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Biomedical subjects

L S Brady

Publications and source records attributed to L S Brady.

At least 19 recordsLinked to original sources

Studies of cerebrospinal fluid flow and penetration into brain following lateral ventricle and cisterna magna injections of the tracer [14C]inulin in rat.

Parasynaptic communication, also termed volume transmission, has been suggested as an important means to mediate information transfer within the central nervous system. The purpose of the present study was to visualize by autoradiography the available channels for fluid movement within the extracellular space following injection of the inert extracellular marker [14C]inulin into the lateral ventricle or cisterna magna. Bolus injections of 5 microl of 1 microCi of [14C]inulin were made in awake rats via chronically implanted cannulae. After survival times ranging from 5 min to 4 h, brains were processed for in vivo autoradiography. At 5 min the tracer distributed throughout the ventricles, subarachnoid spaces and cisterns "downstream" of the injection sites. Penetration into the brain from these sites was complex with preferential entry along the ventral side of the brain, especially into the hypothalamus and brainstem. By 4 h virtually the entire brain was labeled irrespective of the site of tracer application. Sustained tracer entry from subarachnoid spaces suggests that some areas act as depots to trap circulating material. This mechanism may contribute to the pattern of deep penetration at later time-points. The spatial and temporal characteristics of fluid movement throughout the brain are instructive in the interpretation of many experimental procedures involving injection of molecules into the cerebrospinal fluid.

Animals↗

Region-specific up-regulation of opioid receptor binding in enkephalin knockout mice.

Mu and delta opioid receptors were labeled in enkephalin knockout mice by quantitative autoradiography. Discrete, large increases (100-300%) were found in limbic forebrain structures for mu binding and striatum and pallidum for delta binding. The up-regulation of opioid receptors may reflect a form of 'denervation supersensitivity. ' The receptor up-regulation in limbic areas is consistent with the increased emotional and aggressive behaviors observed in the enkephalin knockout mice.

Animals↗

Opioid receptor ligand binding in the human striatum: II. Heterogeneous distribution of kappa opioid receptor labeled with [3H]bremazocine.

Selective kappa opioid receptor autoradiography with [3H]bremazocine (BRM) was used to examine regional and subregional kappa receptor distribution patterns at five rostrocaudal levels through the human striatum. [3H]BRM binding densities were measured in the individual striatal nuclei and in subregions therein. The distribution of [3H]BRM binding sites was found to have a strongly heterogeneous character. At the regional level a rostral-to-caudal decrease in [3H]BRM binding densities was observed. Also, a dorsal-to-ventral differentiation was seen, with higher values in the ventral striatum, especially in the nucleus accumbens, and lower values in the dorsal parts of the caudate nucleus and putamen. These findings suggest an association of kappa receptor function with limbic-related processes in the ventral striatum. Along the ventral edge of the nucleus accumbens and putamen, specific domains with extremely high [3H]BRM binding values were identified.

Adult↗

Unilateral LTP triggers bilateral increases in hippocampal neurotrophin and trk receptor mRNA expression in behaving rats: evidence for interhemispheric communication.

Induction of long-term potentiation (LTP) in the dentate gyrus of awake rats triggered a rapid (2 hour) elevation in tyrosine kinase receptor (trkB and trkC) gene expression and a delayed (6-24 hour) increase in brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) gene expression. Depending on the mRNA species, LTP induction led to highly selective unilateral or bilateral increases in gene expression. Specifically, trkB and NT-3 mRNA elevations were restricted to granule cells in the ipsilateral dentate gyrus, whereas bilateral increases in trkC, BDNF, and nerve growth factor (NGF) mRNA levels occurred in granule cells and hippocampal pyramidal cells. Both unilateral and bilateral changes in gene expression were N-methyl-D-aspartate (NMDA) receptor-dependent and LTP-specific. Bilateral electrophysiological recordings demonstrated that LTP was unilaterally induced; this was corroborated by a dramatic unilateral increase in the expression of the immediate early gene zif/268, a marker for LTP, restricted to the ipsilateral granule cells. The results indicate that LTP triggers an interhemispheric communication manifested as selective, bilateral increases in gene expression at multiple sites in the hippocampal network. Furthermore, our findings suggest that physiological plastic changes in the adult brain may involve coordinated, time-dependent regulation of multiple neurotrophin and trk receptor genes.

Animals↗

Densitometrical analysis of opioid receptor ligand binding in the human striatum--I. Distribution of mu opioid receptor defines shell and core of the ventral striatum.

Changes in opioid neurotransmission have been implicated in several basal ganglia-related neurological and psychiatric disorders. To gain a better insight into the opioid receptor distribution in the normal human striatum, we examined in post mortem brain the distribution of the mu opioid receptor using ligand binding of [3H]O-ala2-N-methyl-phe4, gly-ol5-enkephalin. Our results indicate at the regional level the presence of a dorsal-to-ventral high-to-low density gradient in the striatum, with lowest densities in the ventral one-third of the putamen and in the nucleus accumbens. At the subregional level, the nucleus accumbens shows two major types of heterogeneities. First, low vs intermediate binding densities distinguish the core and shell subdivisions, respectively. The low-density core and intermediate-density shell regions extend into the putamen and are therefore characteristic for the entire ventral striatum. The second type of heterogeneity is formed by small areas located along the ventral contours of the nucleus accumbens and putamen that display the highest binding density of the entire striatum. Since these areas can also be recognized in the distribution patterns of other markers and in the cytoarchitecture, they appear to possess a separate identity. To emphasize their special neurochemical characteristics we propose the description "neurochemically unique domains in the accumbens and putamen". The present results, with the difference between core and shell of the ventral striatum as the most prominent outcome, together with the notion that the connectional relationships and neurochemical organization of the striatum are very heterogeneous, suggest a strong regional functional differentiation for mu receptor function in the human striatum.

Adult↗

Effects of long-term treatment with antidepressant drugs on proopiomelanocortin and neuropeptide Y mRNA expression in the hypothalamic arcuate nucleus of rats.

Antidepressant drugs have in common a delayed onset of clinical efficacy. In rats, long-term, daily administration of four different types of clinically effective antidepressant drugs results in decreased corticotropin releasing hormone (CRH) mRNA expression levels in the hypothalamic paraventricular nucleus (PVN). Because a subpopulation of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (Arc) projects to the PVN, we measured NPY and POMC mRNA expression in the Arc using in situ hybridization histochemistry at several time points following daily administration of four different antidepressant drugs. After 14 and 56 days of imipramine treatment, Arc NPY mRNA levels are decreased to 85% and 75% of control levels, but are unchanged compared to control after one or five days of treatment. Arc POMC mRNA levels are unchanged compared to controls at 1, 5, 14, or 56 days following imipramine treatment. Unlike after imipramine, Arc NPY and POMC mRNA levels are increased significantly to 134-172% of control following 56-day treatment with the antidepressant drugs fluoxetine, phenelzine, or idazoxan. The divergent effects of imipramine vs the other 3 antidepressant drugs on Arc NPY mRNA expression are similar to the pattern of changes in tyrosine hydroxylase (TH) mRNA expression levels in the locus coeruleus (LC) using the same experimental paradigm, but are different from the unidirectional depressive effects of all four drugs on CRH mRNA expression in the PVN. Thus, the Arc NPY and LC noradrenergic systems may act coordinately in mediating antidepressant effects. The present data are consistent with the delayed onset of clinical efficacy for antidepressant drugs, and suggest that Arc NPY and POMC neurotransmitter systems play a role in the pathophysiology of depression.

Adrenergic alpha-Antagonists↗

Age and gender influence basal and stress-modulated hypothalamic-pituitary-thyroidal function in Fischer 344/N rats.

To investigate possible gender- and age-associated changes of the hypothalamic-pituitary-thyroid (HPT) axis at baseline and during stress, we studied healthy young (3-month) and old (23-month) female 344/N Fischer rats at the basal state and after 2 h of immobilization (IMMO), in parallel to age-matched male rats. At baseline, there were no major differences on HPT axis functions between young female and male animals. Old age was associated with impaired central thyroid function in both genders, albeit to a much lesser extent in females than in males. Plasma prolactin (PRL) levels were similar in young females and males but were higher in old females than males. IMMO inhibited HPT axis functions in both genders in young, but not old animals. Thus, plasma TSH and hypothalamic TRH mRNA levels were decreased by IMMO in young, but not in old rats of both genders. IMMO increased plasma PRL in young and old males, but did not have any effect in young and old females. In summary, these data indicate that age and gender exert diverse effects on HPT axis functions at baseline and after stress.

Age Factors↗

Chronic social stress increases levels of preprogalanin mRNA in the rat locus coeruleus.

Galanin is a 29 amino acid neuropeptide that coexists with norepinephrine in approximately 80% of locus coeruleus (LC) neurons in the rat. The effects of chronic, naturalistic stress on preprogalanin mRNA in the LC was studied. The visible burrow system (VBS) served as the stress paradigm. Long-Evans rats (three males and two females) were housed together in the VBS for 13 days. The males established dominance hierarchies during this period. On day 14, preprogalanin mRNA in the LC was significantly elevated in subordinate rats compared to dominant and control rats, as measured by quantitative in situ hybridization. Levels of mRNA were positively correlated with the number of wounds by day 7 and day 14 and negatively correlated with body weight gain by day 14. These results suggest that the neuropeptide galanin may be overexpressed during chronic stress in rats.

Animals↗

Stress-induced inhibition of the hypothalamic-pituitary-thyroid axis is attenuated in the aged Fischer 344/N male rat.

Aging is associated with a progressive decrement in the basal activity of the hypothalamic-pituitary-thyroid axis in male Fischer 344/N rats. The aim of this study was to determine whether stress influences the activity of this axis in young and old rats. As prolactin and growth hormone share some regulatory mechanisms with thyrotropin-releasing and thyroid-stimulating hormones, which are influenced by stress, the plasma levels of these two hormones were also determined during immobilization (Immo). To accomplish this, young (3-month-old) and old (23-month-old) male 344/N Fischer rats were immobilized for 2 h; blood was collected by cannulation from the tail artery at different intervals during Immo (0, 5, 30, 60, and 120 min), and brains were removed at the end of Immo. The basal plasma levels of thyroid-stimulating hormone were similar in both groups, but were significantly and progressively inhibited by Immo in young, but not in old rats. The baseline plasma levels of total triiodothyronine were slightly lower in old than in young rats; Immo caused a significant decrease of total triiodothyronine levels only in the young animals. The baseline plasma levels of free triiodothyronine were similar and were not altered by Immo in either age group. The paraventricular nucleus thyrotropin-releasing hormone mRNA levels were lower in old than in young rats under basal conditions; under stress they were significantly inhibited in young, but remained unchanged in old rats. The basal thyroid-stimulating hormone beta mRNA levels in the anterior pituitary were significantly lower in old than in young rats, but were not affected by Immo in either age group. The plasma prolactin levels were similar at baseline and were significantly increased by Immo in both age groups, but significantly more in old than in young rats. The plasma growth hormone levels were also similar at baseline; they were significantly decreased by Immo to a similar extent in both age groups. In summary, these data indicate that the stress-induced decrease in plasma thyroid-stimulating hormone is in part mediated at the level of the hypothalamic thyrotrophin-releasing hormone neuron and that this phenomenon is attenuated in the aged rat.

Age Factors↗

Decreased stress responsivity of central and peripheral catecholaminergic systems in aged 344/N Fischer rats.

We investigated the effects of stress on central and peripheral sympatho-adrenal and sympatho-neural functions in healthy, intact young (3-4 mo) and aged (24 mo) male Fischer 344/N rats. Extracellular fluid (ECF) levels of the catecholamines norepinephrine (NE), dihydroxyphenylglycol (DHPG), methoxyhydroxyphenylglycol (MHPG), and dihydroxyphenylacetic acid (DOPAC) were obtained by microdialysis in the paraventricular nucleus (PVN) of the hypothalamus at baseline and during immobilization (IMMO). The baseline levels of these substances were similar in both age groups, and their concentrations increased significantly in response to IMMO. The IMMO-induced increases of NE and MHPG, however, were significantly smaller in old than in young rats. Plasma levels of the catecholamines NE, DHPG, MHPG, DOPAC, dihydroxyphenylalanine (DOPA), epinephrine (EPI), dopamine (DA), and HVA were also determined in young and old rats during IMMO. Basal levels of these substances were significantly higher in old than in young rats. The magnitude of the IMMO-induced increases in the majority of these compounds however, was significantly smaller in old than in young rats. We conclude that, at the basal state, aging in the Fischer rat is associated with normal PVN ECF, but high plasma catecholamine levels; at stress state, however, old rats have substantially lesser activation of their central and peripheral catecholaminergic systems than young rats.

Adrenergic Fibers↗

Evidence for two neurochemical divisions in the human nucleus accumbens.

The neurochemical anatomy of the human nucleus accumbens was studied by comparing the distributional patterns of [3H]DAMGE (mu opioid receptor), [3H]bremazocine (kappa opioid receptor), [3H]SCH-23390 (D1-like dopamine receptor), [3H]7-OH-DPAT (D3 dopamine receptor) binding, preproenkephalin mRNA and acetylcholinesterase activity in sections of post mortem human striatum. Our results demonstrate the presence of at least two neurochemically distinct divisions within the human nucleus accumbens, which may be homologous to the 'shell' and 'core' divisions of the nucleus as found in the rat.

Acetylcholinesterase↗

Hypothalamic lesions increase levels of neuropeptide Y mRNA in the arcuate nucleus of mice.

A recent study demonstrated that hypothalamic lesions induced by goldthioglucose (GTG) in mice produced an increase in neuronal immunoreactivity for neuropeptide Y (NPY) in the hypothalamic arcuate nucleus. Since NPY is a potent stimulator of feeding, this increase represented a potential explanation for the hyperphagia seen after GTG lesions. To examine whether or not this increase in NPY immunoreactivity was accompanied by an increase in the mRNA for NPY, in situ hybridization histochemistry for NPY mRNA in control and in lesioned mice was performed. A 47% increase in NPY mRNA levels in the arcuate nucleus was observed in lesioned mice compared with controls, suggesting that an increased expression of the gene for NPY contributes to elevations in hypothalamic NPY after lesioning. This elevation in NPY may, in turn, relate to mechanisms provoking hyperphagia.

Animals↗

Regulation of HSP90 and corticosteroid receptor mRNA by corticosterone levels in vivo.

The non-activated 9S forms of several steroid hormone receptors are heterooligomeric complexes consisting of the aporeceptor and three heat shock proteins, hsp90, hsp70 and hsp56. Hsp90 appears to play a facilitatory role in high-affinity steroid binding and to promote the efficacy of steroid actions on target tissues. Circulating glucocorticoid levels have a major regulatory impact on the binding capacity of hippocampal and hypothalamic corticosteroid receptors, a phenomenon that affects the activity of the hypothalamic-pituitary-adrenal axis and neuronal excitability in general. This study demonstrates that hsp90 mRNA is present in substantial amounts in hippocampal and hypothalamic areas characterized by high densities of corticosteroid receptors, and in the thymus. Steady-state levels of hsp90 mRNA in these regions were altered by chronic changes of circulating glucocorticoid concentrations in a site-specific fashion. In the hippocampus, mRNAs coding for hsp90 and both types of corticosteroid receptors (type I, MR and type II, GR) displayed a coordinate increase following adrenalectomy and castration (ADX/GX); in the hypothalamus only hsp90 mRNA levels were elevated, and none of the parameters studied was affected in the thymus by steroid hormone deprivation. Supplementation of ADX/GX rats with various doses of corticosterone in vivo elicited differential responses. Moderate elevation of circulating corticosterone levels normalized ADX/GX-increased hsp90 mRNA concentrations in the hippocampus and the hypothalamic paraventricular nucleus (PVN); this was associated with similar changes in GR and MR mRNA levels in the hippocampus, while GR mRNA concentrations in the PVN were not altered.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗

Stress, antidepressant drugs, and the locus coeruleus.

This review presents a synthesis of a large body of seemingly inconsistent literature on the role of the locus coeruleus-norepinephrine (LC-NE) system and the corticotropin-releasing hormone (CRH)-median eminence system in mediating the CNS effects of stress and the therapeutic effects of antidepressant drugs. The clinical implications of these findings for the etiology and treatment of stress-related psychiatric disorders such as depression will be discussed.

Animals↗

1,1'-Ethylidenebis[L-tryptophan], a contaminant implicated in L-tryptophan eosinophilia myalgia syndrome, suppresses mRNA expression of hypothalamic corticotropin-releasing hormone in Lewis (LEW/N) rat brain.

The L-tryptophan eosinophilia myalgia syndrome (L-Trp-EMS), related to ingestion of impure L-Trp, occurred in epidemic proportions in the United States in 1989. Epidemiologic studies implicated 1,1'-ethylidenebis[L-tryptophan] (EBT) as the impurity most highly associated with development of human L-Trp-EMS. We have previously shown that Lewis (LEW/N) rats fed L-Trp implicated in the L-Trp-EMS epidemic (case-associated L-Trp) develop fasciitis and perimyositis which is associated with a reduction in corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus (PVN). In this study, we report the effects of EBT- and case-associated L-Trp on CRH mRNA expression in the hypothalamic PVN and secretion of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) into the plasma over a time course of 1-6 weeks in the same rats in which we have found fascial thickening and immune cell activation induced by these compounds. Both control L-Trp and EBT stimulated the secretion of ACTH and CORT at 1-2 weeks, whereas case-associated L-Trp did not. EBT and case-associated L-Trp decreased CRH mRNA expression in the PVN at 2-6 weeks, while control L-Trp had no effect. The striking contrast in the effects of case-associated L-Trp and EBT on the HPA axis suggests that the reduction in CRH mRNA levels in the PVN seen in each case may be related to different mechanisms. It is possible that EBT suppresses CRH mRNA expression directly, in the absence of inflammation, while case-associated L-Trp may act through multiple mechanisms, including that associated with inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Repeated electroconvulsive shock produces long-lasting increases in messenger RNA expression of corticotropin-releasing hormone and tyrosine hydroxylase in rat brain. Therapeutic implications.

Electroconvulsive shock (ECS) is a highly effective therapy for the treatment of major depression, but its mechanisms of action are not known. We report that repeated ECS in rats produces enduring changes in two clinically relevant stress-responsive brain systems: (a) the hypothalamic-pituitary-adrenal axis regulated by corticotropin-releasing hormone (CRH) in the paraventricular nucleus; and (b) the NE system in the locus coeruleus regulated by tyrosine hydroxylase (TH). CRH and TH mRNA levels in these brain regions were assessed by in situ hybridization histochemistry. A single interaural ECS elevated TH but not CRH mRNA measured 24 h later. Repeated daily treatments (3, 7, or 14) elevated both mRNAs, maximally with 7, correlating with the time course of clinical efficacy. The elevations persisted for 3 (CRH) or 8 wk (TH) after the ECS. No other therapeutic treatment is known to produce such long-lasting changes in central nervous system gene expression. The time course of events (delayed onset, long duration) implicate CRH as a principal mediator of the antidepressant effects of ECS. The locus coeruleus-NE system may be important in initiating the central nervous system response.

Analysis of Variance↗

Male Fischer 344/N rats show a progressive central impairment of the hypothalamic-pituitary-adrenal axis with advancing age.

We investigated the effects of aging on the regulation of hypothalamic-pituitary-adrenal function and hippocampal steroid receptors in a series of in vivo and in vitro studies conducted in healthy intact 2-, 8-, 18-, and 24-month-old male Fischer 344/N rats. Basal plasma ACTH levels were similar among age groups, and basal plasma corticosterone levels showed a significant aging-associated decline. Two i.v. doses (2 and 20 micrograms/kg BW) of rat CRF elicited significantly greater and delayed ACTH and greater corticosterone responses in older rats, consistent with the pattern encountered in hypothalamic CRF deficiency. In contrast, the i.v. injection of a muscarinic agonist, arecoline, elicited similar ACTH and corticosterone responses in all age groups. An i.v. injection of ACTH-(1-24) evoked lower corticosterone responses in the older (18- and 24-month-old) than in the younger (2- and 8-month-old) groups of rats, consistent with an impairment of hypothalamic-pituitary-adrenal axis function in older animals. Steady state mRNA levels of mineralocorticoid and glucocorticoid receptors were significantly decreased in the hippocampus of the 8-, 18-, and 24-month-old rats, compatible with maturational, rather than senescent, changes. CRF mRNA levels in the paraventricular nucleus of the hypothalamus, CRF content, and in vitro secretion by whole explanted hypothalami were progressively and significantly reduced with age, whereas the steady state levels of arginine vasopressin mRNA were significantly increased with age. Steady state levels of POMC mRNA were decreased, and ACTH content and in vitro secretion by corticotrophs were increased with age in the anterior pituitary. We conclude that male Fischer 344/N rats show a progressive hypothalamic CRH deficiency with advancing age, which appears to be associated with elevated production of arginine vasopressin in the hypothalamus.

Adrenocorticotropic Hormone↗