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PubMed1983

In rats, the behavioral profile of CCK-8 related peptides resembles that of antipsychotic agents.

The action of some CCK-8 related peptides, desulphated CCK-8 (CCK-DS), the sulphated form of CCK-8 (CCK-8-S) and ceruletide was explored in a number of test procedures with rats, in which antipsychotic agents are active. Following injection into the nucleus accumbens, all three peptides antagonized the hypolocomotion induced by low doses of apomorphine (10 ng). Ceruletide appeared to be the most potent in this respect (ED50: approximately 5 pg). The increased locomotion observed following injection of relatively high doses of apomorphine (10 micrograms) into the nucleus accumbens was antagonized by local pretreatment with CCK-8-S, but not with CCK-8-DS or ceruletide. None of these CCK-8 related peptides affected the stereotyped sniffing response elicited by treatment with apomorphine or amphetamine (10 micrograms) given into the nucleus caudatus. Passive avoidance behavior was facilitated following subcutaneous administration of 10 micrograms of CCK-8-related peptides 1 h before the retention test. The same periods given into the nucleus accumbens (0.3 pg) however attenuated passive avoidance behavior. intraventricular injection with CCK-8-DS and CCK-8-S induced a positive effect in various 'grip tests'. Given subcutaneously, the CCK-8-related peptides decreased the rate of ambulation and rearing especially in the middle of the open field. These results indicate that CCK-8 related peptides, especially CCK-8-DS and ceruletide, exhibit behavioral effects that are similar to those observed following treatment with gamma-type endorphins and that resemble the effects of antipsychotic agents. Very low doses of CCK-8 related peptides exert behavioral effects following injection into the nucleus accumbens, indicating that this brain area is extremely sensitive to the action of these peptides. It is postulated that certain peptides which are either present in neurons (like CCK-8-related peptides) or generated by brain endorphin systems (like gamma-type endorphins) control the activity of specific neurons of the mesolimbic dopaminergic pathways. This may be of relevance for the purported antipsychotic action of these peptides.

Amphetamine↗
PubMed1966

Effect of 5-hydroxytryptophan acting from the cerebral ventricles on 5-hydroxytryptamine output and body temperature.

1. In cats anaesthetized with intraperitoneal pentobarbitone sodium the third ventricle, the anterior or inferior horn of the left lateral ventricle, was perfused with 5-hydroxytryptophan (5-HTP) in different concentrations, and the effluent assayed for 5-hydroxytryptamine (5-HT) on the rat stomach strip preparation of Vane (1957).2. On perfusion of the third ventricle with 5-HTP the output of 5-HT in effluent increased, the increase depending on the 5-HTP concentration: with 1/50,000 it increased 44-69 times (mean 55), with 1/25,000, 81-83 times (mean 82) and with 1/10,000, 71-200 times (mean 128). The 5-HT output depended also on the initial output during the preceding perfusion with artificial c.s.f. The greater this initial output the greater was the maximum output reached during the 5-HTP perfusion.3. The increase in 5-HT output during perfusion of the third ventricle with 5-HTP was usually associated with shivering and a rise in rectal temperature. This association, however, was not invariably obtained, probably because of a central depressant effect of 5-HTP itself.4. On perfusion of the anterior or inferior horn of the left lateral ventricle with 5-HTP, the output of 5-HT in the effluent also increased, but to a lesser extent than in the effluent from the third ventricle. There was no association with shivering nor with a rise in rectal temperature.5. An injection of 1 or 2 mg 5-HTP into the cerebral ventricles of unanaesthetized cats produced a biphasic rise in temperature, shivering, constriction of the skin vessels followed by vasodilatation, tachypnoea, wiping and scratching movements, miaowing and long lasting sleep.6. The biphasic rise in temperature is explained as the result of two opposing effects: increased formation of 5-HT which would raise body temperature, and a central depressant effect of 5-HTP itself or of one of its metabolites which would lower body temperature.7. The initial rise in temperature and the shivering in response to an intraventricular injection of 5-HTP varied from cat to cat. In those in which these effects were strong the 5-HT output during a subsequent perfusion of the third ventricle with artificial c.s.f. was higher, and the maximum 5-HT output reached on perfusion with 5-HTP was greater than in those in which these effects had been weak.

5-Hydroxytryptophan↗
PubMed1985

Modulation of striatal enkephalinergic neurons by antipsychotic drugs.

In this paper we review the detailed mechanisms underlying the modulation of enkephalinergic neurons by dopaminergic neurons in rat striatum. Several lines of evidence, which showed that striatal levels of [Met5]enkephalin (ME) increase after the nigrostriatal dopaminergic pathway was interrupted by hemitransection or direct administration of 6-hydroxydopamine to the substantia nigra, or after repeated injections of either reserpine or haloperidol, suggest that dopamine (DA) plays an important role in regulating the metabolism of ME-containing neurons in the striatum. The increase in ME content after repeated injections of haloperidol was found in areas heavily innervated by DA neurons such as striatum or nucleus accumbens but not in hypothalamus, brain stem, and hippocampus. Further studies suggest that striatal cholinergic interneurons may partially mediate the action of haloperidol on enkephalinergic neurons. Several studies have been carried out to determine whether the elevation of striatal ME content after haloperidol treatment was caused by an increase in the synthesis or by a decrease in the utilization of ME. The rate of decline of striatal ME content in haloperidol-treated rats was steeper than that of controls after intraventricular injection of cycloheximide, which indicated that haloperidol accelerates the turnover of ME. This hypothesis was confirmed by our recent findings that the level of mRNA coding for preproenkephalin A, determined by cell-free translation and blot hybridization with cDNA clones, is increased after repeated injections of haloperidol.

Animals↗
PubMed1980

Methionine recycling in brain: a role for folates and vitamin B-12.

The recycling of methionine via homocysteine was measured in vivo in brain. After constant intravenous infusions (5 h) of both [3H-methyl]methionine and [35S]methionine into rats, the ratios of [3H-methyl]methionine to [35S]methionine in liver, brain, and plasma were determined. Similar experiments were performed in rabbits, except that the [3H-methyl]- and [35S]methionine were injected intraventricularly. If the methyl group of methionine was removed with the formation of homocysteine and then replaced by another (unlabeled) methyl group, the specific activity of the [3H-methyl]methionine would decrease more than that of [35S]methionine; i.e., the ratio of [3H-methyl]- to [35S]methionine in the tissue would decline. The results showed that the ratios of [3H-methyl]- to [35S]methionine in liver and brain were less than the same ratio in plasma in the rats. The comparable ratios in the brain and CSF of rabbits were less than the ratio in the injectate. Since brain contains only one enzyme capable of remethylating homocysteine to methionine, the vitamin B-12-dependent methyltetrahydrofolate-homocysteine methyltransferase (EC 2.1.1.13), our results for methionine recycling via homocysteine in brain strongly support the activity of this enzyme in brain in vivo.

Animals↗
PubMed1989

Release of oxytocin within the supraoptic nucleus during the milk ejection reflex in rats.

To investigate the hypothesis that oxytocin may be released within the magnocellular nuclei in vivo, push-pull cannula perfusions were performed in anaesthetized lactating rats in one supraoptic nucleus of the hypothalamus while recording the intramammary pressure and/or the electrical activity of oxytocin cells in the contralateral supraoptic nucleus. Oxytocin content was measured in samples collected over 15 min, under various conditions: 1) with no stimulation; 2) during suckling and suckling-induced reflex milk ejections; 3) during electrical stimulation of the neuro-hypophysis by trains of pulses that mimicked oxytocin cell bursts; 4) under osmotic stimulation by i.p. injection of 2 ml of 1.5 M NaCl to evoke a tonic and sustained oxytocin release from the neurohypophysis. Oxytocin release within the supraoptic nucleus increased significantly during the milk ejection reflex and, to a lesser extent, during burst-like electrical stimulation of the neurohypophysis. In suckled rats, the increase started before the first reflex milk ejection occurred. There was no apparent correlation between the amount of oxytocin in the perfusates and the number of milk ejections and oxytocin cell bursts occurring during each perfusion period. The amount of oxytocin in the perfusates further increased-during facilitation of the milk ejection reflex by intraventricular injections of oxytocin or its analogue, isotocin. When suckling failed to evoke the milk ejection reflex, there was no change in intra-supraoptic oxytocin release. There was also no change after osmotic stimulation. When the push-pull cannula was positioned outside the supraoptic nucleus, there was no increase in the amount of oxytocin during the three types of stimulation tested. These results provide evidence for an endogenous release of oxytocin within the magnocellular nuclei in lactating rats. It is suggested that the increase in such a release induced by suckling is likely to be a prerequisite for the onset and the maintenance of the characteristic intermittent bursting electrical activity of oxytocin cells leading to milk ejections.

Animals↗
PubMed1978

Inhibition of 5-hydroxytryptamine uptake by tetrahydronorharmane in vivo.

Injection of tetrahydronorharmane (THN) elicited a dose-dependent increase of the level of 5-hydroxytryptamine (5-HT) and a fall of 5-hydroxyindoleacetic acid in the rat brain whereas noradrenaline and dopamine levels remained unchanged. The effect on indoles was shortlasting which may be explained by the short half life of THN or its metabolization to 6-OH-THN. The 5-HT depleting action of parachloro-N-methylamphetamine (CMA) was used to study uptake inhibition in vivo. The results support the notion that THN acts as an inhibitor of the reuptake of 5-HT in vivo. Further evidence for this hypothesis was obtained by intraventricular injection of radiolabelled 5-HT. The disappearance of (3H)-5-HT from brain tissue was reduced by THN. Thus, THN may exert its central 5-HT-like effects in pharmacological experiments by preventing 5-HT from being removed from the synaptic cleft.

Animals↗
PubMed1977

Schedule dependent changes in operant responding after lesions of the dorsal tegmental noradrenergic projection.

The present experiments examined the role of the dorsal tegmental noradrenergic bundle (DTNB) in operant responding for food under various schedules of reinforcement. This catecholaminergic neuronal system originates in the nucleus locus coeruleus and has diffuse projections to hippocampus and cerebral cortex. Bilateral stereotaxic injections of 6-hydroxydopamine into the DTNB of rats reduced hippocampal-cortical noradrenaline to less than 5% of control levels. Animals with these lesions acquired a continuously reinforced (CRF) bar-press response at the same rate as controls. Compared to controls rats with DTNB lesions responded at significantly lower rates on a variable interval 30 (VI 30) schedule. Extinction after VI 30 responding did not differ significantly between control and lesioned animals. In another experiment no significant difference was observed between DTNB lesioned and control groups on the rate of responding on a fixed ratio 30 (FR 30) schedule. The results are discussed with reference to previous reports indicating changes in operant responding after intraventricular injections of 6-hydroxydopamine. The data failed to support the hypothesis that the DTNB is critically involved in learning and memory.

Animals↗
PubMed1994

Neuron damage induced by some potent kainoids and neuroprotective action of new agonists for metabotropic glutamate receptors.

Selective and characteristic neuron damage induced by acromelic acid, a potent kainate analogue, was investigated in comparison to a kainate-induced one. A single systemic injection of acromelic acid A caused behavioral and pathological effects distinct from those seen after systemic kainate. There was an initial marked tonic extension of the rat hindlimb, often followed by convulsions and, in surviving rats, by a transient flaccid paralysis and ultimately, a persistent spastic paraplegia. Pathological examination suggested specific lesions of interneurons in the lower spinal cord with little or no damage to the hippocampal neurons preferentially affected by systemic kainate. Another agonist for kainate-type receptors, which is not a kainoid, demonstrated neurological symptoms and neuron damage quite similar to those of kainate. Pharmacological actions of our newly developed agonists for metabotropic glutamate receptors were described with special reference to kainate excitotoxicity. Intraventricular DCG-IV, a new agonist, caused selective neuron damage in the cingulate cortex and the hippocampal subiculum at relatively high doses, but other agonists did not cause neuron damage in the rat. DCG-IV considerably alleviated the kainate-induced limbic seizures. At relatively low doses, DCG-IV protected some kinds of neurons in the hippocampal CA3 and the amygdala against kainate neurotoxicity, when intraventricularly injected to the rat. These new agonists would provide useful probe for elucidating the mechanism underlying neuron damage induced by kainate-type agonists.

Amino Acids, Dicarboxylic↗
PubMed1984

The TRH analogue CG3509 increases in vivo catechol/ascorbate oxidation in the N. accumbens but not in the striatum of the rat.

The effects of injection of the thyrotrophin-releasing hormone (TRH) analogue, orotyl-histidyl-proline amide (CG3509) into the accumbens and striatum, was studied on dopamine metabolism by means of in vivo voltammetry. Forty minutes after infusion of CG3509 (1-5 micrograms) into the n. accumbens there was a significant dose-related increase in the oxidation peak, corresponding to the oxidation of the dopamine metabolite, dihydroxyphenylacetic acid (DOPAC) and ascorbic acid. The size of this peak returned to normal by 80 min after the infusion. There was no change in the indole oxidation peak. Infusion of CG3509 (5 micrograms) had no effect on the size of either the catechol or the indole oxidation peaks recorded in the striatum. Intraventricular injection of CG3509 (10 micrograms) also increased DOPAC/ascorbic acid oxidation peak recorded in the n. accumbens, without altering the indole peak. While the voltammetric technique used in the present experiments is not able fully to separate ascorbic acid and DOPAC in vivo, the results support the view that TRH and its analogues selectively increase dopaminergic activity in the mesolimbic region.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Factors influencing exit of substances from cerebrospinal fluid into deep cervical lymph of the rabbit.

Experiments have been made to determine the main route by which radio-iodinated albumin reaches deep cervical lymph from cerebrospinal fluid (c.s.f.) in the anaesthetized rabbit. Other factors, influencing drainage through this pathway, have been investigated. After single injection of [125I]albumin into a lateral ventricle of control rabbits, a mean of 14.8% of the radioactivity lost from brain-c.s.f. was recovered during 6 hr in the lymph of the cannulated jugular trunk of one side. Injection of kaolin into the olfactory fossa or sealing of the cribriform plate with cyanoacrylate glue reduced the recovery of [125I]albumin to 3.3% and 1.9% respectively at 2-3 weeks after the procedure designed to block the cribriform plate. This confirms the traditional view that the major connexions between c.s.f. and deep cervical lymph is via prolongations of subarachnoid space around the olfactory nerves, leading into the interstitial spaces of the nasal submucosa. The dense lymphatic plexus in this tissue is known to drain into the retropharyngeal (deep cervical) lymph nodes. Constant infusion of artificial c.s.f. into a lateral ventricle at 10 microliters/min or 30 microliters/min, in order to approximately double or quadruple flow through the system respectively, decreased the recovery of intraventricular [125I]albumin to 8.1% and 6.9% respectively. It also appeared that the increased c.s.f. pressures induced forced relatively more radioactivity from inside the skull into the c.s.f. spaces of the spinal cord. Maintaining the rabbit prone but at 20 degrees from the horizontal caused recoveries of [125I]albumin in lymph of 17.6% (head-up position and 6.6% (head-down). The amounts of radioactivity in nose and spinal cord markedly increased and decreased respectively in the head-down position. They changed in the opposite directions in the head-up position. The amounts of [51Cr]EDTA, [125I]metrizamide and [14C]inulin in deep cervical lymph were negligible after intraventricular injection. Estimations of the ratio of [51Cr]EDTA/[125I]albumin in various tissues on the pathway into lymph, together with measurements of arterio-venous fluxes across the retropharyngeal nodes, indicate that [51Cr]EDTA passed from c.s.f./lymph into blood within both the nose and the lymph nodes.

Albumins↗
PubMed1983

Bicompartmental analysis of cerebrospinal fluid circulation. Theory and clinical applications.

A new model for cerebrospinal fluid (CSF) circulation is proposed. Specific activity/time curves for CSF kinetics determined after intraventricular injection of a radiotracer were produced by fitting a biexponential function to data points and developing a two-compartmental model. Calculation of kinetic parameters of the model provides quantitative data about CSF dynamics. The study of each compartment separately and of the intercompartmental relationship is possible with this model. Sequential scan images and graphic plots of the variations of radioactivity in both compartments, derived from this model, add supplementary information in the evaluation of patients. Ventriculography was performed in 80 patients, who fell into four groups: those with normal CSF circulation, hydrocephalus, infantile hydrocephalus, and functioning ventricular shunts. Normal and hydrocephalic patients showed significant differences between the two groups in the means of some numerical parameters calculated from the new model. An increase of intraventricular radioactivity at 24 hours (p less than 10(-4)) and of the volume of Compartment 1 (p less than 0.01) with decreased volume of Compartment 2 (p less than 10(-4)) and total flow outside the system (p less than 10(-3)) were found in patients with hydrocephalus. The limiting values for normal patients were also estimated. Communicating and obstructive hydrocephalus could be differentiated by this method; however, no differences in mean values were found relating to the etiology or clinical course of the hydrocephalus. Normal-pressure hydrocephalus and cerebral atrophy produced significantly different mean values for the volume of Compartment 2 (p less than 0.01), flow out of the system (p less than 0.01), and intercompartmental flow (p less than 0.01).

Cerebral Ventriculography↗
PubMed2006

Through the central V2, not V1 receptors influencing the endogenous opiate peptide system, arginine vasopressin, not oxytocin in the hypothalamic paraventricular nucleus involves in the antinociception in the rat.

Our previous study has proven that hypothalamic paraventricular nucleus (PVN) played a role in the antinociception. The central bioactive substances involving in the PVN regulating antinociception were investigated in the rat. The results showed that electrical stimulation of the PVN increased the pain threshold, and L-glutamate sodium injection into the PVN elevated the pain threshold, but the PVN cauterization decreased the pain threshold; pain stimulation raised the arginine vasopressin (AVP), not oxytocin (OXT), leucine-enkephalin (L-Ek), beta-endorphin (beta-Ep) and DynorphinA1-13 (DynA1-13) concentrations in the PVN tissue using micropunch method, heightened AVP, L-Ek, beta-Ep and DynA1-13, not OXT concentrations in the PVN perfuse liquid, and reduced the number of AVP-, not OXT, L-Ek, beta-Ep and DynA1-13-immunoreactive neurons in the PVN especially in the posterior magnocellular part of the PVN using immunocytochemistry. There was a negative relationship between the PVN AVP concentration and the pain threshold; pain stimulation enhanced the AVP, not OXT mRNA expression in the PVN using in situ hybridization and RT-PCR; intraventricular injection of anti-AVP serum completely reversed L-glutamate sodium injection into the PVN-induced antinociception, and administration of naloxone - the opiate peptide antagonist, partly blocked this L-glutamate sodium effect, but anti-OXT serum pretreatment did not influence this L-glutamate sodium effect; L-glutamate sodium injection into the PVN-induced analgesia was inhibited by V2 receptor antagonist - d(CH2)5[D-Ile2, Ile4, Ala-NH2(9)]AVP, not V1 receptor antagonist - d(CH2)5Tyr(Me)AVP. The data suggested that the PVN was limited to the central AVP, not OXT, which was through V2, not V1 receptors influencing the endogenous opiate peptide system, to regulate antinociception.

Analysis of Variance↗
PubMed1984

Digital subtraction angiography in the evaluation of left ventricular function and wall motion in man.

The purpose of this study was to examine the usefulness of digital subtraction angiography in the evaluation of left ventricular function (LVF). LVF was examined in 24 patients by three methods, (a) conventional ventriculography using an intraventricular injection (CLV) of 40 ml of contrast medium, (b) small volume (10-15 ml) left ventriculogram (SVLV) and (c) intravenous injection of 30 ml contrast medium (IVLV). Images were recorded via a conventional image intensifier--TV chain on to video tape and later analysed using a nuclear medicine computer with a digital interface. There was excellent correlation of ejection fraction and wall motion abnormalities between CLV and SVLV methods (r = 0.92 and r = 0.71, respectively) and good correlation between CLV and IVLV methods (r = 0.88 and r = 0.67, respectively). However, only minimal contrast induced premature ventricular contractions were observed in either the SVLV or IVLV methods compared with approximately 60% in the CLV method. Exclusion of studies containing ectopic cardiac cycles considerably improved the correlation between CLV and SVLV (r = 0.97) and between CLV and IVLV methods (r = 0.95). In conclusion, our results indicate that conventional left ventriculography may be replaced by either intravenous or small volume intraventricular methods with little loss of wall motion definition or error in ejection fraction estimation. The less invasive nature of the SVLV and IVLV methods should increase the usefulness of left ventriculography and extend its application to the assessment of left ventricular reserve under stress and during drug intervention.

Adult↗
PubMed1980

Central inhibition of basal pancreatic and gastric secretions by beta-endorphin in rats.

The effects of intracerebroventricular injections of synthetic ovine beta-endorphin were tested in conscious rats with gastric and pancreatic fistulas. In the range of 0.8 to 25 microgram injected in the third ventricle of the brain, basal gastric and pancreatic secretions were strongly inhibited in a dose-dependent manner. Pancreatic volume, bicarbonate output, and total protein output were similarly inhibited, while the bicarbonate concentration was only slightly changed. Similar effects were noted after the administration of morphine. In the present model system, morphine was 20-30 times less active than beta-endorphin on a molar basis. Beta-Endorphin inhibition of pancreatic secretion was reversed by naloxone, suggesting that opiate receptors are involved in this phenomenon. Gastric acid secretion participated in the pancreatic effects of beta-endorphin to only a slight extent, since pancreatic inhibition by the endorphin was decreased only slightly in rats with gastic fistula in which gastric juice was diverted and did not reach the duodenum. The comparison of intravenous and intraventricular injections of beta-endorphin and morphine suggested that the observed inhibitions originated in the central nervous system. No effects were detected after the administration of alpha-endorphin, Met-enkephalin or Leu-enkephalin, although pancreatic secretion was measurably inhibited by long-acting synthetic enkephalin analogues.

Animals↗
PubMed1993

Effects of midazolam and flunitrazepam on the release of dopamine from rat striatum measured by in vivo microdialysis.

We have studied the effects of midazolam and flunitrazepam on extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum in freely moving animals using in vivo microdialysis. I.v. injections of midazolam 0.075 and 0.15 mg kg-1 decreased striatal dopamine concentrations in a dose-dependent manner without affecting the concentrations of DOPAC and HVA. Flunitrazepam 0.015 and 0.03 mg kg-1 also decreased striatal dopamine concentrations in a dose-related manner, but the reductions in DOPAC and HVA were not significant. Flumazenil 6 micrograms kg-1 alone did not affect striatal concentrations of dopamine, DOPAC and HVA, but it prevented the effects of midazolam and flunitrazepam. Flunitrazepam 10 mumol litre-1 also decreased striatal dopamine release when infused through a dialysis probe placed into the striatum, but it failed to affect striatal dopamine release when infused into the ipsilateral substantia nigra. Central administrations of midazolam were effective only when the drug was infused into both sites simultaneously (10 and 100 mumol litre-1) or given by intraventricular injection (0.5 and 1 micrograms). These results suggest that midazolam and flunitrazepam affect striatal dopamine release in a different manner.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1976

Thermoregulatory responses to intraventricular norepinephrine in normal and hypothalamic-damaged rats.

We examined the effects of intraventricular injection of low doses of norepinephrine (NE) on internal temperature and on behavioral and reflexive thermoregulatory responses in unrestrained rats. NE lowered the body temperature of the rats in cold and neutral environments but had little effect in the heat. The hypothermia was blocked by alpha-adrenergic antagonists but unchanged by beta-adrenergic antagonists. In the cold, the hypothermia was caused primarily by a lowered metabolic rate. At ambient temperature 25 degrees C, it was caused primarily by vasodilatation while metabolic rate increased. Thus, reflexive responses were not integrated to lower body temperature. Behavioral responding compensated for the hypothermia. In the cold, rats increased responding to get heat after NE. In a warm environment, they did not increase responding to escape heat. Thus, both reflexive and behavioral results support the idea that the set-point is unchanged after intraventricular NE. Wherever in the brain the NE may be acting, it is not in the preoptic-anterior hypothalamic area, because when this area was ablated, the hypothermia in response to intraventricular NE was greatly exaggerated.

Animals↗
PubMed1983

A GABAergic habenulo-raphe pathway mediation of the hypnogenic effects of vasotocin in cat.

Electrolytic lesions, performed in the lateral habenula of cats, specifically altered the sleep-wakefulness cycle and completely prevented the usual actions of intraventricularly administered vasotocin, which are to induce non-rapid eye movement sleep and to suppress rapid eye movement sleep. These alterations are (i) selectively related to lateral habenula, since similar lesions performed in thalamus 2 mm lateral to lateral habenula, were unable to prevent the actions of vasotocin or to reproduce the sleep alterations observed after habenular lesions, and (ii) reversible, since at eight days after habenular lesions there is a total return to normal of the sleep-wakefulness parameters, and vasotocin is able again to induce its hypnogenic effects. Opposite effects, characterized by an increase in non-rapid eye movement sleep and a decrease in rapid eye movement sleep, could be induced by a short (10 min) electrical stimulation of the lateral habenula, but not if the stimulating electrodes are placed 2 mm more laterally. Picrotoxin, a gamma-aminobutyrate antagonist, injected intraventricularly in normal cats was without any apparent effect on the sleep-wakefulness cycle if administered in a dose of 1 ng, but had sleep-increasing effects when administered in a dose of 100 ng. However, the smaller dose of picrotoxin (1 ng), when administered 15 min before vasotocin, completely blocked the hypnogenic effect of vasotocin. It is suggested that vasotocin acts within the brain by activating a descending gamma-aminobutyrate-containing habenulo-raphe pathway, and that this pathway plays an important role in the induction and/or organization of the sleep-wakefulness cycle.

Animals↗
PubMed2005

In normal rat, intraventricularly administered insulin-like growth factor-1 is rapidly cleared from CSF with limited distribution into brain.

BACKGROUND: Putatively active drugs are often intraventricularly administered to gain direct access to brain and circumvent the blood-brain barrier. A few studies on the normal central nervous system (CNS) have shown, however, that the distribution of materials after intraventricular injections is much more limited than presumed and their exit from cerebrospinal fluid (CSF) is more rapid than generally believed. In this study, we report the intracranial distribution and the clearance from CSF and adjacent CNS tissue of radiolabeled insulin-like growth factor-1 after injection into one lateral ventricle of the normal rat brain. METHODS: Under barbiturate anesthesia, 125I-labeled insulin-like growth factor-1 (IGF-1) was injected into one lateral ventricle of normal Sprague-Dawley rats. The subsequent distribution of IGF-1 through the cerebrospinal fluid (CSF) system and into brain, cerebral blood vessels, and systemic blood was measured over time by gamma counting and quantitative autoradiography (QAR). RESULTS: Within 5 min of infusion, IGF-1 had spread from the infused lateral ventricle into and through the third and fourth ventricles. At this time, 25% of the infused IGF-1 had disappeared from the CSF-brain-meningeal system; the half time of this loss was 12 min. The plasma concentration of cleared IGF-1 was, however, very low from 2 to 9 min and only began to rise markedly after 20 min. This delay between loss and gain plus the lack of radiotracer in the cortical subarachnoid space suggested that much of the IGF-1 was cleared into blood via the cranial and/or spinal nerve roots and their associated lymphatic systems rather than periventricular tissue and arachnoid villi. Less than 10% of the injected radioactivity remained in the CSF-brain system after 180 min. The CSF and arteries and arterioles within the subarachnoid cisterns were labeled with IGF-1 within 10 min. Between 60 and 180 min, most of the radioactivity within the cranium was retained within and around these blood vessels and by periaqueductal gray matter. Tissue profiles at two sites next to ventricular CSF showed that IGF-1 penetrated less than 1.25 mm into brain tissue and appreciable 125I-activity remained at the tissue-ventricular CSF interface after 180 min. CONCLUSION: Our findings suggest that entry of IGF-1 into normal brain parenchyma after lateral ventricle administration is limited by rapid clearance from CSF and brain and slow movement, apparently by diffusion, into the periventricular tissue. Various growth factors and other neuroactive agents have been reported to be neuroprotective within the injured brain after intraventricular administration. It is postulated that the delivery of such factors to neurons and glia in the injured brain may be facilitated by abnormal CSF flow. These several observations suggest that the flow of CSF and entrained solutes may differ considerably between normal and abnormal brain and even among various neuropathologies.

Journal Article↗