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PubMedDate not supplied

Predominant involvement of mu-rather than delta- or kappa-opiate receptors in LH secretion.

Opiate alkaloids and opioid peptides have been shown to suppress plasma LH and FSH levels via a naloxone sensitive mechanism in several species including man. Three subtypes of opiate receptors have been characterized: mu, delta and kappa. The present study was designed to investigate their role in gonadotropin release. Three highly selective opioid ligands, DAGO, MRZ and DTE12 (a dimeric tetrapeptide enkephalin), were injected intraventricularly into chronically ovariectomized rats. Injection of the mu-agonist at doses of 1 and 10 nmol produced a significant suppression of LH secretion, while the delta- and kappa-agonists had no significant effect. Thus, the mu-receptor seems to be the primary opiate receptor involved in the regulation of LH secretion. None of the opiate agonists employed had an effect on FSH secretion.

Animals↗

PubMed1999

Fra-1 immunoreactivity in the rat brain during normal postnatal development and after injury in adulthood.

Fra-1 is a member of the Fos family whose functional role in the central nervous system is little understood. In the present study, Fra-1 immunoreactivity is examined in the rat brain during normal development and after different injuries in adulthood, by using Western blotting and immunohistochemistry. Western blots show a band at p35 which corresponds to the molecular weight of Fra-1. During postnatal development, Fra-1 immunoreactivity is observed in nerve fibers of all the main fiber tracts in the cerebrum, whereas Fra-1 immunoreactivity in adult rats is restricted to the hippocampus, mainly the molecular layer of the dentate gyrus and the mossy fiber layer. After administration of colchicine, an axonal transport inhibitor, Fra-1 immunoreactivity accumulates in the perikarya of many cerebral neurons, including those of the dentate gyrus, hippocampus, cerebral cortex, amygdala and thalamus. Fra-1 immunoreactivity is also found in the nuclei of reactive astrocytes, as revealed with double-labeling immunohistochemistry to Fra-1 and GFAP, following either intraperitoneal injection of kainic acid at convulsant doses, intrastriatal injection of quinolinic acid, or intraventricular injection of colchicine. These results suggest a cytoplasmic role for Fra-1 in the neurons, whereas the localization of Fra-1 in the nuclei of reactive astrocytes suggests a participation of this transcription factor in the activation of the AP-1 sequence of selected genes in the early glial response after different brain lesions.

Aging↗

PubMed1980

Riboflavin homeostasis in the central nervous system.

The mechanisms by which riboflavin, which is not synthesized in mammals, enters and leaves brain, CSF, and choroid plexus were investigated by injecting [14C]riboflavin intravenously or intraventricularly. Tracer amounts of [14C]riboflavin with or without FMN were infused intravenously at a constant rate into normal, starved, or probenecid-pretreated rabbits. AT 3 h, [14C]riboflavin readily entered choroid plexus and brain, and, to a much lesser extent, CSF. Over 85% of the [14C]riboflavin in brain and choroid plexus was present as [14C]FMN and [14C]FAD. The addition of 0.2 mmol/kg FMN to the infusate markedly depressed the relative entry of [14C]riboflavin into brain, choroid plexus, and, less so, CSF, whereas starvation increased the relative entry of [14C]riboflavin into brain and choroid plexus. After intraventricular injection (2 h), most of the [14C]riboflavin was extremely rapidly cleared from CSF into blood. Some of the [14C]riboflavin entered brain, where over 85% of the 14C was present as [14C]FMN plus [14C]FAD. The addition of 1.23 mumol FAD (which was rapidly hydrolyzed to riboflavin) to the injectate decreased the clearance of [14C]riboflavin from CSF and the phosphorylation of [14C]riboflavin in brain. Probenecid in the injectate also decreased the clearance of [14C]riboflavin from CSF. These results show that the control of entry and exit of riboflavin is the mechanism, at least in part, by which total riboflavin levels in brain cells and CSF are regulated. Penetration of riboflavin through the blood-brain barrier, saturable efflux of riboflavin from CSF, and saturable entry of riboflavin into brain cells are three distinct parts of the homeostatic system for total riboflavin in the central nervous system.

Animals↗

PubMed1987

Thermoregulatory effects of intracranial norepinephrine injections in goldfish.

Cannulas were implanted into forebrain loci of goldfish (Carassius auratus; 45-90 g) to determine the effects and site of action of intracranial norepinephrine (NE) injections on behavioral thermoregulation. Following 30 min in a thermal gradient, implanted fish were injected with norepinephrine-bitartrate salt (2.5-500 ng NE) in 0.2 microliter 0.7% NaCl. Injections of 5, 10, 25, and 50 ng NE into the anterior aspect of the nucleus preopticus periventricularis (NPP, Ref. 25) led to consistent dose-dependent decreases in selected temperature (Tsel). No effect on Tsel was observed following injections of 2.5 ng NE or control injections of 100 ng tartaric acid. The effects of injections into other loci, including intraventricular injections, were dependent on the dose and proximity to the anterior NPP; at sites adjacent to the anterior NPP, larger doses were required, and the effects became inconsistent. At sites further removed, no effect on Tsel was observed. Included in this category were more caudal sites within the NPP and the nucleus preopticus. We postulate that in fish the anterior NPP is an important locus for thermoregulatory integration and that increased release of NE in this area leads to the selection of cooler water.

Animals↗

PubMed1993

[Effect of anti-opioid peptide sera on oxytocin-induced enhancement of electroacupuncture analgesia].

The effects of intracerebroventricular injection of Anti-opioid peptide sera on oxytocin-induced enhancement of electroacupuncture (EA) analgesia were observed in this study. It was found that injection of anti-beta-endorphin serum (AEPS) alone could attenuate EA analgesia in rats. Injection of AEPS prior to intraventricular injection of oxytocin could not block the enhancement of EA analgesia by oxytocin. The antidynorphin A1-13 serum (ADYNS) alone could also reduce the EA analgesia, whereas injection of ADYNS prior to injection of oxytocin could potentiate the enhancement of EA analgesia by oxytocin. However, neither the anti-methionine enkephalin serum nor the anti-leucine enkephalin exerted any effect on the enhancement of EA analgesia by oxytocin. The above results showed that the dynorphin attenuate oxytocin-induced enhancement of EA analgesia, but Beta-endorphin and enkephalin do not affect this role of oxytocin. These data suggest the enhancement of EA analgesia by oxytocin is not dependent upon the endogenous pioid peptides in brain.

Acupuncture Analgesia↗

PubMed1984

Dermorphin stimulates prolactin secretion in the rat.

The effect of dermorphin, a new opioid peptide originally isolated from amphibian skin, on the release of prolactin (Prl) was studied in vivo and in vitro. In vivo experiments: subcutaneous administrations of different doses of dermorphin ranging from 0.1 to 5 mg/kg body weight to normal male rats induce a statistically significant, dose-related increase in serum Prl levels. Pretreatment with the specific opioid antagonist, naloxone (2 mg/kg i.p.) completely prevents the rise in serum Prl, induced by 2 mg/kg of dermorphin. In normal male rats, the intraventricular injection of 0.25 micrograms/kg of dermorphin is not able to induce any significant changes in serum Prl levels 10 min after injection. Serum Prl levels show a significant enhancement 30 min after the administration of this dose of dermorphin, and return to control values at 60 min. On the contrary, 1 microgram/kg of dermorphin significantly elevates Prl concentrations 10 min after injection, leaving serum Prl levels unchanged 30 and 60 min after the administration. Naloxone (25 and 100 micrograms/kg) alone does not substantially modify serum Prl concentrations at any time interval considered. Treatment with either dose of naloxone performed together with either 0.25 or 1 microgram/kg of dermorphin completely counteracts the stimulatory effect of the peptide at all time intervals in which dermorphin was active when given alone. In orchidectomized (3 weeks) rats, the intraventricular administration of dermorphin at the dose of 0.25 micrograms/kg appears effective in enhancing Prl levels only 30 min after treatment. No statistically significant modifications are observed at 10 and 60 min with this dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Eosinophils and cellular injury: the Gordon phenomenon as a model.

Three eosinophil proteins, eosinophil cationic protein (ECP), eosinophil protein-X (EPX), and eosinophil-derived neurotoxin (EDN), have neurotoxic properties. EDN and EPX may be identical. ECP is by far the most potent neurotoxic eosinophil-derived protein. The damaging effect of the three proteins have been claimed to be selective. This selectivity can, at least in part, be explained by way of the experimental injections. Several observations are in favour of a selectivity through accumulation. Immunocytochemical localization of intraventricular injected ECP supports this hypothesis and indicates furthermore that ECP has an immediate reactivity towards and possible toxic effect against nervous tissue in general.

Animals↗

PubMed1993

Extended CSF cytarabine exposure following intrathecal administration of DTC 101.

PURPOSE: The aims of the present study were to determine ventricular and lumbar CSF pharmacokinetics and the maximum-tolerated dose (MTD) of DTC 101 (DepoFoam; DepoTech Corp, La Jolla, CA) following intraventricular administration. PATIENTS AND METHODS: Twelve patients with neoplastic meningitis were treated with escalating doses of DTC 101. CSF samples were obtained from the right lateral ventricle or from the lumbar subarachnoid space and cytarabine concentrations were determined by high-performance liquid chromatography. RESULTS: Therapeutic ventricular CSF concentrations were maintained for 9 +/- 2 days following administration of a single dose of DTC 101 into the lateral ventricle. Lumbar cytarabine concentrations became equal to those in the ventricle within the first 6 hours after intraventricular injection, and the subsequent decay in concentrations of free and total cytarabine were the same at both sites. Following intralumbar administration, the peak ventricular concentration of free cytarabine was reached within 1 day, and therapeutic ventricular CSF levels were maintained for several days. Therapeutic intralumbar concentration of free cytarabine was maintained for up to 14 days. The MTD was 75 mg of DTC 101, and seven of nine patients manifested cytologic responses. CONCLUSION: Extended CSF exposure to therapeutic cytarabine concentrations was achieved after a single intraventricular or intralumbar dose of DTC 101, permitting drug administration once every 2 weeks.

Adolescent↗

PubMed1982

Relationship between central actions of bradykinin and prostaglandins in the conscious rat.

Intraventricular injection of bradykinin produced a dose-dependent increase in the mean arterial blood pressure of conscious rats. With 5 nmol of bradykinin, a dual pressor response was observed, which was associated with a biphasic behavioral change. With repeated hourly injections of bradykinin, tachyphylaxis developed to the pressor and central nervous system (CNS) stimulating effect. Indomethacin, given intraventricularly, reduced the hypertension and the behavioral excitation caused by bradykinin in a dose-dependent manner. When prostaglandin E2 was injected into the cerebral ventricles, it induced hypertension and behavioral sedation similar to the secondary response to bradykinin. These results suggest that bradykinin has a dual action on the CNS, and this is mediated by prostaglandin-related systems in the brain.

Animals↗

PubMed1989

Evidence for the involvement of the central adrenergic system in interleukin 1-induced adrenocortical response.

The role of central catecholamines in the mediation of adrenocortical activation, induced by interleukin 1 (IL-1), was investigated by measuring ACTH and corticosterone in serum. Adult male rats were injected with either vehicle or the neurotoxin 6-hydroxydopamine (6-OHDA) into the lateral ventricle or the ventral noradrenergic ascending bundle. In vehicle-injected rats, 2 U of IL-1, injected intraventricularly, produced a 5- and 15-fold increase in ACTH and CS, respectively, in serum, 120 min after the injection of IL-1. In contrast, 6-OHDA, injected either intraventricularly or into the ventral noradrenergic ascending bundle, abolished the response to an intracerebral injection of IL-1. In addition, in rats pretreated with the alpha 1-adrenergic antagonist, prazosin, IL-1 failed to activate the adrenocortical axis. In other rats pretreated with the beta-adrenergic antagonist, propranolol, the adrenocortical response did not significantly differ from that of vehicle-pretreated rats. These results suggest that central adrenergic transmission, originating at the ventral noradrenergic ascending bundle and acting through alpha 1-adrenergic receptors, is involved in the adrenocortical response to IL-1.

Adrenal Cortex↗

PubMed1992

Intraventricular corticosterone increases the rate of body weight gain in underweight adrenalectomized rats.

Circulating glucocorticoids are necessary for hyperphagia and excessive weight gain in obese rodents. It has been reported that intraventricular administration of selected glucocorticoids restores hyperphagia and weight gain in anorexic adrenalectomized gold thioglucose-treated mice. We wanted to determine whether administration of glucocorticoids directly into the central nervous system of normal (nonobese) rats will enhance the rate of weight gain. In the initial experiment rats were allowed ad libitum access to chow or were rendered underweight by a 7- to 10-day period of food restriction. Animals were then adrenalectomized or sham operated and allowed ad libitum access to chow. Both groups of adrenalectomized animals consumed less food and gained weight less rapidly than their respective sham controls. Previously food-restricted and therefore underweight adrenalectomized rats consumed significantly more food and gained weight more rapidly than previously ad libitum-fed adrenalectomized rats. These data support the conclusion that adrenalectomized rats, like intact rats, regulate their weight, albeit at a lower level than intact rats. To determine a possible role of central glucocorticoids in this phenomenon, food-restricted or ad libitum-fed rats received a single intraventricular injection of corticosterone or its vehicle on the day after adrenalectomy or sham surgery. Whereas intraventricular corticosterone had no effect on weight gain in ad libitum-fed rats, it significantly increased the rate of weight gain in food-restricted adrenalectomized rats relative to that in vehicle-treated controls. Peripheral administration of corticosterone had no effect in this paradigm. It is concluded that glucocorticoids act directly on the central nervous system of underweight lean rats to augment weight gain.

Adrenalectomy↗

PubMed1988

Actions of nicotine on the acquisition of an autoshaped lever-touch response in rats.

Experimentally naive male, Sprague-Dawley rats maintained at 85% of their original body weight were trained to touch a retractable lever that was presented on a random interval 48-s schedule. The lever retracted when touched or after 15 s had elapsed, and one 45 mg food pellet was delivered simultaneously with lever retraction or after an 8-s delay. Rats received ten daily sessions each consisting of ten lever presentations. Nicotine (0.25-0.8 mg/kg SC) administration, either 15 min prior to (pre-session) or immediately after (post-session) the daily autoshaping sessions, caused a significant dose-related impairment of acquisition with the post-session injections having the greater effect. Low doses of nicotine (0.025-0.1 mg/kg SC) had little effect on acquisition when injected pre-session or post-session. Injections of 0.45 mg/kg nicotine either immediately (t = 0) or at +5 min after the daily sessions impaired acquisition of the lever-touch response. Nicotine injected at +15, +30, +60, or +120 min had no effect on acquisition. A single intraventricular injection of the ganglionic blocker chlorisondamine (5 micrograms) 2 weeks prior to autoshaping blocked the impairment produced by 0.45 mg/kg nicotine. Post-session injections of nicotine did not alter the lever-touch behavior of well-trained animals, but suppressed responding in animals that were partially trained. Thus, nicotine-induced impairment of the autoshaped lever-touch response is dose dependent, centrally mediated, occurs within 5 min of a SC injection, and may interfere with post-training consolidation processes.

Animals↗

PubMed1992

Enhancement of glutaminase-like immunoreactivity in rat brain by an irreversible inhibitor of the enzyme.

Changes of glutaminase immunoreactivity in rat brain were examined after intracranial injection of 6-diazo-5-oxo-L-norleucine (DON), an irreversible inhibitor of glutaminase. When 1 M DON was injected into the lateral ventricle, a half-lethal dose was 7.5-10 mumol. After intraventricular injection of 2-7.5 mumol DON, glutaminase immunoreactivity was dose dependently enhanced with the maximum enhancement 3-5 days after the injection. The enhanced glutaminase immunoreactivity was recognized by enlarged granular immunodeposits in both perikarya and neuropil in many regions, such as the hippocampus, thalamus, hypothalamus, periaqueductal gray, and some brain stem, cerebellar, and spinal cord regions. Intrathalamic injection of 0.2 mumol DON enhanced glutaminase immunoreactivity in many neuronal perikarya in the thalamus and in some perikarya in layer VI of the cerebral cortex. Intrastriatal injection of the same dose of DON enhanced glutaminase immunoreactivity in neuropil of the caudoputamen and in many neuronal perikarya of the intralaminar thalamic nuclei. These results suggested that DON induced a new massive synthesis of glutaminase in the affected neurons.

Animals↗

PubMed1997

Angiotensinergic neurons physiologically inhibit prolactin, growth hormone, and thyroid-stimulating hormone, but not adrenocorticoptropic hormone, release in ovariectomized rats.

Angiotensin II (AII)-containing neurons with cell bodies in the rostral medial hypothalamus and axons project to the external layer of the median eminence, so that AII maybe released into the hypophyseal portal vessels for actions on the pituitary gland. Indeed, intrahypothalamic actions of the peptide on the release of hypothalamic hormones and direct actions on the pituitary have been reported. To determine the role of endogenously released AII in hypothalamic-pituitary hormone release, we have determined the effects of central immunoneutralization of AII upon the plasma concentrations of prolactin (PRL), growth hormone (GH), thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH). Specific antiserum directed against AII (AB-AII) or normal rabbit serum (NRS), as a control, was microinjected into third ventricular (3 V) cannulae of conscious, ovariectomized (OVX) rats. Immediately before and at various intervals after this procedure, blood samples were withdrawn through previously implanted external jugular catheters. Three hours after injection of the AB-AII, plasma PRL levels diverged from those of the NRS-injected animals and progressively increased from 4 to 24 h after administration of the antiserum. Results were similar with respect to plasma GH, except that the increase in the AB-AII animals above that in the NRS-injected controls from 4 to 6 h was not significant, but was highly significant on measurement 24 h after injection, at which time plasma GH was three times higher than in control rats. Similarly, following injection of AB-AII, plasma TSH values did not diverge significantly from those of the NRS-injected controls until 3 h after injection. From 3 to 5 h they remained constant and significantly elevated above values in the NRS-injected controls with a further nonsignificant increase at 6 h. At 24 h, there was no longer a difference between the values in both groups. In contrast to the significant elevations in plasma hormone levels observed with respect to PRL, GH, and TSH following injection of the antiserum, there was no change in plasma ACTH between the AB-AII-injected and NRS-injected animals throughout the same period of observation. Previous results by others have shown that intraventricular injection of AII has a suppressive action on the release of PRL, GH, and TSH. Consequently, we believe that the antiserum is acting intrahypothalamically to block the action of AII within the hypothalamus, resulting in the elevation of the three hormones mentioned. Therefore, the AII neurons appear to have a physiologically significant suppressive action on the release of hypothalamic neurohormones controlling the release of PRL, GH, and TSH. In contrast, there apparently is no effect of intrahypothalamically released AII on the secretion of corticotropin-releasing factors under these nonstress conditions. We cannot rule out an action of the antiserum at the pituitary level; however, in view of the fact that the actions of AII directly on the gland are to stimulate PRL, GH, TSH, and ACTH release, it appears that the antiserum was acting at the hypothalamic level.

Adrenocorticotropic Hormone↗

PubMed1970

Effects of intraventricular 2,4,5-trihydroxyphenylethylamine (6-hydroxydopamine) on rat behaviour and brain catecholamine metabolism.

1. 6-Hydroxydopamine (200 mug injected intraventricularly) caused depletion of noradrenaline from all regions of rat brain within 2 h after injection but depletion of dopamine in the brain was observed only from 2 days after injection. Both catecholamines remained depleted for more than 32 days.2. Rats treated with intraventricular 6-hydroxydopamine were sedated and lethargic, with reduced spontaneous and exploratory activity, for periods of up to 8 days after injection. Conditioned avoidance responding was abolished or reduced for a similar period.3. Intraventricular 6-hydroxydopamine caused a prolonged reduction in the amount of labelled catecholamines in store 4 h following an intraventricular injection of (3)H-dopamine. During the first 6 h after 6-hydroxydopamine injection, there was a marked increase in neutral and acid metabolites from the labelled catecholamines.4. A comparison of the behavioural and biochemical effects of intraventricular 6-hydroxydopamine and reserpine suggests that both drugs affect catecholamine storage mechanisms but by different mechanisms. It was not possible from these experiments to correlate behavioural changes with either catecholamine storage or metabolism.

Animals↗

PubMed1984

Selective neonatal depletion of dopamine has no effect on medial prefrontal cortex self-stimulation in the rat.

The role of the dopaminergic input to the medial prefrontal cortex (MFC) on self-stimulation (SS) was investigated in adult rats injected neonatally with 6-hydroxydopamine (6-OHDA). Each subject on day 3 or 5 received bilateral intraventricular injection of 6-OHDA (total dose 200 micrograms, 50 micrograms/injection/2.5 microliters vehicle which contained 1 mg/ml ascorbic acid) or of the vehicle alone after pretreatment with desmethylimipramine (50 mg/kg i.p.) 30 min earlier. At 150 days of age, the animals were implanted with monopolar (100 microns) stainless steel electrodes in the MFC. One long (10 h) and 5 short (2 h) SS sessions resulted in similar percentages of responders for the brain reward in test and control subjects, and similar response rates in both groups. Biochemical assays of the levels of norepinephrine (NE) and dopamine (DA) in the frontal cortex showed depletion of DA 90% in the test animals, but no depletion of NE. Histochemical fluorescence visualization of the catecholamine input verified the biochemical results in the MFC. These results are viewed as negative evidence for the hypothesis that DA innervations in the MFC are critical neural substrates for SS, and suggest that activation of intrinsic neurons in the MFC are responsible for SS in the region.

Animals↗

PubMed2002

Lipid-sugar particles for intracranial drug delivery: safety and biocompatibility.

Controlled release of drugs to specific locales in the brain has engendered considerable interest. Here we evaluate the safety and biocompatibility of 6-microm diameter particles composed of dipalmitoylphosphatidylcholine and chondroitin sulfate A, when delivered into the cerebral parenchyma and ventricles, and in the case of intravascular injection. Some particles were loaded with fluorescein-labeled albumin to facilitate detection. Particles placed in medium with cultured murine primary cortical neurons did not increase cell death at concentrations as high as 4 mg/ml. When particles (100 microg in 2 microl) were placed stereotactically in the striatum and lateral ventricles, there was no histological evidence on hematoxylin-eosin stained sections of tissue injury outside of the needle track in any animal 3, 7, and 14 days after injection (n=6 each), and no inflammation. Ventricular size was not significantly different between animals given intraventricular injections of particles and albumin solution at those time points (n=4 each). Intracarotid injection of particles at concentrations of 0.2 and 1 mg/ml (n=4 each) did not affect relative cerebral blood flow, and there were no embolic events on histology. In one animal in the group injected with 5 mg/ml (n=3), there was a profound decrease in rCBF, with patchy emboli on histology. These novel biodegradable particles are biocompatible in and around the brain, and may be safe for intracranial sustained drug delivery either in the parenchyma or into the CSF.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1994

Immunocytochemical localization of desferrioxamine in the kidney, liver and brain of the developing and adult mouse: implications for drug processing and therapeutic mechanisms.

The iron chelator, desferrioxamine, has been shown to interfere with hydroxyl radical formation, which mediates tissue damage in several disease states. In this study, young and adult mice were given intraperitoneal injections of desferrioxamine and sacrificed after 1, 24 or 72 hr, and adult rats were given intraventricular injections and sacrificed after 24 or 72 hr. Immunohistochemical experiments, that utilized an anti-desferrioxamine antiserum, were performed to localize the cellular distribution of the drug in the kidney, liver and brain. In the kidney, the findings were as follows: 1) at 0 days, there was heterogeneous distribution of desferrioxamine, which suggests that there are functional differences between nephrons in the immature kidney; 2) with increasing age, the degree of staining decreased, which suggests that the efficiency of renal clearance of desferrioxamine increases with maturity; 3) punctate staining was superimposed onto diffuse staining, which suggests that the drug can get taken up in pinocytotic vesicles during tubular reabsorption; and 4) staining was present at 72 hr, which suggests a prolonged clearance period. In the liver, there was an absence of staining at 24 and 72 hr and only diffuse staining at 1 hr, which suggests a rapid processing of the drug by the liver. In the normal mouse brain, the drug was found localized to the choroid plexus and ependymal cells at all ages, and the staining decreased with increasing time following injection. These results indicate that there are differences in the way that desferrioxamine is processed by cells in different tissues and indicate possible therapeutic mechanisms.

Aging↗