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Biomedical subjects

J Licinio

Publications and source records attributed to J Licinio.

At least 109 records · Page 6Linked to original sources
PubMed1996

Localization of urocortin messenger RNA in rat brain and pituitary.

Pituitary function is regulated by hypothalamic releasing hormones secreted into hypophyseal-portal blood. A new hypothesis is that pituitary function might also be regulated at the local level by releasing hormones synthesized within the pituitary. Here we show that the pituitary expresses high levels of the gene encoding for urocortin. We suggest that urocortin synthesized by the pituitary may modulate pituitary function, and that adrenocorticotropic hormone (ACTH) secretion is dependent on input not only from the hypothalamus as previously described, but it may also be regulated by urocortin synthesized locally. Urocortin binds to the corticotropin-releasing hormone (CRH) receptor type 1 (CRH-R1) with high affinity and potently stimulates pituitary-adrenal function. Our group and others have previously localized high levels of CRH-R1 mRNA in the pituitary. Using a 35S-labeled rat urocortin riboprobe we have now localized urocortin mRNA in rat brain and pituitary. The finding of urocortin gene expression in the pituitary may help explain why proopiomelanocortin (POMC) mRNA levels are not decreased during hypothalamo-pituitary disconnection, and also describes a new level of complexity in the regulation of hypothalamo-pituitary function. Future studies should consider the possibility that pituitary function might be regulated at the local level by urocortin.

Animals↗
PubMed1996

Dysthymia in neurological disorders.

Dysthymia is characterized by long-lasting periods of lowered mood. Epidemiological studies in the USA and Europe have demonstrated that the prevalence of dysthymia is at least 3% of the general population. Its pervasive occurrence makes dysthymia a public health problem worldwide. One feature of this disorder is its co-occurrence with medical and neurological disorders. A World Health Organization meeting on dysthymia in neurological disorders was held in Geneva, 1-3 July 1996 to address this topic. Some of the major goals of this meeting were to clarify the definition of dysthymia in the presence of neurological disorders and to evaluate current research in the field, to point out new areas for investigation, and to discuss current psychological and pharmacological treatments for dysthymia in neurological disorders. The potential roles of neuroendocrine and molecular mechanisms in dysthymia were identified through specific problems related to dysthymia occurring in disorders such as Parkinson's disease, Alzheimer's disease, stroke, multiple sclerosis and epilepsy. This meeting provided direction and opportunity for future studies in the under-recognized and under-investigated relationship between dysthymia and neurological disorders.

Dysthymic Disorder↗
PubMed1995

Corticotropin releasing hormone in the pathophysiology of melancholic and atypical depression and in the mechanism of action of antidepressant drugs.

Hypercortisolism in depression seems to preferentially reflect activation of hypothalamic CRH secretion. Although it has been postulated that this hypercortisolism is an epiphenomenon of the pain and stress of major depression, our data showing preferential participation of AVP in the hypercortisolism of chronic inflammatory disease suggest specificity for the pathophysiology of hypercortisolism in depression. Our findings that imipramine causes a down-regulation of the HPA axis in experimental animals and healthy controls support an intrinsic role for CRH in the pathophysiology of melancholia and in the mechanism of action of psychotropic agents. Our data suggest that hypercortisolism is not the only form of HPA dysregulation in major depression. In a series of studies, commencing in patients with Cushing's disease, and extending to hyperimmune fatigue states such as chronic fatigue syndrome and examples of atypical depression such as seasonal affective disorder, we have advanced data suggesting hypofunction of hypothalamic CRH neurons. These data raise the question that the hyperphagia, hypersomnia, and fatigue associated with syndromes of atypical depression could reflect a central deficiency of a potent arousal-producing anorexogenic neuropeptide. In the light of data presented elsewhere in this symposium regarding the role of a hypofunctioning hypothalamic CRH neuron in susceptibility to inflammatory disease, these data also raise the question of a common pathophysiological mechanism in syndromes associated both with inflammatory manifestations and atypical depressive symptoms. This concept of hypofunctioning of hypothalamic CRH neurons in these disorders also raises the question of novel forms of neuropharmacological intervention in both inflammatory diseases and atypical depressive syndromes.

Adrenocorticotropic Hormone↗
PubMed1995

Focal cerebral ischemia induces CRH mRNA in rat cerebral cortex and amygdala.

Corticotropin-releasing hormone (CRH) antagonism has neuroprotective effects in models of ischemia. We examined CRH mRNA by in situ hybridization in a well-established rat model of focal cerebral ischemia caused by permanent middle cerebral artery occlusion (MCAo). In ischemic cortex CRH mRNA levels were elevated 2.6-fold 60 min after MCAo, compared with sham operated animals. CRH mRNA was also induced in the amygdala, 60 min following ischemia, in a pattern which was qualitatively different from that of sham operated animals. This rapid and profound increase in CRH mRNA levels during focal cerebral ischemia is likely to be associated with neurotoxicity, as CRH antagonism has been reported to cause a significant reduction in neuronal loss during ischemia.

Amygdala↗
PubMed1995

A molecular mechanism for stress-induced alterations in susceptibility to disease.

Corticotropin-releasing hormone (CRH) is a 41-amino acid peptide which mediates behavioural and physiological responses to stress. A major target of CRH is the proopiomelanocortin (POMC) gene. Three transcription factors have been identified that affect transcription of the POMC gene by binding to two different sites within the CRH-responsive element of that promoter. We searched Genbank and found that nucleotide sequences in the POMC promoter which bind POMC-transcription factors are also contained in the genome of HIV-1 and cytomegalovirus, in c-fes and human MAT-1 breast cancer oncogenes, and in proinflammatory molecules, such as the interleukin-1 beta converting enzyme. We hypothesise a mechanism of hormone action by which a peptide hormone, such as CRH, might affect disease susceptibility by eliciting the production of transcription factors which may bind to unexpected intracellular targets, such as viruses, oncogenes, or the genes encoding for inflammatory mediators. Infection, inflammation, and possibly neoplastic transformation would thus be facilitated. This hypothesis can be tested. If confirmed, CRH antagonists may prove useful in the treatment of disorders whose pathophysiology involves molecules that respond to CRH-regulated POMC transcription factors.

Base Sequence↗
PubMed1995

The gene encoding for the novel transacting factor proopiomelanocortin corticotropin-releasing hormone responsive element binding protein 1 (PCRH-REB-1) is constitutively expressed in rat pituitary and in discrete brain regions containing CRH or CRH receptors: pathophysiological implications.

The nucleotide sequence CTGTGCGCGCAG is a core corticotropin-releasing hormone (CRH) responsive element in the proopiomelanocortin (POMC) promoter that gives 5-7 fold stimulation of POMC transcription by CRH. This region binds a novel transacting factor, proopiomelanocortin corticotropin-releasing hormone responsive element binding protein 1 (PCRH-REB-1), recently cloned from CRH-stimulated pituitary cells. We conducted in situ hybridization histochemistry experiments, using a species-specific, antisense, 35S-labeled PCRH-REB-1 riboprobe, to determine the pattern of PCRH-REB-1 gene expression in the brain, and showed that PCRH-REB-1 mRNA is localized not only in pituitary, but it is also found in discrete brain regions such as septal nuclei, hypothalamus, cortex, hippocampus, amygdala, and cerebellum. Those regions contain CRH or CRH receptors, and respond to CRH. We hypothesize that PCRH-REB-1 may be a marker of cellular responsiveness to CRH in the brain and pituitary, and might therefore be useful in the evaluation of CRH function and in the identification of clinically effective CRH agonists and antagonists.

Animals↗
PubMed1994

Effects of sleep deprivation on serotonin function in depression.

There is considerable evidence that antidepressant treatments enhance serotonin (5-HT) function. In order to evaluate whether sleep deprivation (SD) produces alterations in 5-HT function, the increase in prolactin (PRL) produced by intravenous tryptophan (TRP) was assessed in depressed patients following SD and undisturbed sleep (US). Eleven depressed patients received mood ratings and TRP infusions after either SD or US, 1 week apart. In five women, but not six men, the TRP-induced PRL rise was markedly enhanced after SD compared to US. Mood score changes were not significantly different between US and SD and there was no significant relationship of mood changes to the TRP induced PRL response. The data suggests that SD produces an increase in 5HT function in female depressed patients. The lack of identified SD-induced changes in 5-HT function in men may be due to lower sensitivity of the TRP-induced PRL rise in depressed men than women.

Adolescent↗
PubMed1994

Localization of corticotropin-releasing hormone (CRH) receptor mRNA in adult rat brain by in situ hybridization histochemistry.

Even though functional CRH receptors have been identified in several brain regions by ligand binding, the identity of brain areas expressing the CRH receptor gene has not been described. The recent cloning of the rat CRH receptor gene has permitted us to conduct an in situ hybridization histochemistry study to localize CRH receptor mRNA in brain, using an antisense 35S-labeled riboprobe and autoradiography. In virus- and pathogen-free, unstressed, adult male Sprague-Dawley rats we observed CRH receptor gene expression in several brain regions, most of which had been previously shown to bind radiolabeled CRH. Those regions include the pituitary, olfactory bulb, hippocampal formation, cerebral and cerebellar cortexes, hypothalamus, median eminence, amygdala, olfactory tubercle, choroid plexus, thalamus, and inferior colliculus. Further studies are needed to determine the cell types expressing both CRH receptor mRNA and the CRH receptor peptide in nervous system as well as in peripheral tissues.

Animals↗
PubMed1994

Effects of electroconvulsive therapy on the CRH-ACTH-cortisol system in melancholic depression: preliminary findings.

Hypercortisolism is one of the most consistent biological abnormalities seen in patients with major depression, particularly the melancholic subtype. We present preliminary data regarding the effects of electroconvulsive therapy (ECT) on urinary-free cortisol (UFC) excretion and on the secretion of its principal regulatory hormone, corticotropin-releasing hormone (CRH), into the cerebrospinal fluid (CSF) of patients with major depression. Our preliminary results indicate that, while acute elevations in UFC may occur with the initiation of ECT or other antidepressant treatments, successful treatment with ECT is associated with a reduction in both UFC excretion and the diurnal pattern of CSF immunoreactive CRH levels. These findings are compatible with data in experimental animals that show reductions in hypothalamic CRH expression and pituitary-adrenal function with long-term antidepressant treatments.

Adrenocorticotropic Hormone↗
PubMed1993

Activity-induced anorexia in rats does not affect hypothalamic neuropeptide gene expression chronically.

Hypothalamic neuropeptides are thought to contribute to the pathophysiology of eating disorders. In an animal model with chronic abnormalities of energy expenditure, appetitive behavior, and body weight, without acute food restriction, we found alterations in peripheral levels of adrenocorticotropic hormone and corticosterone, but no alterations in the expression of neuropeptides genes that are known to regulate ingestive behavior and food intake acutely. Our data suggest that activation of hypothalamic-pituitary-adrenal function in activity anorexia may not be due to increased transcription of corticotropin-releasing hormone gene, but might be related to posttranscriptional events or to other neuropeptides, such as arginine vasopressin. Furthermore, we suggest that abnormalities in neuropeptides observed in eating disorders may be caused by acute food restriction, rather than by chronic hyperactivity, anorexia, and low weight.

Adrenocorticotropic Hormone↗
PubMed1993

Differential effects of kindled and electrically induced seizures on a glutamate receptor (GluR1) gene expression.

To address the question of whether the mode of seizure induction contributes to the effects of seizures on glutamate receptor gene expression, we examined rat dorsal hippocampal slides by in situ hybridization after kindling by electrical stimulation of the amygdala, or after electrically induced tonic-clonic seizures. Levels of a glutamate receptor subtype (GluR1) mRNA were analyzed at three periods post kindled seizures and found to be decreased only in brains that were obtained 24 h after the last kindled seizure. This downregulation of GluR1 mRNA was transient and was observed only in animals that had behavioral manifestations after being electrically stimulated. It is probable that maintenance of the kindled state cannot be explained by a long-lasting change in GluR1 gene expression. Repeated electroshock-induced seizures increased GluR1 mRNA levels in the hippocampus. Our results show that mode of induction is an important determinant of the effects of seizures on the levels of expression of a glutamate receptor gene.

Analysis of Variance↗
PubMed1993

Elevated CSF levels of interleukin-2 in neuroleptic-free schizophrenic patients.

Levels of CSF fluid interleukin-2, but not interleukin-1 alpha, were found to be higher in 10 neuroleptic-free schizophrenic patients than in 10 healthy subjects matched for sex and age. Because interleukin-2 increases dopaminergic neurotransmission and participates in autoimmunity and cell growth, the authors postulate that elevated levels of central interleukin-2 might contribute to the increased dopaminergic neurotransmission, autoimmune phenomena, and abnormal brain morphology described in some patients with schizophrenia.

Adult↗
PubMed1993

Monoamines and the mechanism of antidepressant action: effects of catecholamine depletion on mood of patients treated with antidepressants.

Brain catecholamines can be rapidly reduced by inhibiting their synthesis with alpha-methyl-para-tyrosine (AMPT). In order to assess the role of catecholamines in antidepressant action AMPT challenges were administered in a double-blind, placebo-controlled, crossover fashion to 14 depressed patients having maintained a therapeutic antidepressant response for > or = 2 weeks (3 desipramine, 2 mazindol, 5 fluoxetine, 4 sertraline). Each patient participated in two challenges one week apart. Each challenge included a baseline, two days of either AMPT or diphenhydramine (active placebo), and a followup. Antidepressant drugs were continued throughout testing. The 3 desipramine- and 2 mazindol-responders had a rapid increase in depression score during AMPT but not placebo (diphenhydramine) challenge whereas only 1 of 9 selective serotonin reuptake inhibitor (SSRI)-treated patients did. The implication of this is that the antidepressant response to desipramine may be more acutely dependent on brain catecholamine content than the response to SSRIs. In the context of our previous work with tryptophan depletion, these results suggest that the neurobiological mechanisms underlying the antidepressant responses to different drugs involve alterations in the functioning of different neurotransmitter systems and reinforce the importance of changes in both the serotonin and catecholamine systems for successful antidepressant responses.

Adult↗
PubMed1992

Induction of constitutive heat shock protein 73 mRNA in the dentate gyrus by seizures.

We examined the effects of generalized seizures on heat shock protein (hsp) mRNA induction in the rat brain using in situ hybridization. Seizures induced by electroconvulsive shock, electrical or cocaine kindling caused a selective induction of the constitutive hsp 73 gene in the dentate gyrus. In these seizure paradigms, not thought to induce widespread tissue damage, neither the heat-inducible hsp 72 gene nor a member of the hsp 90 family (hsp 84) were induced. Hsp 73 may play a role in the adaptation and/or in the maintenance of dentate granule cell integrity following seizures.

Amygdala↗
PubMed1992

Neutrophil-activating peptide-1/interleukin-8 mRNA is localized in rat hypothalamus and hippocampus.

Neutrophil-activating peptide-1/interleukin-8 (NAP-1/IL-8) is a cytokine synthesized by various cell types. In the immune system NAP-1/IL-8 is part of an immune cascade initiated by IL-1 production. NAP-1/IL-8 affects hypothalamic function and its production is suppressed by steroids. Therefore, it might be expected that NAP-1/IL-8 would be produced in brain areas involved in the control of the hypothalamic-pituitary-adrenocortical axis (HPA). NAP-1/IL-8 mRNA was localized by in situ hybridization in the paraventricular nucleus of the hypothalamus and hippocampus. Those areas also express the genes encoding interleukin-1-alpha (IL-1 alpha), IL-1 beta, IL-1 receptors, and IL-1 receptor antagonist (IL-1ra). This suggests that an immune cascade, which is well characterized in the immune system, may exist in brain, in areas of relevance to the regulation of stress-related neuroendocrine function.

Animals↗
PubMed1992

Acute tryptophan depletion: a method of studying antidepressant action.

Serotonin (5-HT) has been implicated in the pathophysiology of depressive syndromes and in the mechanism of antidepressant drug action. Rapid dietary depletion of tryptophan (TRP) provides a paradigm for studying the role of 5-HT in depressed patients. Drug-free depressed patients do not show mood changes during TRP depletion but about one third have a clinically apparent, transient improvement in mood on return to normal TRP intake. Depressed patients in clinical remission after 6 to 8 weeks of antidepressant therapy experience a transient depressive relapse during acute TRP depletion. The significance of these findings will be discussed. Tryptophan depletion in other psychiatric syndromes will also be reviewed.

Antidepressive Agents↗