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PubMed1991

Neuroendocrine regulation of growth hormone secretion in sheep. II. Effect of somatostatin on growth hormone and glucose levels.

The effect of intravenous (iv) and intracerebroventricular (icv) administration of somatostatin on the plasma levels of growth hormone (GH) and glucose was studied in sheep. Intravenous somatostatin decreased (P less than 0.001) circulating GH when infused at the rate of 5 micrograms/min (150 ng/kg/min) over 1 hr, but when used at 1 microgram/min there was no effect on plasma GH levels during infusion. At both doses used there was an indication of an increase in GH following the cessation of somatostatin infusion. Somatostatin given at both these doses iv had no effect on plasma glucose levels. When given icv neither 1.8 micrograms, 18 micrograms nor 180 micrograms somatostatin had any significant effect of plasma GH levels, although there was a significant (P less than 0.05) elevation in GH levels 75 min after 180 micrograms somatostatin icv. Plasma glucose levels did not increase following injection of somatostatin icv at 1.8 or 18 micrograms, but there was a clear hyperglycaemic episode following 180 micrograms icv. Despite a lack of effect of somatostatin on GH release when given icv, there was a clear elevation (P less than 0.05) in plasma GH levels immediately following icv administration of a somatostatin antiserum. These data indicate that iv administration of somatostatin at pharmacological levels can depress unstimulated GH levels in sheep while administration icv does not. Central administration of somatostatin increases plasma glucose levels only at high doses and seems unlikely to be of physiological importance in glucose homeostasis.

Animals↗
PubMed1994

Effect of morphine and naloxone on LH response and sexual behavior of rams (Ovis aries).

Effects of the opiate agonist, morphine, and antagonist, naloxone, on LH release, courtship behavior and ejaculation frequency of mature, sexually active or sexually inactive rams were investigated. Plasma LH concentrations were monitored from blood samples collected every 15 min for 10 hr (0800 to 1800 hr) from eight rams that were isolated from or in contact with estrous females. Plasma LH concentration was higher (P < .05) in sexually active rams exposed to receptive females compared with hormone concentration of rams isolated from ewes. Intravenous infusion of morphine sulphate (1 mg/kg) into rams 4 and 6 hr after exposure to ewes reduced (P < .05) plasma LH concentration as compared to rams given saline. Morphine did not affect (P > .05) courtship behavior (investigatory sniff, mount attempt, foreleg kick, flehmen, vocalization) but diminished (P < .05) number of ejaculations. In another trial, LH concentrations were higher (P < .05) in seven sexually active rams given naloxone iv or when given to three rams through an intracerebroventricular cannula (icv) as compared to LH response of sexually inactive rams. LH did not differ (P > .05) in seven sexually inactive rams before or after administration of naloxone. Investigatory sniffs by sexually active rams were increased (P < .03) after treatment with the opiate antagonist. Four of the seven sexually active rams had more ejaculations after naloxone compared with the pretreatment period, but mean ejaculation frequency after treatment did not differ (P = .31). Naloxone did not stimulate courtship behavior of sexually inactive males.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Development of antinociceptive tolerance and physical dependence following morphine i.c.v. infusion in mice.

The chronic i.c.v. infusion of morphine has been reported for rats but not for mice. In the current report, the antinociceptive tolerance to both i.c.v. morphine infusion and s.c. implantation of morphine pellets in mice was compared. Physical dependence after i.c.v. morphine infusion was also evaluated. Osmotic minipumps were filled with morphine (50 mM), connected to i.c.v. cannulae, and implanted s.c. to deliver 50 nmol/h for 3 days (i.e., 3.6 micromol total). Robust jumping precipitated by naloxone (1 mg/kg, s.c.) indicated the development of physical dependence. Tolerance to i.c.v., i.t., and i.v. morphine (6.3-, 2.0-, and 4.4-fold, respectively) was observed using the tail flick test. Mice implanted with pellets containing 75 mg morphine for 3 days (i.e., approximately 260 micromol total) were also tolerant to morphine (6.5-, 7.5- and 18-fold, respectively). Thus, the tolerance developed using the two methods was not identical. These results allow comparison of morphine tested by 3 different routes (i.c.v., i.t., and i.v.) after chronic morphine treatment by two routes (i.c.v. and s.c.) in a single study.

Adaptation, Physiological↗
PubMed2006

Intracerebroventricular delivery of dominant negative prion protein in a mouse model of iatrogenic Creutzfeldt-Jakob disease after dura graft transplantation.

We have developed a novel procedure in which a small collagen sheet (3 mm x 3 mm) absorbing prion-infected brain homogenates was transplanted onto the brain surface of highly prion-susceptible transgenic mice (Tg(MoPrP)4053/FVB), as an animal model of iatrogenic Creutzfeldt-Jakob disease (iCJD) caused by prion-contaminated cadaveric dura graft transplantation. Using the iCJD model, we further investigated the in vivo efficacy of dominant negative recombinant prion protein with lysine substitution at mouse codon 218 (rPrP-Q218K), which is known to inhibit prion replication in vitro (H. Kishida, Y. Sakasegawa, K. Watanabe, Y. Yamakawa, M. Nishijima, Y. Kuroiwa, N.S. Hachiya, K. Kaneko, Non-glycosylphosphatidylinositol (GPI)-anchored recombinant prion protein with dominant-negative mutation inhibits PrPSc replication in vitro, Amyloid, vol. 11, 2004, pp. 14-20.). Following 7-day intracerebroventricular administration of the rPrP-Q218K via an indwelling catheter connected to the implanted osmotic pump, the median incubation period of Tg(MoPrP)4053/FVB was prolonged considerably from 117 days to 131 days (p=0.016, log-rank test) in the rPrP-Q218K-treated group, even after a lengthy latency period of as long as 30 days by starting the rPrP-Q218K injection. Whether wild-type rPrP, other mutant rPrPs, or the combination of rPrP-Q218K with other anti-prion compounds might extend the survival period in that condition must be further investigated.

Animals↗
PubMed2003

Effect of the gadolinium ion on body fluid regulation.

Both osmoreception and baroreception are thought to involve ion channels that are sensitive to changes in membrane stretch. We investigated the effect of a blocker of stretch-activated ion channels, the Gd3+ ion, on osmoregulatory and cardiovascular responses in the intact rat. Intracerebroventricular injection of 50-100 nmol Gd3+ reduced thirst induced by various treatments. Similar doses also reduced intake of saline induced by various treatments. Intracerebroventricular injection of 100 nmol Gd3+ transiently increased arterial pressure and reduced the pressor response to intracerebroventricular angiotensin II (Ang II). Systemic administration of Gd3+ failed to alter thirst, except for a high dose (270 micromol/kg) that induced illness. This high dose failed to prevent urinary hypertonicity and excretion of a load of hypertonic NaCl. Intravenous infusion of 270 micromol/kg of Gd3+ reduced blood pressure and pressure responses to intravenous phenylephrine, but did not reduce the baroreceptor reflex control of heart rate. We conclude that the effects of Gd3+ on thirst and on the cardiovascular system are probably not due to a direct effect of the drug on stretch-sensitive ion channels. Instead, many of the effects of Gd3+ were compatible with blockade of voltage-gated Ca2+ channels.

Angiotensin II↗
PubMed1999

Dissociation between the effects of interleukin-1 on excitotoxic brain damage and body temperature in the rat.

The cytokine interleukin-1beta (IL-1beta) mediates and exacerbates excitotoxic brain damage in the rat striatum. Co-injection of the selective glutamate receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA) with human recombinant IL-1beta (hrIL-1beta) in the striatum of rats results in both local (striatal) damage and extensive, distant neuronal death in the cortex. The objective of the present study was to investigate the mechanisms underlying IL-1beta actions on excitotoxic damage, and to determine whether this effect of IL-1beta, a potent pyrogen, is due to modification of body temperature. Striatal infusion of S-AMPA (7.5 nmol) in anaesthetised rats produced localised striatal damage. Intrastriatal co-infusion of hrIL-1beta (10 ng) with S-AMPA caused similar striatal damage, but also produced extensive cortical damage, together with a modest increase in body temperature (0.9 degrees C) compared to rats infused with S-AMPA alone. Infusion of S-AMPA into the striatum, together with intracerebroventricular (i.c.v.) injection of hrIL-1beta, produced a similar rise in temperature to striatal co-infusion of S-AMPA and hrIL-1beta, but resulted in only local (striatal) neuronal damage, that was similar to that caused by striatal infusion of S-AMPA alone. These data suggest that the effects of IL-1beta on AMPA-receptor mediated neuronal damage in the striatum can be dissociated from its pyrogenic effects on body temperature.

Animals↗
PubMed2001

Huperzine A attenuates cognitive dysfunction and neuronal degeneration caused by beta-amyloid protein-(1-40) in rat.

Huperzine A, a promising therapeutic agent for Alzheimer's disease, was examined for its potential to antagonize the deleterious neurochemical, structural, and cognitive effects of infusing beta-amyloid protein-(1-40) into the cerebral ventricles of rats. Daily intraperitoneal administration of huperzine A for 12 consecutive days produced significant reversals of the beta-amyloid-induced deficit in learning a water maze task. This treatment also reduced the loss of choline acetyltransferase activity in cerebral cortex, and the neuronal degeneration induced by beta-amyloid protein-(1-40). In addition, huperzine A partly reversed the down-regulation of anti-apoptotic Bcl-2 and the up-regulation of pro-apoptotic Bax and P53 proteins and reduced the apoptosis that normally followed beta-amyloid injection. The present findings confirm that huperzine A can alleviate the cognitive dysfunction induced by intracerebroventricular infusion of beta-amyloid protein-(1-40) in rats. The beneficial effects are not confined to the cholinergic system, but also include favorable changes in the expression of apoptosis-related proteins and in the extent of apoptosis in widespread regions of the brain.

Alkaloids↗
PubMed2001

Noradrenaline in the bed nucleus of the stria terminalis is critical for stress-induced reactivation of morphine-conditioned place preference in rats.

The effect of noradrenaline in the bed nucleus of the stria terminalis and locus coeruleus on maintenance and reactivation of morphine-conditioned place preference induced by footshock stress was investigated in rats. After receiving alternate injection of morphine (10 mg/kg) and saline for 6 consecutive days, the rats spent more time in the drug-paired compartment (morphine-conditioned place preference) on day 7. These animals did not show morphine-conditioned place preference on day 37 following sham-footshock once every 3 days from days 8 to 36 (28 days drug-free). However, 15 min of intermittent footshock once every 3 days could induce the maintenance of morphine-conditioned place preference on day 37 with significantly more time spent in the drug-paired compartment than on day 0. Microinjection of the alpha(2)-adrenoceptor agonist, clonidine (0.1 or 1 microg), into the locus coeruleus 30 min before footshock did not affect stress-induced maintenance of conditioned place preference. However, infusions of clonidine (1 microg) into the bed nucleus of the stria terminalis significantly attenuated the maintenance of conditioned place preference induced by footshock stress. In another experiment, after a 21-day extinction of morphine-conditioned place preference, a single footshock could reactivate the morphine place preference that was significantly blocked by pretreatment with infusion of clonidine (0.1 or 1 microg) into the bed nucleus of the stria terminalis but not the locus coeruleus. Reactivation of morphine-conditioned place preference elicited by footshock stress was significantly inhibited by 6-hydroxydopamine-induced lesions in the ventral noradrenergic bundle, most of the norepinephrine input to the bed nucleus of the stria terminalis arising from caudal brain stem noradrenergic cell groups. In contrast, chemical lesions of the dorsal noradrenergic bundle that arises from the locus coeruleus had no such effects. These findings suggest that noradrenergic neurons in locus coeruleus are not involved in stress-induced reinstatement of drug-seeking and further clearly demonstrate that noradrenaline in the bed nucleus of the stria terminalis plays a critical role in mediating this effect. Comprehension of the neurochemical events underlying the stress-induced and the bed nucleus of the stria terminalis-mediated reinstatement of drug-seeking may, therefore, throw more light on the biological bases of drug dependence and addictive behavior

Adrenergic alpha-Agonists↗
PubMed2003

Tolerance and dependence following chronic intracerebroventricular infusions of Tyr-D-Arg2-Phe-Sar4 (TAPS).

The dermorphin-derived tetrapeptide Tyr-D-Arg(2)-Phe-Sar(4) (TAPS) was tested for its ability to induce tolerance, cross-tolerance, withdrawal and its substitution properties in rats subjected to chronic intracerebroventricular (i.c.v.) infusions of mu-opiate receptor agonists. Tolerance and cross-tolerance were assessed by quantification of the thermally induced tail-flick response. Chronic intracerebroventricular infusion of TAPS resulted in antinociception at almost 1000-fold lower doses compared to morphine sulphate and [D-Ala(2), MePhe(4)Gly(ol)(5)]enkephalin (DAMGO). Tolerance to the antinociceptive effect of TAPS developed similar to DAMGO and morphine sulphate. Cross-tolerance to intracerebroventricular bolus injections of DAMGO, but not of TAPS, was evident in rats rendered tolerant to morphine sulphate and TAPS. Naloxone-induced withdrawal was equally pronounced in animals treated with morphine sulphate, DAMGO or TAPS. TAPS substituted for morphine sulphate and vice versa regarding the withdrawal syndrome in a cross-over experimental design. In contrast to DAMGO, TAPS retains its antinociceptive effect following bolus administration in rats rendered tolerant to mu-opioid receptor agonists.

Analgesics, Opioid↗
PubMed1997

Subchronic administration of N-[2-(3,4-dichlorophenyl) ethyl]-N-methyl-2-(dimethylamino) ethylamine (BD1047) alters sigma 1 receptor binding.

BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine) is known to bind with high affinity and selectivity to sigma sites in vitro. In prior in vivo studies, it has been shown to attenuate the dystonic postures and orofacial dyskinesias that are produced by sigma receptor ligands, including the neuroleptic haloperidol. Since abnormal movements, such as dystonic postures and orofacial dyskinesias, are side effects that are associated with many sigma-active neuroleptics, compounds such as BD1047 may have therapeutic potential for preventing and treating these unwanted movements. A possible limitation to the therapeutic potential of BD1047, however, is that at least in cell culture and albeit weak, it can be cytotoxic. Therefore, the present study analyzed the possible neurotoxic effects of in vivo subchronic intracerebroventricular infusion of BD1047 (10 nmol/h) or artificial cerebrospinal fluid (CSF) into rat brains using osmotic minipumps for 7 or 14 days. Following a 24 h wash-out period, the animals were killed, the brains removed, and P2 membranes prepared. Membranes from rats treated for 7 or 14 days with BD1047 showed a marked decrease in [3H](+)-pentazocine binding as compared to membranes from CSF-treated animals, suggesting a loss of sigma 1 receptor binding. Histological examination of brain sections processed for Nissl stains and glial fibrillary acidic protein (GFAP) immunohistochemistry excluded the possibility of a cytotoxically induced down-regulation, suggesting possible receptor internalization or desensitization mediated via sigma 1 sites. Under the conditions used in our study, BD1047 does not appear to be neurotoxic, and the data, when taken together with other studies, suggest that BD1047 acts as a partial agonist at sigma sites.

Analysis of Variance↗
PubMed1999

Tetrahydroaminoacridine and D-cycloserine fail to alleviate the water maze spatial navigation defect induced by hippocampal inactivation.

The present study examined the efficacy of single and combined treatment with an anticholinesterase, tetrahydroaminoacridine (i.p.), and a glycine-B site partial agonist, D-cycloserine (i.p.; a positive allosteric modulator of NMDA receptors), in alleviating the deficit in water maze spatial navigation induced by electrolytic lesion of the medial septum or lidocaine infusion into the dorsal hippocampi. In medial septum-lesioned rats, a combination of tetrahydroaminoacridine 3 mg kg(-1) and D-cycloserine 10 mg kg(-1) facilitated acquisition of the water maze test more effectively than either of the drugs alone. Single or combined treatment with tetrahydroaminoacridine 3 mg kg(-1) and D-cycloserine 10 mg kg(-1) had no effect on the water maze deficit induced by hippocampal lidocaine infusion. These results suggest that combined treatment with tetrahydroaminoacridine and D-cycloserine can effectively stimulate water maze spatial navigation, and that functioning of the hippocampus is a prerequisite for this effect.

Anesthetics, Local↗
PubMed1997

Diuretic and antinatriuretic responses produced by the endogenous opioid-like peptide, nociceptin (orphanin FQ).

Nociceptin (orphanin FQ) is a novel peptide isolated from brain tissue that has an amino acid sequence most similar to that of the endogenous opioid peptide dynorphin A. Aside from this similarity, the association of nociceptin to the endogenous opioid peptide systems and the functional importance of this new peptide in vivo are not completely known. Here we report that nociceptin is physiologically active in vivo and produces marked changes in the renal excretion of water and sodium. In conscious Sprague-Dawley rats, intravenous infusion of nociceptin produced a profound increase in urine flow rate and decrease in urinary sodium excretion. In further studies, intracerebroventricular (i.c.v.) injection of nociceptin into conscious rats produced a concurrent diuresis (dose-dependent) and antinatriuresis. The magnitude and pattern of the central nociceptin-induced water diuresis was similar to that produced by i.c.v. dynorphin A. Whereas i.c.v. pretreatment with the selective kappa-opioid receptor antagonist, nor-binaltorphimine, completely prevented the renal responses produced by dynorphin A, this antagonist did not alter the diuresis or antinatriuresis produced by central nociceptin. Thus, these results indicate that in conscious rats, nociceptin produces a selective water diuresis via a central nervous system mechanism independent of kappa-opioid receptors. Together, these observations suggest that endogenous nociceptin may be a novel peptide involved in the central control of water balance and ultimately in the regulation of arterial blood pressure. In the future, analogues of nociceptin may prove to be the first clinically useful water diuretics for patients with water-retaining diseases.

Animals↗
PubMedDate not supplied

Leptin responsiveness in mice that ectopically express agouti protein.

Agouti protein is an endogenous antagonist of melanocortin receptors (MCR), including MCR3 and MCR4, which have been implicated as part of the hypothalamic mechanism that mediates leptin-induced hypophagia. In this experiment we examined the effects of peripheral and central leptin administration in male and female beta-actin promoter (BAPa) mice that express agouti protein ectopically and have a phenotype that includes obesity and diabetes which is exaggerated in males compared with females. Intraperitoneal infusion of 10 microg leptin/day for 13 days caused weight loss and a transient inhibition of food intake in wild-type mice, with a greater effect in males than females. Male BAPa mice were resistant to leptin infusion whereas female mice lost weight. All of the mice lost body weight following a single intracerebroventricular injection of leptin but the effect was greater in female BAPa mice than any other group. There also was a delayed suppression of food intake that was the same for wild-type and BAPa female mice, whereas food intake recovered faster in BAPa than wild-type males. The dissociation between food intake and body weight loss implies a significant effect of leptin on energy expenditure in BAPa mice. These results demonstrate that the effect of leptin on energy balance is not entirely dependent upon the melanocortin system.

Agouti Signaling Protein↗
PubMed2002

Oligodeoxynucleotides induce brain inflammation in rats when infused intracerebroventricularly.

Antisense oligodeoxynucleotides (ODNs) can inhibit gene expression in a specific manner. However, several studies described problems with cerebral ODN application. Here, we investigated the immune effects (interleukin-6 (IL-6) release, cell invasion into cerebrospinal fluid (CSF) and brain parenchyma) of 'non-sense' randomized ODNs with different counterions (NH(4)(+), Na(+)) and modifications (with or without thioat-backbone) which were administered intracerebroventricularly for 48 h using osmotic mini-pumps in a rat model. All animals receiving ODNs showed increased IL-6 levels in the CSF as well as cell invasion into the CSF and brain parenchyma (P<0.05). However, the use of thioat-backbone and ammonium as the counterion induced the highest IL-6 levels (7210+/-1696 pg/ml, P<0.05) and the highest cell numbers in the CSF (31.6+/-15.5x10(5)/ml, P<0.05) as well as brain parenchyma (268.1+/-143.2 HIS-48+ cells/mm(2), P<0.01; and 31.3+/-10.7 OX-6+cells/mm(2), P<0.05) compared with the other groups.

Animals↗
PubMed1997

Physiological and behavioral effects of chronic intracerebroventricular infusion of corticotropin-releasing factor in the rat.

The present study was conducted to investigate the long-term effects of chronic elevation of centrally circulating levels of corticotropin-releasing factor (CRF) on behavior and physiology. For this purpose ovine CRF was infused continuously for a period of 10 days into the lateral ventricle of rats with the aid of osmotic pumps (calculated CRF delivery was 4.9 micrograms/day). Changes in daily rhythms in body temperature and home cage motor activity were recorded telemetrically during the infusion period. The most prominent physiological findings were a delayed body weight gain and a long-lasting hyperthermia following CRF infusion. The peptide treatment furthermore increased adrenal weight and suppressed the weight of the thymus at the end of the experiment. Behaviorally, CRF administration elicited a short-lasting increase in activity during the light phase and an increased anxiety in an elevated plus-maze 1 week after the start of infusion. The similarities between the present results and the long-term changes previously described in behaviorally stressed rats indicate that chronically elevated levels of CRF in the brain might play an important role in the induction and persistence of stress-related behavioral and physiological disorders.

Animals↗
PubMed2000

kappa-opioid agonist stimulated regional distribution of [(35)S]GTPgammas binding in butorphanol continuously infused rat.

Butorphanol is a mixed agonist/antagonist opioid analgesic agent, which exerts its effects mainly by interaction with the kappa-opioid receptor. Opioid receptors are coupled to G proteins of G(i)/G(o) family, and recently a decrease in micro-opioid activation of G proteins has been reported in specific brainstem nuclei after chronic morphine administration. The influence of centrally administered butorphanol on agonist-stimulated G protein coupling was examined in the rat brain, using in situ guanylyl-5'-O-(gamma-[(35)S]thio)-triphosphate (GTPgammaS) binding autoradiography. Rats were treated with butorphanol (26 nmol/microl/h) by intracerebroventricular infusion via osmotic minipumps for 3 days. The distribution of [(35)S]GTPgammaS binding in the brain 7 h after the termination of butorphanol infusion was measured in the presence or absence of the selective kappa-opioid agonist, U-50,488. This agonist significantly increased [(35)S]GTPgammaS binding in the parietal cortex, caudate putamen, thalamus, and central gray of control rats, but not in those regions of the butorphanol-infused animals. These results suggest that chronic administration of butorphanol developed tolerance and abolished U-50,488 activation of G proteins in these brain areas.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2003

Effect of prolactin infused into the third ventricle on LH secretion in follicular-phase and ovariectomized ewes.

This study tested a hypothesis that an acute enhancement of prolactin concentration within the central nervous system (CNS) would affect the LH secretion in ewes, depending on the level of endogenous estrogens in the organism. A 3-h long intracerebroventricular (icv.) infusion of ovine prolactin was made in late follicular-phase ewes, experiment 1, and in ovariectomized (OVX) ewes (experiment 2). No significant differences were found in mean LH concentrations and LH peak number before, during and after prolactin administration (50 microg/100 microl/h) in intact cyclic ewes. No diurnal rhythm in LH was detected in prolactin-infused ewes. From the two doses of prolactin used in OVX ewes (25 and 50 microg/100 microl/h) only the lower dose suppressed significantly the mean plasma LH concentration after the infusion, compared to those noted before (P < 0.01) and during (P < 0.001) prolactin treatment. Prolactin had no effect on LH pulse frequency in OVX ewes, however, a tendency to decrease in LH peak number was observed after administration of a lower dose. Plasma prolactin levels decreased significantly (P < 0.01 and P < 0.001) after the icv. infusion in all groups, indicating a high degree of effectiveness for exogenous prolactin at the level of the CNS.

Animals↗