Activities of narcotic and narcotic-antagonist analgesics following the intraventricular injection of various substances.
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Animals↗
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Catatonia and convulsive activity following intraventricular injections of quaternary ammonium compounds in the rat.
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Animals↗
[The effect of an intraventricular injection of ribonuclease on rat conditioned reflexes].
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Animals↗
Inhibition of acetylcholine turnover rate in rat hippocampus and cortex by intraventricular injection of adenosine analogs.
The effects of i.c.v. administration of adenosine receptor agonists and antagonists on the turnover rate of acetylcholine (TRACh) in various areas of the rat brain were examined in an effort to better understand the role of adenosine as a neuromodulator or cotransmittr. TRACh was determined by gas chromatographic-mass fragmentographic analysis of the rate of deuterium incorporation into ACh and choline during a constant rate infusion of deuterated phosphorylcholine. The i.c.v. administration of the adenosine receptor agonist, 2-chloroadenosine (2-CIAdo), in a dose of 82 nmol failed to change the ACh or choline content of any of the brain areas examined. This dose of 2-CIAdo elicited significant reductions in the TRACh in both the hippocampus and frontal cortex, but not in the striatum. The extent of the TRACh reduction was 67 and 36% in hippocampus and cortex, respectively. This inhibition of TRACh elicited by 2-CIAdo was antagonized by pretreatment (i.c.v.) with theophylline (278 nmol), suggesting that an activation of adenosine receptors is operative in the action of 2-CIAdo. Further support for a participation of adenosine receptors in the action of 2-CIAdo was obtained by comparing the effects of the L- and D-isomers of phenylisopropyladenosine (PIA) on TRACh. The i.c.v. administration of L-PIA (65 nmol) elicited a 79% reduction in the TRACh in the hippocampus, whereas D-PIA (65 nmol i.c.v.) had no significant effect on hippocampal TRACh. This finding supports the view that these effects on TRACh may be mediated by adenosine A1 receptors, but not by A2 receptors, because the former, but not the latter, display marked stereoselectivity toward PIA. It also was demonstrated that intraseptal injections of L-PIA or theophylline failed to reduce the TRACh in the hippocampus, suggesting that adenosine receptors located in the septum are not operative in mediating the i.c.v. action of PIA.
2-Chloroadenosine↗
Toxicity studies and distribution dynamics of retroviral vectors following intrathecal administration of retroviral vector-producer cells.
The use of intrathecal, retroviral-mediated transfer of the herpes simplex thymidine kinase (HStk) gene and subsequent ganciclovir (GCV) administration has recently been shown to improve survival in a rat model of leptomeningeal carcinomatosis. Clinical application of this approach is attractive because access to the cerebrospinal fluid (CSF) space is relatively noninvasive and distribution of producer cells and vectors may be facilitated by circulation of CSF, overcoming distribution problems inherent in solid tumors. However, meningeal inflammation, transduction and injury to normal CNS tissue, proliferation of the xenogeneic producer cells in the subarachnoid space, immune-mediated injury, and development of hydrocephalus are possible complications of intraventricular or intrathecal administration of vector-producer cells. In addition, the dynamics of producer cell and vector distribution in the CSF are unknown. To address these issues, we evaluated the safety of this approach for gene delivery and assessed the dynamics of distribution of producer cells and retroviral vectors in rats and non-human primates. In rats, transduction of normal central nervous system (CNS) structures surrounding the subarachnoid space was evaluated after intrathecal and intraventricular injections of beta-galactosidase and HStk vector-producer cells, with and without GCV. In primates, beta-galactosidase and HStk vector-producer cells were injected intraventricularly and GCV was administered either intrathecally or intravenously. Toxicity was evaluated by neurologic examination, serial gadolinium-enhanced MRI scans of the brain, and blood and CSF profiles. A subgroup of monkeys received repeated intraventricular injection of vector-producer cells and intravenous GCV. The titer of retroviral-vector was measured in cisternal and lumbar CSF samples after repeated producer cell injection.(ABSTRACT TRUNCATED AT 250 WORDS)
3T3 Cells↗
Effects of prostaglandin antagonism on sodium arachidonate fever in rabbits.
1. Sodium arachidonate, the prostaglandin precursor substance, when injected intraventricularly into rabbits, results in dose-dependent hyperthermia, which is rapid in onset and of several hours duration. 2. Arachidonate fever was inhibited by intraventricular injection of indomethacin, but not by the simultaneous intraventricular injection of either of the two prostaglandin antagonists SC 19220 or HR 546. 3. Both antagonists effectively inhibited the fever induced by the intraventricular injection of an equipotent dose of PGE1. 4. Our results show that a derivative of arachidonic acid other than prostaglandin is pyrogenic.
Animals↗
The role of calcitonin gene-related peptide in the control of growth hormone and prolactin release.
In order to evaluate the actions of calcitonin gene-related peptide (CGRP), a neuropeptide which is found within the hypothalamus, male and ovariectomized (OVX) female rats were injected intraventricularly (third ventricle, 3V) with varying doses of CGRP or antiserum directed against the peptide and the effect on plasma growth hormone (GH) and prolactin (Prl) concentrations studied. Intraventricular injection of the peptide (0.5 or 5.0 micrograms; 0.125 or 1.25 nmol) induced a suppression of GH release in conscious, OVX female and intact male rats. Conversely, intraventricular injection of diluted (1:10) highly specific antiserum against the peptide produced the reverse effect and a transient elevation in plasma GH occurring 2 h after the injection in males. A longer-lasting elevation occurred in OVX females which persisted for the 24-hour duration of the experiment. The elevation was delayed as has been the case with other antisera suggesting that the site of action was at some distance from the site of injection into the 3V. Since the peptide had an action to inhibit GH release from dispersed, overnight cultured anterior pituitary cells in vitro at doses of 10(-11) M, it is not certain from these results whether or not the effects of the peptide are exerted directly on the hypothalamus or the pituitary, but the results indicate a physiologically significant action of this peptide to suppress GH release. Similarly, intraventricular injection of the peptide produced a dose-related suppression of Prl release in OVX animals; however, antiserum directed against the peptide failed to alter Prl release. In males, only the lower 0.5-microgram dose effectively inhibited Prl release.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
beta-Endorphin-(1-27) inhibits the spinal beta-endorphin-induced release of Met-enkephalin.
The effect of intraventricular beta-endorphin-(1-27) on the spinal release of Met-enkephalin induced by intraventricular beta-endorphin was studied using the intrathecal superfusion technique in urethane anesthetized rats. Intraventricular injection of beta-endorphin at a dose of 15 micrograms released Met-enkephalin from the spinal cord. This release of Met-enkephalin induced by beta-endorphin was significantly reduced by beta-endorphin-(1-27), 60 micrograms, injected intraventricularly. Injection of beta-endorphin (1-27) itself did not cause any release of Met-enkephalin. The finding is in line with the previous report that beta-endorphin (1-27) inhibited the analgesia induced by beta-endorphin.
Animals↗
Nerve growth factor promotes collateral sprouting of cholinergic fibers in the septohippocampal cholinergic system of aged rats with fimbria transection.
Nerve growth factor (NGF) was injected intraventricularly into aged (24 months) rats with unilateral fimbria transection. Controls received intraventricular injections of cytochrome c. A quantitative analysis of acetylcholinesterase (AChE)-positive fibers was used to evaluate whether the NGF treatment can stimulate regeneration and reinnervation of the cholinergic axons in the septohippocampal system of aged rats with fimbria transection. A marked increase in the density of AChE-positive fibers was observed in the lateral septum, the dorsal fornix and the dorsal hippocampus of the NGF-treated animals, as compared to the controls. In the lateral septum, the increase was observed in the 2-month NGF-treated animals but not in the 15-day NGF-treated animals. In the dorsal fornix at the level of the dorsal hippocampus, the increase was observed on both the lesioned and unlesioned sides of both the 15-day and 2-month NGF-treated animals. In the denervated (lesioned side) hippocampus, the increase took place in the dorsal hippocampus but not in the ventral hippocampus of both the 15-day and 2-month NGF-treated animals. There was no recovery of AChE-positive fibers on the lesioned side of the fimbria distal to the lesion site even in the 2-month NGF-treated animals. These results demonstrate that intraventricular injections of NGF can stimulate collateral sprouting of intact cholinergic axons in the septohippocampal system and promote cholinergic reinnervation of the denervated hippocampus of aged rats with fimbria transection.
Acetylcholinesterase↗
Role of substance P in suppressing growth hormone release in the rat.
To evaluate a possible physiological role of endogenous substance P (SP) in the control of growth hormone (GH; somatotropin) secretion, a specific antiserum against SP (anti-SP) was injected intraventricularly (3 microliters into the third cerebral ventricle) in unanesthetized unrestrained normal male rats. Control rats received an equivalent volume of normal rabbit serum (NRS). Intraventricular injection of the NRS lowered plasma GH concentrations significantly. The lowering was detected on first measurement at 10 min after injection and was maximal at 30 min. This was followed by a return toward the initial levels. Third ventricular injection of antiserum significantly increased plasma GH in comparison with control animals injected with NRS. The effect was observed within 10-20 min, and levels remained elevated for the 120-min duration of the experiment. To confirm the possible inhibitory role of endogenous SP on GH release, 3 microliters of 0.9% NaCl (saline) alone or saline containing a specific antagonist of SP, [D-Pro2,D-Trp7,9]SP, was injected into the third ventricle of normal male rats. The antagonist also increased plasma GH significantly (P less than 0.005) within 5 min compared with values in the saline-injected control group. Levels remained elevated for 30 min but had returned toward control values 60 min after injection. In contrast, synthetic SP significantly decreased plasma GH when injected intravenously or intraventricularly compared with plasma GH in the control saline-injected group. To investigate a possible direct action of SP on GH release from the anterior pituitary gland, we incubated synthetic SP with dispersed anterior pituitary cells for 1 hr. The release of GH from incubated anterior pituitary cells was not affected at any dose of SP (10(-9) to 10(-6) M) tested. These data strongly indicate that endogenous SP has a physiological inhibitory role in the control of GH secretion at the level of the hypothalamus in the male rat.
Animals↗
Central administration of the opioid antagonist, LY255582, decreases short- and long-term food intake in rats.
A variety of opioid antagonists have been reported to decrease short-term food intake, but few appear to reduce long-term intake. In the present study we evaluated the effect of a relatively new class of opioid antagonists, 3,4-dimethyl-4-phenylpiperidines, on short-term and long-term food intake after central administration. We also evaluated their affinities for the mu and kappa opioid receptor sites in synaptosomal membranes derived from rat whole brain tissue (minus cerebellum) and guinea-pig cortex, respectively. The affinities for the mu receptor sites were LY255582 greater than LY217273 greater than LY256897 greater than naloxone greater than LY227444. The affinities for the kappa receptor sites were LY255582 greater than LY256897 = LY217273 greater than LY227444. LY255582 reduced food intake for up to 24 h after a single intraventricular injection. Doses as low as 1 microgram of LY255582 decreased food intake for up to 4 h. All other drugs were much less powerful. Naloxone and LY256897 only decreased food intake after injection of the 100 microgram dose. LY227444 and LY217273 failed to decrease intake at all doses tested. LY255582 (100 micrograms) decreased food intake over a 7 day period when injected intraventricularly once per day. The body weight of the rats also decreased during the 7 day period. Upon cessation of drug administration body weights and food intake approached control levels. Thus, LY255582 appears to be a very potent and long-acting anorectic agent which may be useful in the treatment of obesity. The mu and kappa binding profile of the phenylpiperidines does not seem to clearly correlate with their anorectic activity.
Animals↗
Cocaine differentially affects benzodiazepine receptors in discrete regions of the rat brain: persistence and potential mechanisms mediating these effects.
The effects of cocaine on benzodiazepine (BZD) receptor binding in the rat brain were investigated using homogenate receptor binding and quantitative autoradiography. Although acute cocaine injections produced little or no effect on BZD binding sites, chronic administration resulted in differential effects in brain regions associated with the mesocorticolimbic and nigro-striatal dopaminergic neuronal system, respectively. BZD receptor binding was increased significantly in the caudate nucleus and decreased in the substantia nigra for up to 2 days after the final injection, whereas binding was decreased in the nucleus accumbens and medial prefrontal cortex and increased in the ventral tegmental area after daily injections of cocaine for 15 days. Binding was altered significantly only in the medial prefrontal cortex and ventral tegmental area 2 weeks after the final cocaine injection. Intraventricular injections of 6-hydroxydopamine attenuated or reversed the cocaine-induced changes in BZD receptor binding, suggesting that these effects were mediated, in part, through the effects of the drug on dopaminergic neuronal activity. Dopamine may be involved in the regulation of BZD receptors because 6-hydroxydopamine administration produced changes in BZD receptor binding in saline-treated rats that were generally in the opposite direction to those observed in cocaine-treated rats following sham treatment.
Animals↗
The influence of central chemical sympathectomy and reserpine on peripheral effects of noradrenaline and cyclic AMP dibutyrate injected into the cerebral ventricles.
Chemical sympathectomy of the central nervous system by injection of 6-hydroxy-dopamine (2 X 250 mug) or 6-hydroxydopa (90 mug) intensified some of the peripheral effects of noradrenaline and cyclic AMP dibutyrate injected into the cerebral ventricles. Reserpine (5 mg/kg) injected intraperitoneally weakened the peripheral reactions to noradrenaline injected intraventricularly. The results of the experiments indicate that peripheral reactions to intraventricularly injected noradrenaline depend on changes in the content of endogenous narodrenaline in the brain and on the mechanisms leading to these changes.
Animals↗
[Comparative study of the effects of carbachol, eserine and dibutyryl cyclic guanosine monophosphate on the behaviour of the cat].
Carbachol and eserine injected into cerebral ventricles of conscious cats evoked aggressive behaviour accompanied with autonomic and motor phenomena. However, db-cGMP also injected into cerebral ventricles of conscious cats elicited autonomic effects with miaowing, restlessness, ear twitching and scratching. When butyrate sodium and butyryc acide were injected intraventricularly no visible gross behavioural phenomena in conscious cats were observed. The gross behavioural effects of db-cGMP were substantially the same when the cats were pretreated by intraventricular injections of aminophylline.
Aggression↗
Active transport of methotrexate from cerebrospinal fluid in humans.
The cerebrospinal fluid (CSF) efflux kinetics of methotrexate (MTX) were studied in three patients with indwelling Ommaya reservoirs. A small dose of MTX was injected intraventricularly several hr after the start of a high-dose continuous i.v. infusion of MTX. In all patients, the CSF antifolate concentration returned to the preinjection level before the end of the i.v. infusion. This result indicated that the efflux of MTX from CSF in humans is independent of plasma drug concentrations. Efflux kinetics were further characterized in one patient. Serially obtained CSF samples after intraventricular injections demonstrated a biphasic disappearance curve with alpha- and beta-phase half-disappearance times of 1.7 and 6.6 hr, respectively. Prolongation of the beta-phase half-time was associated with oral acetazolamide medication and with increased intracranial pressure, indicating that inhibition of CSF production slows MTX clearance. CSF MTX concentration, however, declined more rapidly than that of simultaneously administered diethylenetriaminepentaacetic acid, an extracellular marker substance excreted by bulk flow, indicating that bulk flow excretion alone is insufficient to account for MTX efflux from human CSF. Evidence that there is an active transport component was provided by probenecid pretreatment which also prolonged the CSF MTX half-life. These findings suggest that both passive and active mechanisms govern MTX efflux from the CSF in humans and that they can be inhibited by acetazolamide and probenecid, respectively.
Acetazolamide↗
The effect of substance P and its fragments on passive avoidance retention and brain monoamine activity.
It has been shown that substance P(SP), as well as its carboxy and amino terminal fragments, affects a wide range of behaviors. In order to test the CNS activity of these fragments, we measured their effects on passive avoidance learning and monoamine activity. Following one-trial passive avoidance training, mice were injected intraventricularly with either a carboxy or amino terminal SP fragment (SP-C or SP-N), SP itself or phosphate-buffered saline (PBS). SP-N enhanced avoidance retention, which was tested 24 h after training. In a second experiment, monoamine activity was measured one hour after intraventricular injection of SP, PBS or SP fragments. SP-C decreased both nigral 5-hydroxyindoleacetic acid/5-hydroxytryptamine (5-HIAA/5-HT) and, to a lesser extent, 3,4-dihydroxyphenylacetic acid/dopamine, while SP-N increased nigral 5-HIAA/5-HT. It was concluded that SP-N and SP-C can exert behavioral and neurochemical effects that may be independent of the parent SP molecule.
3,4-Dihydroxyphenylacetic Acid↗
Delta sleep inducing peptide (DSIP) stimulates the release of LH but not FSH via a hypothalamic site of action in the rat.
Long term ovariectomized (OVX) Sprague-Dawley rats were injected intraventricularly (3rd ventricle) with 5 micrograms (2 microliter) of DSIP. This caused a significant elevation (p = 0.01) of LH levels within 30 min. The values remained elevated for 2 hr; however, FSH levels remained unchanged. The minimal effective dose of DSIP to evoke this effect was 1 microgram. If plasma PH was lowered by pretreatment of the animals with estradiol, the 5 micrograms dose evoked an even greater effect to elevate LH significantly at 30 and 60 min following its intraventricular injection. To determine the site of action of DSIP, dispersed, overnight cultured pituitary cells from OVX rats were incubated with varying concentrations (10(-7) to 10(-12) M) of DSIP in an in vitro system. There was no response to DSIP from the cells in the above system. To evaluate its possible action on the hypothalamus, median eminence (ME) fragments from male rats were incubated in vitro with DSIP in varying concentrations from 10(-7) to 10(-10) M. There was a significant (p less than 0.001) increase in LHRH released from the ME at a concentration of DSIP of 10(-7) M. A sleep-related increase in LH release is seen during puberty in man. It is possible that DSIP released within the hypothalamus may play a physiological role in sleep-related LH release.
Animals↗
Effects of substance P on anterior pituitary secretion in the female rhesus monkey.
The effects of substance P on anterior pituitary secretion were studied in 3 female rhesus monkeys. In nine experiments, 100 microgram substance P was injected intraventricularly, and the results were compared to those obtained following intraventricular injection of the control vehicle. In 7 out of 9 experiments, substance P induced a significant increase in prolactin secretion within 5 min. Peak levels at 10 min were approximately 15-20 times those of the baseline control. Substance P also induced a slight but significant decrease in GH secretion 20 min following injection, but at other times GH levels were not significantly changed. LH and FSH as well as cortisol concentrations remained unaltered. In 2 monkeys a decrease in systolic pressure of 40-70 mm Hg within 10-60 sec and lasting 180-300 sec was observed following the administration of substance P but not the control vehicle. The results indicate that substance P, which in the monkey has been shown to be associated with hypothalamic regions implicated in the control of anterior pituitary secretion, can alter prolactin and GH release.
Animals↗