suggest that hemodynamic stress elicited by nitroprusside infusion activates LC neurons by releasing CRF within the LC region. The onset of LC activation by nitroprusside was temporally correlated with electroencephalographic (EEG) activation recorded from the frontal cortex and hippocampus. EEG activation was characterized by a change from low frequency, high amplitude activity to high frequency low amplitude activity recorded from the cortex and theta rhythm recorded from the hippocampus. LC activation usually outlasted the EEG activation. Nitroprusside infusion following local LC injection of alpha helical CRF9-41 was also associated with EEG activation in most rats. However, the duration of hippocampal theta rhythm was shorter in rats administered alpha helical CRF9-41. Thus, LC activation during cardiovascular challenge may play some role in EEG activation but is not necessary for this effect.

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Neuroendocrine and catecholamine dysfunctions in depression may be linked by corticotropin-releasing factor (CRF) effects on locus coeruleus (LC) neurons. One consequence of CRF hypersecretion in depression would be persistent elevated levels of LC discharge and diminished responses to phasic sensory stimuli. The hypothesis that antidepressants could reverse these changes was tested by characterizing effects of pharmacologically distinct antidepressants on LC sensory-evoked discharge, LC activation by stress, and LC activation by CRF. The most consistent effect of all of the antidepressants tested was a decrease in LC sensory-evoked discharge after acute administration. However, tolerance occurs to these effects after chronic administration. With chronic administration each of the antidepressants produced effects which could potentially interfere with CRF function in the LC. Desmethylimipramine and mianserin attenuated LC activation by a stressor which requires endogenous CRF, suggesting that these antidepressants attenuate stress-elicited release of CRF and perhaps the hypersecretion that occurs in depression. The serotonin reuptake inhibitor, sertraline (SER), enhanced the signal-to-noise ratio of the LC sensory response, an effect opposite to that of CRF. Thus, SER could serve as a functional antagonist of CRF that is hypersecreted in depression. The finding that three pharmacologically distinct antidepressants share the potential to interfere with CRF function in the LC implies that this may be an important common mechanism for antidepressant activity.

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Corticotropin-releasing factor (CRF) has been implicated as a neurotransmitter in the noradrenergic nucleus, locus coeruleus (LC), and is thought to be hypersecreted in depression. Therefore, the hypothesis that antidepressants interfere with CRF neurotransmission in the LC was tested. The acute and chronic effects of desmethylimipramine (DMI), sertraline (SER), phenelzine (PHE), mianserin (MIA), and cocaine (COC) were quantified on LC spontaneous discharge, LC sensory-evoked discharge, LC activation by intracerebroventricular (i.c.v.)-administered CRF, and LC activation by stress in halothane-anesthetized rats. No consistent effect of the drugs on LC spontaneous discharge rate or sensory responsiveness was observed after acute administration. LC spontaneous discharge rates in rats chronically administered the drugs were similar to rates recorded in matched controls, with the exception of PHE and COC. In these rats, LC spontaneous discharge rates were lower than those of untreated rats. Interestingly, LC responses to repeated sciatic nerve stimulation (as measured by the ratio of evoked-to-tonic LC discharge rate) were enhanced in rats chronically administered SER and PHE. This is opposite to the reported effects of i.c.v.-administered CRF. This was not observed with chronic administration of DMI, MIA, or COC. The most striking effect associated with chronic administration of DMI and MIA was the attenuation of LC activation by hemodynamic stress. Because this activation requires CRF release in the LC region, and because none of the antidepressants altered LC activation by i.c.v.-administered CRF, the data suggest that chronic administration of either antidepressant, DMI or MIA, results in attenuation of stress-elicited CRF release in the LC.(ABSTRACT TRUNCATED AT 250 WORDS)

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Corticotropin-releasing factor (CRF), which may serve as a neurotransmitter in the noradrenergic nucleus, locus coeruleus (LC), has been postulated to be hypersecreted in depression. The present study was designed to test the hypothesis that antidepressants interfere with CRF putative neurotransmission in the LC. The acute and chronic effects of the atypical antidepressant mianserin on LC spontaneous discharge, LC sensory-evoked discharge, LC activation by a stressor which requires endogenous CRF, and LC activation by ICV CRF were characterized in halothane-anesthetized rats. Acute IV administration of mianserin (0.0001-1.0 mg/kg) increased LC spontaneous discharge and decreased LC discharge evoked by repeated sciatic nerve stimulation in a dose-dependent manner. Additionally, mianserin (0.1 mg/kg) inhibited LC activation by hemodynamic stress (IV infusion of nitroprusside) and by ICV administration of CRF (3.0 micrograms). In rats chronically administered mianserin LC spontaneous and sensory-evoked discharge rates, and LC activation by CRF were similar to those of untreated rats or rats chronically administered saline. Moreover, acute IV administration of mianserin (0.1 mg/kg) to rats chronically treated with mianserin was less effective in altering LC spontaneous and sensory-evoked discharge. In contrast, LC activation by hemodynamic stress was still greatly attenuated in rats chronically administered mianserin. This is similar to the previously reported effect produced by chronic administration of the antidepressant, desmethylimipramine. The present results demonstrate that acute administration of low doses of mianserin attenuates LC activation by a variety of stimuli and suggest that tolerance develops with chronic administration to some of the effects of mianserin on LC discharge characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)

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Corticotropin-releasing factor (CRF), the hormone responsible for adrenocorticotropin release during stress, is thought to be hypersecreted in depression. Because recent studies suggest that CRF may serve as a neurotransmitter in the major noradrenergic nucleus, locus coeruleus (LC), it was hypothesized that antidepressants interfere with the putative neurotransmitter role of CRF in the LC by either: 1) decreasing release of CRF; 2) pharmacologically antagonizing CRF; or 3) functionally antagonizing CRF by producing effects on LC cells that oppose these of CRF. In order to test this hypothesis, the effects of acute and chronic administration of two antidepressants, a norepinephrine re-uptake inhibitor (desmethylimipramine, DMI) and a serotonin re-uptake inhibitor (sertraline, SER), on LC spontaneous discharge, LC sensory evoked discharge, LC activation by a stressor and LC activation by CRF, were compared in halothane-anesthetized rats. Acute i.v. administration of DMI decreased both LC spontaneous discharge and discharge evoked by repeated sciatic nerve stimulation. In contrast, acute i.v. SER administration decreased only evoked LC discharge rate. Chronic DMI administration (10.0 mg/kg/day, i.p., 21 days) resulted in tolerance to its effects on spontaneous and sensory-evoked LC discharge. However, chronic DMI administration attenuated LC activation by hemodynamic stress, which is thought to require CRF release. LC activation by intracerebroventricular CRF was not altered in the chronic DMI rats. In contrast to DMI, chronic SER (10 mg/kg/day, i.p., 21 days) did not alter LC activation by either stress of CRF. However, the response of LC cells to repeated sciatic nerve stimulation was somewhat enhanced in chronic SER rats. This is an effect that is opposite that produced by CRF.(ABSTRACT TRUNCATED AT 250 WORDS)

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In the present study, the nature, role and location of the alpha-adrenoceptors, modulating the tooth pulp stimulation (TPS)-evoked jaw-opening reflex (JOR), was investigated. Clonidine, a lipophilic alpha 2-adrenoceptor agonist, rapidly, reversibly and significantly elevated the threshold of the digastric electromyogram (dEMG) evoked by tooth pulp stimulation which was antagonized by yohimbine or piperoxane (two alpha 2-adrenoceptor antagonists) but not by prazosin (an alpha 1-adrenoceptor antagonist). 4-Hydroxyclonidine and ST-91 non lipophilic alpha 2 adrenoceptor agonists, were ineffective on the tooth pulp stimulation-evoked threshold of the digastric electromyogram. Clonidine was ineffective upon digastric muscle stimulation (DMS)-evoked threshold of the digastric electromyogram of the curarized digastricus and mylohyoid (motor) nerve stimulation (MNS)-evoked digastric EMG. It is concluded that modulation by clonidine of the tooth pulp stimulation-evoked jaw-opening reflex is devoid of a peripheral efferent component and that such modulation is predominantly expressed through interactions with centrally located alpha 2 adrenoceptors.

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The ability of alpha adrenoceptor agonists to modulate the tooth pulp stimulation evoked (TPS) jaw-opening reflex (JOR) was investigated in rats and rabbits. Low doses of clonidine (6.25-50 micrograms/kg, IV) significantly increased dEMG thresholds. These effects were antagonized by alpha 2 adrenoceptor antagonists (e.g., yohimbine), but not by alpha 1 adrenoceptor antagonists (e.g., prazosin) or mu receptor antagonists (e.g., naloxone). Polar alpha 2 adrenoceptor agonists (e.g., ST-91 and 4-hydroxyclonidine) that cross the blood brain barrier (BBB) poorly and lipophilic alpha 1 adrenoceptor agonists (e.g., ST-587) that cross the BBB easily were without affect on the TPS-JOR. Structures of the peripheral efferent neurocircuitry of the JOR (e.g., the digastric muscle and the neuromuscular junction of the digastric muscle and its motor nerve, the mylohyoid) were shown not to be active sites of clonidine's effect on the TPS-JOR. Treatment with phentolamine (an alpha adrenoceptor antagonist that poorly crosses the BBB) completely poorly crosses the BBB) completely antagonized clonidine's initial transient cardiovascular (pressor) effect without altering its TPS-JOR effects. Pretreatment with reserpine (a catecholamine depleting agent) failed to alter clonidine's affects on the TPS-JOR. Our studies suggest that alpha 2 adrenoceptors potently modulate the TPS-JOR and such modulation may be important in understanding trigeminal neuronal circuitries that partake in pain processing.

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