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R J Valentino

Publications and source records attributed to R J Valentino.

At least 19 recordsLinked to original sources
PubMed1999

Glucocorticoid receptor-immunoreactivity in corticotrophin-releasing factor afferents to the locus coeruleus.

The stress-related neurohormone, corticotropin-releasing factor (CRF), also acts as a neurotransmitter to activate the brain noradrenergic nucleus, locus coeruleus (LC). Previous electrophysiological findings demonstrating that tonic CRF secretion in the LC is increased in adrenalectomized rats suggest that activity of certain CRF afferents to the LC is under inhibitory regulation by endogenous corticosteroids. The present study was designed to identify putative CRF afferents to the LC that may be regulated by glucocorticoids. Retrograde tract tracing from the rat LC and pericoerulear regions was combined with immunohistochemistry to visualize CRF and glucocorticoid receptors in the same sections of rat brain. The retrograde tracer, wheat germ agglutinin conjugated to horseradish peroxidase coupled to gold (WGA-Au-HRP) was injected into either the nucleus LC or the rostrolateral pericoerulear region (peri-LC), where CRF-immunoreactive terminals have been demonstrated to synapse with LC dendrites. Sections were processed to visualize the tracer, as well as CRF- and glucocorticoid receptor-immunoreactivity. Following injections of WGA-Au-HRP into the nuclear LC, triple labeled neurons were observed primarily in Barrington's nucleus, where 74+/-4% of retrogradely labeled CRF-immunoreactive neurons colocalized glucocorticoid receptor immunoreactivity. In contrast, injections that incorporated the rostrolateral peri-LC retrogradely labeled numerous neurons that were immunoreactive for both CRF and glucocorticoid receptors in the central nucleus of the amygdala. Thus, 94+/-2% of the retrogradely labeled CRF-immunoreactive neurons in the central nucleus of the amygdala colocalized glucocorticoid receptor immunoreactivity. Additionally, triple labeled neurons were observed in the bed nucleus of the stria terminalis following WGA-Au-HRP injections that incorporated the rostrolateral peri-LC. The present results implicate Barrington's nucleus, the central nucleus of the amygdala and the bed nucleus of the stria terminalis as glucocorticoid-sensitive sources of CRF that can influence the LC-noradrenergic system. Alterations in glucocorticoid levels or glucocorticoid receptor function would be predicted to affect the impact of these specific CRF systems on LC activity.

Amygdala↗
PubMed1999

Pontine regulation of pelvic viscera: pharmacological target for pelvic visceral dysfunctions.

The pathophysiology and pharmacological targets of disorders of the bladder and colon have focused predominantly on the periphery. However, these viscera are regulated by the CNS, which, in turn, must integrate their functions with compatible behaviours. This review focuses on the role of the pontine micturition centre, Barrington's nucleus, as a key to this integration. Through its efferent network this pontine centre links parasympathetic preganglionic neurones with forebrain-projecting nuclei, providing an anatomical substrate for coregulation of pelvic visceral and forebrain activity. Disorders characterized by multiple pelvic visceral symptoms and comorbidity with psychiatric disorders (for example functional bowel disorders) might have their roots in dysfunctions of this circuit, which could provide a novel target for pharmacological treatment.

Animals↗
PubMed1999

Long-term regulation of locus ceruleus sensitivity to corticotropin-releasing factor by swim stress.

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.

Action Potentials↗
PubMed1998

Novel role for the pontine micturition center, Barrington's nucleus: evidence for coordination of colonic and forebrain activity.

This report provides evidence for a novel role of Barrington's nucleus, considered the pontine micturition center, in regulation of colonic function. Barrington's activation elicited increases in colonic intraluminal pressure that were eliminated by scopolamine and intrathecal lidocaine, suggesting an impact of Barrington's neurons on colonic activity via projections to lumbosacral parasympathetic neurons. Consistent with this, Barrington's neurons were transsynaptically labeled from the distal colon by pseudorabies virus and several of these were also retrogradely labeled from the locus coeruleus, which projects extensively to the forebrain. Thus, Barrington's nucleus is strategically positioned to coordinate colonic and forebrain activity. Dysfunctions within this divergent system may underlie the frequent comorbidity of colonic and psychiatric symptoms.

Animals↗
PubMed1998

Lack of sensitization to the effects of d-amphetamine and apomorphine on sensorimotor gating in rats.

This study assessed whether repeated injections of d-amphetamine or apomorphine could induce sensitization to the disruptive effects of these psychomotor stimulants on sensorimotor gating in rats. In the first experiment, rats were given six pre-exposures to either 2.0 mg/kg d-amphetamine or saline before being tested for the effects of d-amphetamine (0.0, 0.5, 1.0, 2.0 or 4.0 mg/kg, i.p.) on prepulse inhibition of acoustic startle (PPI) and locomotor activity. The tests for PPI confirmed that sensorimotor gating could be disrupted by a high dose of d-amphetamine (4.0 mg/kg). However, comparison of the dose-response curves for the drug and saline pre-exposed groups did not reveal evidence for sensitization to this d-amphetamine effect in drug-pre-exposed rats, despite indications that sensitization had developed to the locomotor stimulant effects of d-amphetamine. A similar pattern of results was obtained in a second experiment that examined the effects of apomorphine (0.0, 0.1, 0.2, 0.4 and 0.8 mg/kg, s.c.) on PPI and locomotion in rats pre-exposed to 2.0 mg/kg of this drug or its vehicle. These findings demonstrate that treatments which induce sensitization to the behavioral activating effects of psychomotor stimulants do not necessarily produce sensitization to the disruptive effects of stimulants on sensorimotor gating. The implications of these results for hypotheses linking sensitization-like processes to the etiology of schizophrenia are discussed.

Animals↗
PubMed1998

Effects of corticotropin-releasing factor on brain serotonergic activity.

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.

Animals↗
PubMed1998

Amygdaloid corticotropin-releasing factor targets locus coeruleus dendrites: substrate for the co-ordination of emotional and cognitive limbs of the stress response.

Corticotropin-releasing factor (CRF), the neurohormone that initiates the endocrine limb of the stress response via its actions on the anterior pituitary, also acts as a neurotransmitter in the noradrenergic locus coeruleus (LC) to activate this system during stress. Because the central nucleus of the amygdala contains numerous CRF-immunoreactive neurones, the present study examined whether CRF projections from the central nucleus of the amygdala target LC dendrites, thereby providing a mechanism for limbic-CRF modulation of brain noradrenergic activity. Retrograde tracers injected into the rostrolateral pericoerulear region, where CRF-immunoreactive fibres are dense, labelled numerous CRF-immunoreactive neurones in the central nucleus of the amygdala. Consistent with this, ultrastructural analysis of the rostrolateral pericoerulear region in sections that were dually labelled for an anterograde tracer (biotinylated dextran amine, BDA) injected into the central nucleus of the amygdala and CRF immunoreactivity revealed that a substantial percentage (35%) of amygdaloid axon terminals were CRF-immunoreactive. These terminals formed synaptic specializations with unlabelled dendrites that were more often of the asymmetric (excitatory) type. Additionally, ultrastructural analysis of sections that were dually labelled to visualize CRF-and tyrosine hydroxlase-immunoreactivity demonstrated synaptic specializations between CRF-immunoreactive terminals and LC dendrites in the rostrolateral peri-LC, which were also frequently asymmetric. Taken together with previous ultrastructural findings that LC dendrites in the rostrolateral pericoerulear region are targeted by anterogradely labelled terminals from the central nucleus of the amygdala, the present results implicate this nucleus as a source of CRF that can impact on LC activity via effects on dendrites in the rostrolateral pericoerulear region. This cellular substrate for amygdaloid-CRF modulation of brain noradrenergic activity may serve as a mechanism for the integration of emotional and cognitive responses to stress.

Amygdala↗
PubMed1997

Locus coeruleus activation by colon distention: role of corticotropin-releasing factor and excitatory amino acids.

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.

Animals↗
PubMed1997

Regulation of a putative neurotransmitter effect of corticotropin-releasing factor: effects of adrenalectomy.

This study tested the hypothesis that endogenous glucocorticoids regulate a putative neurotransmitter function of corticotropin-releasing factor (CRF) in the locus coeruleus (LC). LC spontaneous discharge and activation by intracerebroventricularly administered CRF, hypotensive challenge, sciatic nerve stimulation, and carbachol were compared in adrenalectomized and sham-operated halothane-anesthetized rats. LC spontaneous discharge was higher in adrenalectomized versus sham-operated rats. Intracoerulear microinfusion of a CRF antagonist decreased LC discharge rates of adrenalectomized rats to rates comparable with those observed in sham-operated rats but had no effect in sham-operated rats. The CRF dose-response curve was shifted in a complex manner in adrenalectomized rats, suggesting that a proportion of CRF receptors were occupied before CRF administration, and low doses of CRF were additive. Higher doses of CRF produced effects that were greater than predicted by simple additivity. Hypotensive challenge increased LC discharge rates of adrenalectomized rats by a magnitude greater than that predicted on the basis of additivity. In contrast, LC responses to carbachol and sciatic nerve stimulation were similar in both groups. The results suggest that adrenalectomy enhances tonic and stress-induced CRF release within the LC and also alters postsynaptic sensitivity of LC neurons to CRF. Because adrenalectomy also alters release of neurohormone CRF, the present study suggests that CRF actions as a neurohormone and as a neurotransmitter in the LC may be co-regulated. Such parallel regulation may underlie the coexistence of neuroendocrine and noradrenergic dysfunctions in stress-related psychiatric disorders.

Adrenalectomy↗
PubMed1997

Activation of the locus coeruleus noradrenergic system by intracoerulear microinfusion of corticotropin-releasing factor: effects on discharge rate, cortical norepinephrine levels and cortical electroencephalographic activity.

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.

Animals↗
PubMed1996

Enhanced norepinephrine release in prefrontal cortex with burst stimulation of the locus coeruleus.

The present study was designed to determine the relationship between the discharge of noradrenergic locus coeruleus (LC) neurons and norepinephrine release in the medial prefrontal cortex, a target of LC projections. The LC was electrically stimulated at varying frequencies and patterns for 20 min and extracellular norepinephrine levels were measured in the medial prefrontal cortex of halothane-anesthetized rats using in vivo microdialysis. Electrical stimulation of the LC at 3-10 Hz with an evenly spaced pattern of pulses (tonic stimulation) increased cortical norepinephrine levels in a frequency-dependent manner, with 5- and 10-Hz stimulation increasing norepinephrine levels by 49 +/- 3% and 66 +/- 20%, respectively. The LC was also stimulated with bursts of pulses designed to deliver physiologically relevant phasic stimulation using the same number of stimuli in a 20-min period as delivered by tonic stimulation at 3 Hz. Results revealed that norepinephrine levels were significantly higher with phasic stimulation compared to tonic stimulation. The present findings indicate that both frequency and pattern of LC discharge are determinants of norepinephrine terminal release. Additionally, bursts of LC activity, similar to those that occur in behaving animals, may be more effective in increasing terminal norepinephrine release on a per spike basis than tonic increases in activity.

Animals↗
PubMed1996

Evidence for divergent projections to the brain noradrenergic system and the spinal parasympathetic system from Barrington's nucleus.

The present study was designed to determine whether Barrington's nucleus, which lies ventromedial to the locus coeruleus (LC) and projects to the sacral parasympathetic nucleus, is a source of afferent projections to the LC. Restricted injections of the anterograde tracer, biocytin, into Barrington's nucleus labeled varicose fibers that extended from the injection site into the LC. Consistent with this, injections of the retrograde tracers, wheatgerm agglutinin conjugated to horseradish peroxidase coupled to gold particles (WGA-Au-HRP) or fluorescein-conjugated latex beads, into the LC labeled numerous (approximately 10%) Barrington's neurons that were also retrogradely labeled by Fluoro-Gold (FG) injections in the spinal cord. Retrograde tracing from the LC combined with corticotropin-releasing hormone (CRH) immunohistochemistry revealed that at least one third of the retrogradely labeled neurons in Barrington's nucleus were CRH-immunoreactive (CRH-IR). Finally, in triple labeling studies, CRH-Barrington's neurons were consistently observed that were retrogradely labeled from both the and spinal cord. These findings implicate Barrington's nucleus as an LC afferent and a source of CRH-IR fibers in the LC. Additionally, the results suggest that some Barrington's neurons diverge to innervate both the spinal cord and the LC. This divergent innervation may serve to coregulate the sacral parasympathetic nervous system and brain noradrenergic system, thus providing a mechanism for coordinating pelvic visceral functions with forebrain activity.

Afferent Pathways↗
PubMed1996

Corticotropin-releasing factor-containing axon terminals synapse onto catecholamine dendrites and may presynaptically modulate other afferents in the rostral pole of the nucleus locus coeruleus in the rat brain.

Physiological and immunohistochemical studies have suggested that corticotropin-releasing factor (CRF), the hypophysiotropic peptide that initiates endocrine responses to stress, may serve as a neurotransmitter to activate noradrenergic neurons in the nucleus locus coeruleus (LC). We combined immunoperoxidase labeling for CRF and immunogold-silver localization of the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) in single sections through the rat LC to determine potential substrates for interactions between these two transmitters. Light microscopic analysis indicated that CRF processes are dense and highly varicose in the rostral LC region in the vicinity of noradrenergic dendrites. Electron microscopy of this rostral region revealed that immunoperoxidase labeling for CRF was mainly restricted to axons and axon terminals and was rarely seen in somata or dendrites. Axon terminals containing CRF immunoreactivity varied in size, content of synaptic vesicles, and formation of synaptic specializations. The postsynaptic targets of the CRF-labeled axon terminals consisted of both TH-labeled dendrites and dendrites lacking detectable TH-immunoreactivity. Of 113 CRF-immunoreactive axon terminals, approximately 70% were in direct contact with TH-labeled and unlabeled dendrites. Of the CRF-labeled axon terminals forming synapses with TH-labeled and unlabeled dendrites, they were either of the asymmetric (excitatory type; 19%) or symmetric (inhibitory type; 11%) variety or did not form identifiable contacts in the plane of section analyzed. Unlabeled axon terminals and glial processes were also commonly located adjacent to the plasma membranes of CRF-labeled axon terminals. These results provide the first direct ultrastructural evidence that axon terminals containing CRF-immunoreactivity 1) directly contact catecholamine-containing dendrites within the rostral pole of the LC, 2) may presynaptically modulate other afferents, and 3) are often enveloped by astrocytic processes.

Animals↗
PubMed1995

Evidence for corticotropin-releasing hormone projections from Barrington's nucleus to the periaqueductal gray and dorsal motor nucleus of the vagus in the rat.

The present study used anterograde and retrograde tract tracing and immunohistochemistry to determine the efferent projections of corticotropin-releasing hormone (CRH) neurons of Barrington's nucleus in the rat. Injections of Phaseolus vulgaris-leucoagglutinin into Barrington's nucleus resulted in anterograde labeling in the dorsal motor nucleus of the vagus, periaqueductal gray, medial thalamic nuclei, lateral hypothalamus, paraventricular nucleus of the hypothalamus, lateral preoptic area, and lateral septum. The retrograde tract tracer, fluorogold, injected into the lumbosacral spinal cord labeled many, but not all, CRH-immunoreactive neurons in Barrington's nucleus. Moreover, some Barrington's neurons that were retrogradely labeled from the spinal cord were not CRH-immunoreactive. Several CRH-immunoreactive Barrington's neurons were retrogradely labeled by fluorogold injections into the periaqueductal gray, and these were located predominantly in the dorsal part of the nucleus. Additionally, some CRH-immunoreactive Barrington's neurons were retrogradely labeled from fluorogold injections into the dorsal motor nucleus of the vagus. In contrast, fluorogold injections into the lateral hypothalamus, lateral preoptic area, or lateral septum did not result in double labeling of CRH-immunoreactive neurons in Barrington's nucleus. These results suggest that many, but not all, CRH-containing neurons of Barrington's nucleus project to the lumbosacral spinal cord. In addition to their previously documented projections to the spinal cord, these neurons may be a source of CRH in the periaqueductal gray and dorsal motor nucleus of the vagus. CRH projections of Barrington's nucleus may play a role in behavioral or autonomic aspects of stress responses, in addition to their proposed role in micturition.

Animals↗
PubMed1995

Central regulation of micturition in the rat the corticotropin-releasing hormone from Barrington's nucleus.

Barrington's nucleus, a pontine nucleus implicated in micturition, contains numerous corticotropin-releasing hormone (CRH) neurons that project to the spinal parasympathetic nucleus that innervates the bladder. We now report that CRH from Barrington's nucleus may serve to inhibit micturition. Selective chemical activation of Barrington's nucleus by microinjection of glutamate evoked bladder contractions that were increased in magnitude after intrathecal administration of a CRH antagonist, D-PheCRH12-41. In contrast, intrathecally administered CRH decreased the magnitude of Barrington's stimulated bladder contractions. These results suggest that activation of Barrington's nucleus releases an excitatory neurotransmitter responsible for bladder contractions, and CRH, which inhibits this neurotransmitter. The balance between these two neuromediators may regulate bladder contractility, and thereby, urinary continence.

Animals↗
PubMed1995

Previous stress alters corticotropin-releasing factor neurotransmission in the locus coeruleus.

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.

Animals↗