Effects Of Intracerebroventricular Administration Research Articles

Hemodynamic effects of centrally administered adrenomedullin (13-52) in anesthetized rats.

This study was conducted to investigate the effect of intracerebroventricular administration of adrenomedullin (13-52) [ADM(13-52)], a novel hypotensive peptide, on the hemodynamic parameters of anesthetized rats. ADM(13-52) was administered centrally in a dose of 0.4-3.2 nmol/kg. It provoked marked, prolonged and dose-dependent increases in mean arterial blood pressure, heart rate, stroke volume, cardiac index, left ventricular pressure, left ventricular dp/dtmax and dp/dtmin, but reduction in total peripheral resistance index. In addition, intracerebroventricular administration of ADM(13-52; 1.6 nmol/kg) provoked a marked increase in renal sympathetic nerve activity. Intracerebroventricular administration of artificial cerebrospinal fluid had no effect on the hemodynamic parameters and renal sympathetic nerve activity. The results indicate that ADM(13-52) exerts a central action on the cardiovascular system. The mechanisms of hemodynamic changes induced by central ADM(13-52) were preliminarily analyzed in this study. ADM might play a role in the central control of the cardiovascular system, although the confirmed mechanisms and the physiological implications are undetermined.

メンヨウにおけるムシモールの脳室内投与が粗飼料および濃厚飼料の採食に及ぼす影響

γ-アミノ酪酸のアゴニストであるムシモールを,粗飼料または濃厚飼料により飽食させたメンヨウの側脳室に投与した際に生じる採食行動の違いを検討した.妊娠•泌乳していない雌メンヨウ4頭を濃厚飼料で飽食させた後に,側脳室カテーテルから70nmolまたは正40nmolのムシモールを投与した.いずれの投与量のムシモールも投与15分以内に採食促進が生じ,この傾向は投与後30分まで持続した.またこの採食促進作用は用量依存的であった.この結果から,ムシモールは中枢神経に作用し,濃厚飼料による満腹感を抑制することが示された.次いで,先の試験で用いたメンヨウの内3頭を用いて,ムシモール投与が粗飼料および濃厚飼料摂取促進に及ぼす影響を比較検討した.いずれの飼料で飽食させた場合でも投与15分以内に採食促進が生じ,ムシモールは,粗飼料による満腹感も抑制することが示された.しかしながらこの採食行動誘発作用は粗飼料飽食時には濃厚飼料飽食時と比較し微弱であった.粗飼料飽食時にはムシモール投与30分以降には著しい採食抑制が生じ,その結果,投与後22時間の総採食量は低下した.一方,濃厚飼料飽食時には,ムシモールの採食促進作用は投与30分後まで持続し,またその後の採食抑制は粗飼料飽食時と比較すると弱く,ムシモール投与後21時間の総採食量は生理的食塩水投与を行なった場合と比較し差は認められなかった.この結果から,ムシモールによる満腹感抑制は粗飼料給与時と比べ濃厚飼料給与時で強い,またはムシモールは満腹中枢以外の中枢神経系に作用し,粗飼料の摂取を抑制する可能性があることが推察された.

Activation of mesolimbic dopaminergic neurons following central administration of histamine is mediated by H1 receptors

The effect of intracerebroventricular administration of histamine on the activity of mesolimbic and nigrostriatal dopaminergic (DA) neurons was determined in male rats. The activity of these neurons was estimated by measuring: (1) the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after administration of a decarboxylase inhibitor, and (2) the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens and striatum, which contain the terminals of these neurons. Central administration of histamine increased both DOPA accumulation and DOPAC concentrations in the nucleus accumbens, but was without effect in the striatum. The increase in DOPAC concentrations in the nucleus accumbens occurred within 10 min and was sustained for at least 120 min. The H1 antagonist mepyramine blocked whereas the H2 antagonist zolantidine did not affect histamine-induced increases in DOPAC concentrations in the nucleus accumbens. Neither mepyramine nor zolantidine affected basal DOPAC concentrations in the nucleus accumbens. These results indicate that central administration of histamine stimulates mesolimbic DA neurons through an action at the H1 receptor, but has no effect upon the activity of nigrostriatal DA neurons.

Effects of intracerebroventricular administration of D,L-2-amino-5-phosphonovaleric acid, an N-methyl-D-aspartate receptor antagonist, on luteininizing hormone release in ovariectomized lambs.

To determine whether endogenous glutamate and aspartate control LH secretion via N-methyl-D-aspartate (NMDA) receptors in the sheep, we evaluated the effects of the NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid (AP5) on secretion of LH in ovariectomized lambs. Twelve lambs were ovariectomized and surgically implanted with lateral cerebroventricular cannulae. At the time of the experiment, (38 wk of age) they received intracerebrally 4 injections of either 50 (n = 4), 100 (n = 4), or 200 micrograms (n = 4) of AP5. Blood samples were collected every 10 min for 8 h with animals receiving AP5 at hours 4, 5, 6, and 7. Patterns of LH during the preinjection period were compared to those during the period encompassing AP5 injections. Mean concentrations of LH were lower during AP5 injections than during the preinjection periods, a response that was not influenced by dose (0.87 +/- 0.08 vs. 0.69 +/- .07 ng/ml; p < 0.01). LH pulse amplitude decreased during AP5 treatment relative to the preinjection periods, but this difference was not statistically significant (0.79 +/- 0.11 vs. 0.68 +/- 0.10 ng/ml; p = 0.09). There were no effects of AP5 on LH pulse frequency (1.00 +/- 0.10 vs. 0.83 +/- 0.15 pulses/h for injection and preinjection periods; p > 0.10). A second experiment was done to evaluate a higher dose of AP5. Four animals were chosen to receive 4 injections of 2 mg of AP5 in a design identical to that used in the first experiment.

Behavioral effects of atrial and brain natriuretic peptides in rats.

The effects of intracerebroventricular administration of rat atrial natriuretic peptide (rANP-1-28) and porcine brain natriuretic peptide-32 (pBNP-32) on passive and active avoidance behavior and on electroconvulsive shock-induced amnesia were studied in rats. The dose range for both peptides was selected to lie between 0.016 and 0.32 nmol. The two peptides were found to facilitate consolidation of the passive avoidance response, to delay extinction of the active avoidance response, and to prevent electroconvulsive shock-induced amnesia in a similar way. It is suggested that some modulatory functions in the central nervous system of the rat, so far attributed to ANP, may in fact involve a dual control by both ANP and BNP, and there is no difference in the biological activity of the two peptides as far as fear-motivated learning behavior is concerned.

The Effect of Intracerebroventricular Administration of Somatostatin on Prolactin and TSH Release in Rats

We investigated the effect of intracerebroventricular (icv) administration of somatostatin (SRIF) on prolactin (PRL) and thyroid-stimulating hormone (TSH) release in freely moving rats chronically cannulated with an atrial catheter. The plasma PRL levels were significantly elevated following the icv administration of 0.5 microgram SRIF. No further increase in PRL following the icv administration of SRIF were found in the rats in the course of repeated intravenous of injection of 5.0 mg/kg sulpiride, a specific D2 receptor antagonist. On the other hand, the injection of 5.0 micrograms SRIF resulted in no significant change in the plasma TSH levels. These results suggest that the effect of SRIF on PRL release was exerted through brain D2 receptors.

Effects of the administration of a-methyl-p-tyrosine on the striatal dopamine increase and the behavioral motor disturbances in rats exposed to high pressure

When human divers and experimental animals are exposed to increased environmental pressure, they develop the high pressure neurological syndrome (HPNS). Moreover, it has been recently demonstrated that pressure exposure induced an increase in striatal dopamine (DA) release. In this study, the effects of intracerebroventricular administration of a-methyl-p-tyrosine on the pressure-induced striatal DA increase, and the behavioral motor disturbances of HPNS, including hyperlocomotor activity (HLA), tremor, and myoclonia were monitored in free-moving rats. Striatal DA release was monitored by in vivo voltammetry, and behavioral symptoms using piezoelectrical sensors. Results suggested that the pressure-induced striatal DA increase could be the consequence of a release in both newly synthesized and vesicular DA. Elsewhere, data also confirmed that the pressure-induced DA disturbances would be involved in the development of HLA.

Centrally administered NPY stimulated gastric acid and pepsin secretion by a vagally mediated mechanism

We investigated the possible roles of centrally administered neuropeptide Y (NPY) on gastric secretion, serum gastrin levels and gastric mucosal blood flow in anesthetized rats. Centrally administered NPY dose-dependently stimulated gastric acid and pepsin secretion. The stimulatory effect of intracerebroventricular administration of NPY was more potent than that of intracisternal administration. Centrally administered NPY also increased gastric secretion in the central noradrenaline depleted rats. In contrast, intravenously administered NPY had no influence on gastric secretion. These stimulatory effects were abolished by vagotomy or atropine pretreatment. The serum gastrin levels did not change after central NPY injection. Although intravenously administered NPY slightly increased gastric mucosal blood flow, centrally administered NPY slightly diminished gastric mucosal blood flow. These results indicate that centrally administered NPY markedly influences gastric functions in the rat.

Central administration of a specific angiotensin II receptor antagonist on baroreflex function in spontaneously hypertensive rats.

To determine whether the increase in baroreflex sensitivity previously reported in lifetime captopril-treated spontaneously hypertensive rats (SHR) was due to an inhibition of brain angiotensin II mechanisms, we tested the effect of intracerebroventricular administration of an angiotensin II receptor antagonist on baroreflex control of heart rate in lifetime captopril-treated and untreated male and female SHR. Baroreceptor reflex control of heart rate was assessed by the slope of the relationship between changes in mean arterial pressure (delta MAP, mmHg) and changes in pulse interval (delta PI, ms). MAP was raised and lowered with infusions of phenylephrine and nitroprusside, respectively. Following basal assessment of baroreflex control of heart rate, rats received an intracerebroventricular injection (100 pmol) of Sar1Thr8 angiotensin II (sarthran) and reflex control of heart rate was reassessed. Adequacy of blockade was tested with central and peripheral administration of angiotensin II. Captopril-treated male (130 +/- 7 mmHg) and female (123 +/- 4 mmHg) rats had significantly lower MAP than untreated rats (174 +/- 4 and 173 +/- 8 mmHg, respectively) and enhanced bradycardia in response to increases in MAP. Intracerebroventricular administration of sarthran had no effect on basal blood pressure or heart rate but enhanced the bradycardia in response to increases in MAP in both untreated and captopril-treated rats. The increase in the slope of the line relating delta MAP to delta PT was greater for untreated than captopril-treated SHR (male untreated 2.7-fold versus captopril-treated 1.5-fold; female untreated 1.6-fold versus captopril-treated 1.5-fold).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of Na+, K+ -ATPase in the centrally mediated hypotensive effects of potassium in anaesthetized rats

Several investigators have demonstrated the antihypertensive properties of potassium in various models of hypertension. The present studies were conducted to determine whether central mechanisms contribute to these salutary effects of potassium. In Inactin-anaesthetized rats, intracerebroventricular administration of KCl solutions (0.375, 0.75 and 1.25 mumol/5 microliters) produced concentration-dependent reductions in arterial pressure and heart rate. These effects were significantly attenuated by prior central administration of ouabain, a selective inhibitor of the sodium pump. In a separate series of experiments, prior central administration of alpha 1- and alpha 2-antagonist phentolamine, or the dopamine receptor (DA1 and DA2) antagonist RS-sulpiride, was also effective in inhibiting the hypotensive and bradycardiac effects of intracerebroventricular administration of potassium. Thus, these data suggest that activation of Na+,K(+)-ATPase and central noradrenergic and dopaminergic mechanisms are involved in the central actions of potassium and these central mechanisms may contribute to the salutary effects of a potassium-rich diet in hypertensive subjects. The present studies demonstrate a potentially important relationship between Na+,K(+)-ATPase activity in the central nervous system and neural regulation of arterial blood pressure.

Effects of intracerebroventricular administration in rabbits of taurine and some taurine analogues on thermoregulation and [Ca] in cerebrospinal fluid (CSF)

Effects of intracerebroventricular administration in rabbits of taurine and some taurine analogues on thermoregulation and [Ca] in cerebrospinal fluid (CSF)

Central nervous system cardiovascular actions of CRF in sinoaortic-denervated rats

Studies were performed in unrestrained conscious Sprague-Dawley rats to examine the central nervous system (CNS) mechanism by which corticotropin-releasing factor (CRF) produces simultaneous elevations of arterial pressure and heart rate. To test the hypothesis that CRF inhibits ongoing impulse transmission through and/or transmitter release from the CNS terminations of baroreceptor afferents, the cardiovascular effects of intracerebroventricular administration of CRF were compared in rats subjected to prior sham surgery (Sham) or sinoaortic denervation (SAD). Resting levels of arterial pressure and heart rate were elevated after SAD. In addition, SAD resulted in greater chronotropic sympathetic tone and reduced chronotropic parasympathetic tone as assessed by intravenous injections of atropine methyl nitrate and DL-propranolol. Intracerebroventricular administration of CRF in both surgical groups elicited significant increases in arterial pressure and heart rate, although a tendency for reduced tachycardic responses after SAD was apparent. Pretreatment with atropine or propranolol revealed that both the parasympathetic and sympathetic nervous systems contribute to CRF-induced heart rate responses in both surgical groups. These results suggest that ongoing baroreceptor afferent transmission is not requisite for the expression of CRF-induced cardiovascular changes. Thus it is unlikely that CRF elevates arterial pressure and heart rate through an exclusive action at the CNS terminations of baroreceptor sensory fibers.

Effect of leukotriene D4 on blood flow to cerebrum and choroid plexus.

The purpose of this study was to examine effects of leukotriene D4 on blood flow to the cerebrum and choroid plexus. Blood flow was measured with microspheres in anesthetized rabbits. Under control conditions, blood flow to the cerebrum was 37 +/- 4 ml. min-1.100 g-1 (mean +/- SE) and blood flow to the choroid plexus was 428 +/- 52 ml.min-1.100 g-1. Intra-atrial infusion of leukotriene D4 at 0.1 and 1.0 microgram.kg-1.min-1 did not alter blood flow to the brain or choroid plexus, but produced a 49 +/- 3% and 69 +/- 5% decrease in blood flow to the bowel. We also examined effects of intracerebroventricular administration of leukotriene D4. Intraventricular injection of 1.0 microgram of leukotriene D4 did not affect blood flow to the cerebrum or choroid plexus. In contrast, intraventricular injection of 1.0 microgram of angiotensin II produced a 42 +/- 4% decrease in blood flow to the choroid plexus. In summary, neither intravascular nor intraventricular administration of leukotriene D4 affects blood flow to the brain or choroid plexus.

Central effect of endothelin on blood pressure in conscious rats.

This study was conducted to investigate the effect of intracerebroventricular administration of endothelin (EDT), a novel potent vasoconstricting peptide, on blood pressure in conscious rats. The lateral cerebral ventricle of male Wistar rats was cannulated, and the femoral artery was also cannulated to measure the mean arterial blood pressure (MABP) and heart rate (HR). EDT dissolved in 10 microliters of artificial cerebrospinal fluid (ACSF) (8.25-66 pmol icv) provoked a dose-dependent increase in MABP. EDT also increased HR, although the effect of 66 pmol was variable. Intracerebroventricular ACSF did not provoke any effects on MABP and HR. Intracerebroventricular EDT also provoked contralateral rotational behavior. Pretreatment with 2 mg/kg iv phenoxybenzamine significantly suppressed the 16.5 pmol icv EDT-induced increase in MABP. Moreover, 16.5 pmol icv EDT markedly increased plasma epinephrine and norepinephrine concentration. These results indicate that EDT has a central pressor action, and the action might be mediated, at least in part, by catecholamine release to the periphery. EDT might play a role in the central control of blood pressure, although the physiological implications have not yet been determined.

Central autonomic modulation of cardiac baroreflex by corticotropin-releasing factor.

The effects of intracerebroventricular administration of corticotropin-releasing factor (CRF) on baroreflex control of heart rate were studied in conscious, unrestrained rats. Stimulus-response curves relating mean arterial pressure (MAP) to pulse interval were constructed for assessment of baroreflex function. CRF, intracerebroventricularly injected, elicited dose-related reductions of resting pulse interval, response range, and reflex gain and elevations of resting arterial pressure and MAP50 (arterial pressure at midrange). Earlier peripheral blockade of cardiac vagal influences with atropine methyl nitrate greatly attenuated the effects of CRF on resting pulse interval, response range, and reflex gain. In contrast, earlier blockade of cardiac sympathetic influences with intravenous propranolol treatment did not alter the ability of CRF to reduce resting pulse interval, response range, and reflex gain. The central nervous system effects of CRF on cardiac baroreflex function were qualitatively similar to the actions of atropine methyl nitrate. It is concluded that CRF alters transmission in central nervous system pathways mediating baroreceptor-induced activation of cardiac vagal motor neurons.

Intracerebroventricular administration of cholecystokinin inhibits the activity of the dopaminergic and serotoninergic systems of the brain.

The behavioral and biochemical effects of intracerebroventricular administration of cholecystokinin were investigated in experiments on male Wistar rats. Cholecystokinin induced specific dose-dependent changes in the behavior of the animals. At low doses the inhibiting influence on behavior predominated; at high doses stereo-typed behavior, shaking of the head and increased reactivity to pain stimuli were observed. Cholecystokinin appreciably inhibited the circulation of serotonin and dopamine in the brain structures in comparison with physiological saline solution. Administration of cholecystokinin against a background of phenamine and 5-hydroxy-tryptophan briefly entirely inhibited the behavioral effects induced by these substances. On the basis of the data obtained it can be assumed that cholecystokinin is an endogenous modulator of the activity of the monoaminergic systems of the brain.

Central nervous system cardiovascular effects of bombesin in conscious rats.

The effects of intracerebroventricular administration of bombesin on mean arterial pressure and heart rate were studied in conscious, freely moving rats. Injection of bombesin produced dose-dependent elevations of mean arterial pressure and reductions of heart rate. These effects were not caused by leakage of bombesin into the peripheral circulation. Adrenalectomy abolished the pressor action of bombesin but did not alter bombesin-induced bradycardia. Systemic phentolamine pretreatment prevented bombesin-induced changes of mean arterial pressure, whereas rats treated intravenously with captopril or a vasopressin antagonist still exhibited pressor responses to bombesin administration. Bombesin-induced bradycardia was partially antagonized by intravenous atropine methyl nitrate administration, whereas systemic injections of propranolol did not modify this response. It is concluded that bombesin acts within the central nervous system to elevate mean arterial pressure through an adrenal-dependent mechanism involving alpha-adrenergic receptors and to reduce heart rate through an adrenal-independent mechanism involving, at least in part, cardiac parasympathetic nervous activation.

Effects of insulin on thermoregulatory responses and hypothalamic neuronal activity.

In the first series of experiments, the effects of administration of insulin (0.04-0.12 IU/microliter) into the preoptic anterior hypothalamic area on thermoregulatory responses were assessed in unanesthetized rats at various ambient temperatures (Ta). Intrahypothalamic administration of insulin induced a dose-dependent rise in rectal temperature. At Ta = 8 degrees C, the hyperthermia in response to insulin was due to increased metabolism, whereas at Ta = 30 degrees C, the hyperthermia was due to cutaneous vasoconstriction. However, at Ta = 22 degrees C, the insulin-induced hyperthermia was due to both increased metabolism and cutaneous vasoconstriction. In the second series of experiments, the effects of intracerebroventricular administration of insulin on 35 hypothalamic units classified as cold-responsive, warm-responsive, or thermally unresponsive were assessed in 35 rats anesthetized with urethane. It was found that the majority (80%) of the warm-responsive units were depressed by insulin, whereas the majority (70%) of the cold-responsive units were excited by insulin. The data indicate that insulin acts on the hypothalamic thermally responsive neurons to induce hyperthermia by promoting an increase in heat production and/or vasoconstriction.

Analgesic cross-tolerance between morphine and opioid peptides.

The analgesic effect of intracerebroventricular administration of morphine, ketocyclazocine, [D-ala2]-methionine enkephalinamide (DAM), [D-ala2-D-leu5]-enkephalin (DADLE), leuenkephalin, metenkephalin, and beta-endorphin on acetic acid-induced abdominal writhing (AAW) was investigated in naive and morphine-tolerant mice. It was found that the relative potencies of a series of opioids are different in naive and morphine-tolerant groups. In naive animals, the order of potency (ED50, nmol) was beta-endorphin greater than morphine = DAM greater than DADLE greater than ketocyclazocine = leuenkephalin = metenkephalin. The morphine-tolerant animals were cross-tolerant to ketocyclazocine and to all the peptides studied; DAM and beta-endorphin exhibited the highest degree of tolerance. In morphine-tolerant animals, the order of potency was morphine = DADLE = beta-endorphin greater than DAM = ketocyclazocine = metenkephalin greater than leuenkephalin. The results indicate that endogenous opioid systems may be affected by tolerance development to morphine.

Endocrine Influences on the Actions of Morphine

As part of an assessment of endocrine influences on the actions of morphine, we have studied the effects of intracerebroventricular administration of somatostatin and thyrotropin releasing hormone (TRH) on the antinociceptive, temperature and cataleptic responses to subcutaneous morphine in both intact and hypophysectomized rats. Somatostatin significantly antagonized morphine-induced antinociception in intact, but not in hypophysectomized, animals. TRH, on the other hand, had no effect on antinociceptive response to morphine in either intact or hypophysectomized animals. Neither hormone altered hyperthermic response to morphine but TRH antagonized the hypothermic response. Similarly, TRH antagonized the cataleptic actions of morphine whereas somatostatin had no effect. These results indicate that somatostatin and TRH can attenuate certain actions of morphine in vivo and suggest that specific opiate actions may be modulated by specific hypothalamic hormones.