Autonomic and behavioral effects of centrally administered corticotropin-releasing factor in rats

Changes in heart rate, core temperature, and gross locomotor activity were recorded simultaneously by a wireless telemetry system for periods up to 60 min after intracerebroventricular (icv) administration of synthetic human CRF-(1-41) (CRF) or artificial cerebrospinal fluid in rats in their home cages. The telemetry system provides a highly sensitive method to monitor autonomic nervous system (ANS) activity without imposing restraint on the animal. CRF was administered at lower doses than hitherto used to study central effects on the ANS (0.03, 0.1, 0.3, and 1 microgram). Starting 10 min after icv injections, behavioral responses to CRF, i.e. grooming, locomotion, and digging, were determined by a time sampling method. Within 5 min after icv treatment, CRF, in a dose-related fashion, produced a significant increase in heart rate, core temperature, and behavioral activity. The absence of effect of 30 ng CRF, which already may be regarded as a supraphysiological amount, suggests that CRF does not modify ANS and behavioral activity under resting conditions. Tachycardiac responses in rats receiving 0.1 microgram CRF, icv, in the morning were more marked than those in rats given the same treatment in the late afternoon. In addition, the presumed intrinsic activity of the CRF receptor antagonist, alpha-helical CRF-(9-41) (alpha hCRF) at doses of 0.1, 1, 5, and 25 micrograms was evaluated. Intracerebroventricular injections of 0.1 and 1 microgram alpha hCRF failed to produce detectable effects. At the 5- and 25-micrograms doses, alpha hCRF dose-dependently induced tachycardia and behavioral activation, suggesting partial agonistic activity. Taken together, these results demonstrate that CRF does not play a role in the regulation of ANS and behavioral activity under resting conditions. The responses produced by icv injected supraphysiological amounts of CRF, however, may serve to model a stressful situation during which the massively released CRF induces similar effects on ANS and behavior, after reaching high local concentrations at brain sites involved in the mediation of these actions.     

Effect of peripherally and centrally administered calcitonin on gallbladder emptying in dogs

The effect of calcitonin on meal-stimulated gallbladder emptying (GBE) was examined after intravenous (i.v.) and intracerebroventricular (i.c.v.) administration in six mongrel dogs. The gallbladder contraction was surveyed by means of real-time ultrasonography in conscious dogs. Calcitonin given i.v. elicited an immediate and strong inhibition of postprandial GBE—the integrated 0- to 120-min gallbladder response was 118.1±8.0%·h after placebo, whereas it was 91.8±2.1%·h, 59.4±17.9%·h (P<0.001), and 14.2±20.5%·h (P<0.001) after 3.6, 18.0, and 90.0 pmol·kg^?1 calcitonin, respectively. After i.c.v. administration (1.8 and 18.0 pmol·kg^?1), only the higher calcitonin dose exerted a moderate inhibitory effect on postprandial GBE. The calcitonin doses required to evoke a 50% inhibition of meal-stimulated GBE were 15- to 10-fold lower after i.v. than i.c.v. application. Peripherally given calcitonin brought about a dose-dependent increase in the interdigestive gallbladder volume—the linear regression of the relative gallbladder volume versus calcitonin dose was y=11.60 [ln(dose+1)]+97.02 (r=0.864,P<0.001). Intravenous application of calcitonin did not affect caerulein-induced GBE. The results obtained imply that: (i) calcitonin exerts an inhibitory influence on meal-induced GBE and that this effect is more pronounced after i.v. than after i.c.v. administration, and (ii) peripherally given calcitonin does not inhibit caerulein-induced gallbladder contraction in the dog.     

Effect of [Asu1,7]eel calcitonin on prolactin release in normal subjects and patients with prolactinoma

The effect of [Asu1,7]eel calcitonin (ECT), an equipotent analogue of eel CT, on prolactin (Prl) secretion was examined in 12 healthy male subjects and in 6 patients with prolactinoma. In healthy subjects, ECT (0.5 microgram/kg body weight . h) or saline was infused for 2 h and TRH was injected iv as a bolus of 500 micrograms at 1 h of ECT or saline administration. ECT did not affect basal Prl levels during 1 h of infusion. TRH caused a significant increase of plasma Prl with peak values of 75.2 +/- 11.6 ng/ml in ECT-infused subjects, which did not differ from those infused with saline (68.5 +/- 8.3 ng/ml). Next, an iv bolus injection of regular insulin (0.1 U/kg body weight) was followed by an infusion of ECT or saline alone. Plasma Prl peaks after hypoglycaemic stress were significantly lower in ECT-infused subjects than those in saline-injected controls (ECT, 16.5 +/- 3.1 vs 33.5 +/- 9.6 ng/ml, P less than 0.05). In patients with prolactinoma, basal levels of plasma Prl ranging from 42.0-4130 ng/ml failed to change during iv infusion of ECT. Moreover, ECT (10(-9) - 10(-6)M) did not affect Prl release from prolactinoma tissues perifused in vitro. These findings suggest that ECT may not act directly on the pituitary to modify Prl release. Rather, peripherally administered ECT appears to suppress Prl release via the central nervous system.     

Hypotensive and bradycardic effects of centrally administered vasopressin in stroke-prone spontaneously hypertensive rats

The cardiovascular effects of centrally administered arginine vasopressin were studied in stroke-prone spontaneously hypertensive rats and Wistar-Kyoto rats. Arginine vasopressin was infused intracerebroventricularly into conscious rats at a rate of 2 pg/kg/min (4.6 microliter/hr) for 21 hours, and blood pressure and heart rate were monitored. Arginine vasopressin caused transient hypertension and tachycardia in Wistar-Kyoto rats, whereas it induced delayed hypotension and bradycardia in stroke-prone spontaneously hypertensive rats. The effects on the latter lasted for 24 to 72 hours after cessation of the infusion. Intravenous administration of arginine vasopressin at a rate of 2 pg/kg/min did not cause any change in blood pressure and heart rate in these rats. These results suggest that arginine vasopressin acts centrally to depress cardiovascular activities, at least in stroke-prone spontaneously hypertensive rats.     

Effects of calcitonin on basal and thyrotropin-releasing hormone-stimulated prolactin secretion in man

Plasma PRL fell in nine healthy subjects and four patients with hyperprolactinemia after iv administration of salmon calcitonin (CT). The maximum fall was observed 30--60 min after the infusion. There was no change in the plasma concentrations of the other anterior pituitary hormones tested (GH, FSH, LH, and TSH). In five healthy subjects, TRH was injected 60 min after the CT infusion. This protocol was repeated in the same subjects at 3-day intervals, except CT was not administered. Plasma PRL before TRH injection was clearly lower when CT had been administered. Plasma concentrations of the other anterior pituitary hormones did not change. PRL and TSH responses to TRH were markedly inhibited when CT had been previously infused. These observations are in agreement with preceeding studies showing a similar effect of CT on the plasma concentration of various other polypeptide hormones. This general effect of CT could be attributed to a change in intracellular calcium of the secreting cells.     

Differential cardiovascular effects of centrally administered vasopressin in conscious Long Evans and Brattleboro rats

The cardiovascular effects of arginine vasopressin (AVP) administered into a lateral cerebral ventricle or into the cisterna magna were investigated in conscious Long Evans (control) rats and AVP-deficient Brattleboro rats. The effects of subpressor intracerebroventricular and intracisternal doses of AVP on cardiac baroreflex sensitivities were also determined. Intracerebroventricular and intracisternal AVP increased blood pressure of both strains of rat in a dose-dependent manner. The maximum pressor response produced by intracerebroventricular AVP in Long Evans rats was 13 +/- 2/13 +/- 1 mm Hg (systolic/diastolic, n = 6) after 100 ng AVP. The pressor response to the highest intracerebroventricular dose of AVP tested in Brattleboro rats (30 ng) was 46 +/- 13/21 +/- 6 mm Hg (n = 6). Intracerebroventricular AVP caused a tachycardia in Brattleboro rats but had no effect on heart rate of Long Evans rats. At doses greater than 1 ng, the increases in blood pressure produced by intracisternal AVP in both groups of rats were significantly greater than the increases produced by the same doses given intracerebroventricularly. Heart rate fell in a dose-dependent manner after intracisternal AVP in Long Evans rats but not in Brattleboro rats. Cardiac baroreflex sensitivities of Brattleboro rats were not significantly different from those of Long Evans rats and were not modified by intracerebroventricular (0.3 ng) or intracisternal (0.1 ng) AVP. In Long Evans rats, intracisternal AVP (0.3 ng) increased cardiac baroreflex responses to both increases and decreases in pressure. Intracerebroventricular AVP (0.3 ng) increased the sensitivity of the reflex in response to an elevation but not to a reduction in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of SMS 201-995 on basal and stimulated pancreatic secretion in rats

Somatostatin (SRIF) is a potent inhibitor of most gastrointestinal and pancreatic functions. Recently, we showed that SRIF given either iv or intraduodenally (id) strongly inhibited stimulated pancreatic secretion induced by pancreatic juice diversion (PJD) from the duodenum. In this study we evaluate the effects of iv and id infusion of a long acting analog of SRIF, SMS 201-995 (SMS), on pancreatic secretion during basal conditions (pancreatic juice returned) and PJD. Conscious rats prepared with bile, pancreatic, duodenal, and jugular cannulae were studied 3-8 days postoperatively. Protein and fluid outputs were evaluated, and plasma cholecystokinin (CCK) was measured by bioassay. iv SMS infusion (5 micrograms kg-1 h-1) inhibited basal pancreatic protein and fluid secretion by 84 and 64%, respectively. Addition of atropine (500 micrograms kg-1 h-1 ip) did not cause further inhibition. During PJD, SMS iv from 0.005-1.28 micrograms kg-1 h-1 for 3 h caused a dose-dependent inhibition with maximal 90% and 75% reductions of protein and fluid, respectively, at 1.28 micrograms SMS. Plasma CCK was also reduced by 83% from 3.01 +/- 1.15 to 0.51 +/- 0.22 pM. SMS, id at 1.7 micrograms kg-1 h-1 for 1.5 h before and 2 h after PJD, caused inhibition of basal secretion by 25% and that induced by PJD by 60%. Plasma CCK, measured 1.5 h after diversion, increased from 1.55 +/- 0.06 to 5.9 +/- 1.14 pM in the presence of SMS. Intravenous SMS was 20 times more potent than SRIF in inhibiting pancreatic protein and volume secretion stimulated by PJD. Iv SMS inhibited basal and stimulated fluid and protein pancreatic secretion as well as plasma CCK levels. SMS was also effective when given id in inhibiting fluid and protein pancreatic secretion, but id SMS increased plasma CCK levels. This effect on plasma CCK may be due to the inhibition of hormonal inhibitors of CCK release.     

Further studies on the absence of hypocalcemic effects of eel calcitonin in the eel, Anguilla japonica

Within 8 hr after an intraarterial injection of synthetic eel calcitonin (500 mU/100 g) into either freshwater- or seawater-adapted eels, no effect was observed on plasma Na, Ca, or Mg concentrations. In freshwater eels, a single injection of eel calcitonin (100 mU/100 g) into the caudal vein was without effect on ion concentrations of the urine or on blood pressure. There was no significant difference in plasma ion concentrations between freshwater eels infused with anticalcitonin rabbit serum and those infused with normal rabbit serum, although Ca and Mg concentrations decreased significantly after 3 days in both cases. There was also no difference in the circulating calcitonin levels between eels in fresh water and those in seawater. When the corpuscles of Stannius were removed from freshwater or seawater eels, plasma Ca concentration increased significantly after 2 to 4 weeks, whereas there was no change in the plasma calcitonin levels. Hypophysectomy of freshwater eels resulted in a significant decrease in plasma ion concentrations including Ca, but was without effect on plasma calcitonin levels. These observations indicate that calcitonin may play no significant role in maintenance of plasma Ca concentrations in the eel.     

Effects of the three neuropeptides, vasoactive intestinal peptide, substance P, and calcitonin gene related peptide on basal and stimulated calcitonin release in the rat

Calcitonin is secreted from the thyroidal C-cells. Except that calcitonin secretion is stimulated by calcium, little is known of its regulation. Vasoactive intestinal peptide (VIP), substance P, and calcitonin gene related peptide (CGRP) have recently been detected within intrathyroidal neurons, and CGRP also within the C-cells, and may therefore affect calcitonin secretion. In this study, we investigated whether VIP, substance P or CGRP could influence calcitonin secretion in the rat. Each of these peptides was administered as a single injection (1.5 nmol/animal) or as a 30-min infusion (1.5 nmol/animal per 30 min) during which calcium chloride, 456 mumol/animal, was injected iv. We found that the peptides had no effect on basal calcitonin secretion, but that VIP potentiated the calcium-induced calcitonin release. Thus, the peak plasma calcitonin level following calcium chloride injection was doubled by the infusion of VIP (P less than 0.001). In contrast, neither substance P nor CGRP significantly influenced the calcium-induced calcitonin release. We conclude that VIP, a neuropeptide within intrathyroidal nerves, has the capacity to augment calcium-induced calcitonin secretion in the rat and we therefore suggest that VIP is a regulator of calcitonin secretion.     

In vitro studies on basal and stimulated prolactin release by rat anterior pituitary: a possible role for calmodulin

The mechanism by which PRL is released from mammotrophs is a calcium-dependent process. Although calcium seems to function as a second messenger, its regulatory mechanism in PRL release has not been clarified. The binding of calcium to calmodulin and the activation of calmodulin-dependent enzymes have been suggested to be important steps during stimulus-secretion coupling in various cells. In the present work we investigated the in vitro effect of penfluridol, a potent neuroleptic that also possesses the ability to inhibit calmodulin's biological activity, on basal and stimulated PRL release. The effect of pimozide and haloperidol on basal PRL release was also investigated. Penfluridol, pimozide, and haloperidol inhibited basal PRL secretion in a dose-related manner, with the EC50 ranging from 0.5-1 microM for penfluridol to 1-2 microM for pimozide and more than 3 microM for haloperidol. These concentrations are similar to those necessary for the inactivation of calmodulin-dependent enzymes in vitro. Ionophore A-23187, a compound whose ability to mobilize extracellular calcium is not affected by neuroleptics, stimulated PRL secretion in vitro. This effect, however, was blocked by penfluridol pretreatment. The site of action of penfluridol may occur after calcium mobilization, with calmodulin a possible target for penfluridol's inhibitory action on PRL secretion. TRH, K+, (Bu)2cAMP, and theophylline, compounds that affect calcium mobilization, also significantly stimulated PRL release. The coincubation of varying concentrations of penfluridol with 70 nM TRH, 50 mM K+, 3 mM (Bu)2cAMP, or 5 mM theophylline resulted in a dose-related inhibition of secretagogue-stimulated PRL secretion. Perifusion of dispersed anterior pituitary cells with 1 microM penfluridol reduced the ability of 70 nM TRH to stimulate PRL release by approximately 50%, whereas removal of the penfluridol perifusion allowed the cells to again be fully responsive to TRH. These results are consistent with the hypothesis that calmodulin is involved in the stimulus-secretion coupling of PRL.     

GLP-1 and GLP-1(7-36) amide: influences on basal and stimulated insulin and glucagon secretion in the mouse

We studied the cellular distribution of glucagon-like peptide-1 (GLP-1) in the pancreas and gut and the effects of GLP-1 and its truncated form, GLP-1(7-36) amide, on basal and stimulated insulin and glucagon secretion in the mouse. Immunofluorescence staining showed that GLP-1 immunoreactivity occurred within peripheral islet cells and in cells located mainly distally in the small intestine and in the entire large intestine. Double-immunostaining revealed that the GLP-1-immunoreactive cells were identical to the glucagon/glicentin cells. Experiments in vivo revealed that basal insulin secretion was stimulated by GLP-1(7-36) amide at the dose levels of 8 and 32 nmol/kg, and by GLP-1 at 32 nmol/kg. Furthermore, GLP-1(7-36) amide showed additive stimulatory influence with glucose (2.8 mmol/kg), the cholinergic agonist carbachol (0.16 mumol/kg), and the C-terminal octapeptide of cholecystokinin (CCK-8, 5.3 nmol/kg), when injected at 8 or 32 nmol/kg. In contrast, stimulated insulin secretion was unaffected by GLP-1. Moreover, the glucagon secretory responses to carbachol and CCK-8 were inhibited by GLP-1(7-36) amide but were unaffected by the entire GLP-1. We conclude that GLP-1(7-36) has the potential for being a modulator of islet hormone secretion.     

The effects of transient dopamine antagonism on thyrotropin-releasing hormone-induced prolactin release in pseudopregnant rats

The effectiveness of TRH in releasing PRL after transient dopamine (DA) blockade was investigated in female rats between days 3 and 11 of pseudopregnancy (PSP). At 0930 h on the morning of the experiment, each animal was injected with the DA antagonist domperidone (0.01 mg/rat, iv) or vehicle (acetic acid in saline); 5 min later, the DA agonist 2-bromo-alpha-ergocryptine maleate (CB-154; 0.5 mg/rat, iv) was administered. Sixty minutes later, TRH (1.0 micrograms/rat, iv) was administered. Blood samples were withdrawn via indwelling catheters before, 5, 20, 40, and 70 min after domperidone or vehicle administration, and 5 and 10 min after TRH administration. On day 3 of PSP, TRH-induced PRL release was significantly enhanced by the domperidone-CB154 treatment compared to that in vehicle-treated control rats. By day 9 of PSP, the effectiveness of TRH in stimulating PRL release after domperidone treatment was decreased by 50% compared to that on day 3 of PSP. This reduction in PRL response to TRH was not due to decreased progesterone levels, as no difference was observed in plasma progesterone between days 3 and 9. Rats that were given domperidone on day 11 of PSP did not exhibit a significant increase in sensitivity to TRH; however, the effectiveness of TRH was enhanced by domperidone on day 11 of PSP in animals that were hysterectomized on day 2 of PSP. Since DA receptor blockage increased the sensitivity to a putative PRL-releasing factor (TRH) and this mechanism was eliminated around the time that the PRL surges of PSP disappear, we suggest that this pituitary mechanism is a critical component of the PRL release mechanism during the surges of PSP. Further, the observed loss of the mechanism between days 9 and 11 of PSP may be due to the direct influence at the anterior pituitary of a uterine PRL inhibitory factor which has been recently described.     

Central effects of calcitonin receptor-stimulating peptide-1 on energy homeostasis in rats

The CT-R [calcitonin (CT) receptor] is expressed in the central nervous system and is involved in the regulation of food intake, thermogenesis, and behaviors. CT-R-stimulating peptide-1 (CRSP-1), a potent ligand for the CT-R, was recently isolated from the porcine brain. In this study, we first confirmed that porcine CRSP-1 (pCRSP-1) enhanced the cAMP production in COS-7 cells expressing recombinant rat CT-R, and then we examined the central effects of pCRSP-1 on feeding and energy homeostasis in rats. Intracerebroventricular (icv) administration of pCRSP-1 to free-feeding rats suppressed food intake in a dose-dependent manner. Chronic icv infusion of pCRSP-1 suppressed body weight gain over the infusion period. Furthermore, icv administration of pCRSP-1 increased body temperature and decreased locomotor activity. The central effects of pCRSP-1 were more potent than those of porcine CT in rats. In contrast, ip administration of pCRSP-1 did not elicit any anorectic or catabolic effects. Administration icv of pCRSP-1 also induced mild dyskinesia of the lower extremities and decreased gastric acid output. Fos expression induced by icv administration of pCRSP-1 was detected in the neurons of the paraventricular nucleus, dorsomedial hypothalamic nucleus, arcuate nucleus, locus coeruleus, and nucleus of solitary tract, areas that are known to regulate feeding and energy homeostasis. Administration icv of pCRSP-1 increased plasma concentrations of ACTH and corticosterone, implying that the hypothalamic-pituitary-adrenocortical axis might be involved in catabolic effects of pCRSP-1. These results suggest that CRSP-1 can function as a ligand for the CT-R and may act as a catabolic signaling molecule in the central nervous system.     

吲哚美辛对β淀粉样蛋白1-42诱发BV-2细胞产生炎性介质的抑制作用

目的研究吲哚美辛对β淀粉样蛋白1-42（Aβ1-42）刺激小胶质细胞释放炎性介质一氧化氮（NO）及白细胞介素-1β（IL-1β）的抑制作用。方法应用高度纯化的BV-2小胶质细胞作为体外小胶质细胞模型，应用不同浓度吲哚美辛（10^-9，10^-8，10^-7，10^-6，10^-5mol／L）与20μmol／LAβ1—42单独或同时培养12h，测定细胞上清NO及IL，1β含量；RT—PCR法测定BV-2细胞iNOSmRNA及IL-1βmRNA的表达。结果吲哚美辛单独作用对BV-2细胞产生NO、IL-1β及iNOSmRNA、IL-1βmRNA表达无明显作用。Aβl—42可以刺激BV-2细胞产生NO及IL-1β，并增加iNOSmRNA及IL-1βmRNA表达，这种作用均可被吲哚美辛所抑制，在吲哚美辛浓度为10^-7～10^-5mol／L时抑制作用较为明显。结论在体外吲哚美辛可以降低Aβ1—42介导的BV-2细胞iNOSmRNA及IL-1βmRNA表达，从而减少NO及IL-1β的产生，上述抑制作用可能参与了吲哚美辛在阿尔茨海默病治疗中的神经元保护机制。     

Angiotensin-(1-7) inhibitory mechanism of norepinephrine release in hypertensive rats

Release of norepinephrine (NE) by the hypothalamic nuclei may contribute to regulation of sympathetic nervous system (SNS) activity. Angiotensin-(1-7) [Ang-(1-7)] has an antihypertensive effect and may decrease SNS activity. We tested the hypothesis that Ang-(1-7) inhibits the release of NE in hypothalami, via the Ang-(1-7) and angiotensin II type 2 (AT2) receptors, acting through a bradykinin (BK)/NO-dependent mechanism. Hypothalami from normotensive controls and spontaneously hypertensive rats (SHR) were isolated and endogenous NE stores labeled by incubating the tissues with [3H]NE. [3H]NE release from the hypothalami was stimulated by KCl in the presence or absence of Ang-(1-7) alone or combined with various antagonists and inhibitors. Ang-(1-7) significantly attenuated K+-induced NE release by hypothalami from normotensive rats but was more potent in SHR. The Ang-(1-7) receptor antagonist [D-Ala7]Ang-(1-7), the AT2 receptor antagonist PD 123319, and the BK B2) receptor antagonist icatibant all blocked the inhibitory effect of Ang-(1-7) on K+-stimulated NE release in SHR. The inhibitory effect of Ang-(1-7) disappeared in the presence of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester and was restored by the precursor of NO, l-arginine. The diminished NE release caused by Ang-(1-7) was blocked by a soluble guanylyl cyclase inhibitor as well as by a cGMP-dependent protein kinase (PKG). We concluded that Ang-(1-7) decreases NE release from the hypothalamus via the Ang-(1-7) or AT2 receptors, acting through a BK/NO-mediated mechanism that stimulates cGMP/PKG signaling. In this way, Ang-(1-7) may decrease SNS activity and exert an antihypertensive effect.     

Effects of osmotically stimulated endogenous vasopressin on basal and CRH-stimulated ACTH release in man

Two groups of six healthy young males participated in separate experiments to examine the physiological role of endogenous vasopressin in h-CRH-induced (100 micrograms iv) ACTH release: a) after drinking of 3500 ml of water; b) after thirsting for 23 h; c) after 0.9% saline infusion, and d) after 5.0% saline infusion (0.06 ml/kg per min for 120 min). AVP levels were markedly elevated (4 ng/l) after thirsting and 5% saline infusion when compared with water loading or infusion of physiological saline. Although basal and h-CRH-stimulated ACTH and cortisol levels tended to be higher during hypertonic saline infusion and dehydration, no significant difference was observed between states of high or low endogenous AVP levels. These results are not in accordance with previous studies using ovine CRH, which might be due to its longer half-time or the timing of the changes in AVP plasma levels in relation to the CRH injection. Our data suggest that the osmotic modulation performed in this study results in AVP concentrations in the adenohypophysis, which are in the threshold range for influencing ACTH release induced by exogenous h-CRH.     

Comparative effects of various stressors on immunoreactive versus bioactive prolactin release in old and young male rats

The Nb2 rat lymphoma cell prolactin (PRL) bioassay was used, in conjunction with standard radioimmunoassay techniques, to examine the effects of various stressors on plasma bioactive (bio) and immunoreactive (ir) PRL levels in 3- to 5- and 22- to 24-month-old male Copenhagen-Fischer 344 rats. The animals were implanted with chronic intracardiac venous cannulas 24-48 h prior to experimentation. Serial blood samples were taken prior to, during and after exposure to either 15 min restraint stress, 15 min strobe light stress or 2 min ether stress. In 2 of 3 studies, basal prestress irPRL levels were significantly higher in old as compared to young male rats. However, in all studies, basal bioPRL levels were significantly lower in the older animals. Exposure to restraint, strobe light or ether stress induced significant and parallel increases in plasma ir- and bioPRL levels in young rats, and these stressors did not affect the ratio of blood bio/irPRL. Old rats exposed to the same stressors displayed similar increases in plasma irPRL, but bioPRL release was significantly attenuated and the ratio of plasma bio/irPRL levels was significantly lower when compared to young rats. In contrast, ether stress induced similar increases in plasma ir- and bioPRL levels in both age groups and restored the ratio of plasma bio/irPRL levels in old rats to that of young animals. These results demonstrate that, despite having significantly higher basal plasma irPRL levels, the bioactivity of this hormone is significantly diminished in old as compared to young male rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Suppression of ethanol responding by centrally administered CTOP and naltrindole in AA and Wistar rats

BACKGROUND: Both mu- and delta-opioid receptors have been implicated in the reinforcing actions of ethanol. However, selective opioid receptor antagonists have not altered ethanol intake in all rodent strains consistently, which suggests that genotype may modulate their suppressive effects. Therefore, we tested the effects of the selective mu-antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) and the selective delta-antagonist naltrindole in both high-drinking AA (Alko, Alcohol) and heterogeneous Wistar rats. METHODS: AA and Wistar rats were trained to respond for ethanol (10% w/v) in a two-lever operant condition by using a saccharin fading procedure. After stable baseline responding was established, rats were implanted stereotaxically either with a guide cannula above the lateral ventricle or with bilateral cannulas above the nucleus accumbens, basolateral amygdala, or ventral tegmental area. After postoperative recovery, AA and Wistar animals were tested after intracerebroventricular microinjections of either CTOP (0-3 microg) or naltrindole (0-30 microg) or subcutaneous injections of naloxone (0-1 g/kg), which was used as a reference antagonist. Effects of intracerebral microinjections of CTOP and naltrindole (both 0-500 ng) were tested only in Wistar rats. RESULTS: Subcutaneous naloxone and intracerebroventricular CTOP and naltrindole suppressed ethanol self-administration in a similar manner in AA and Wistar rats. Cumulative response patterns indicated that naloxone and naltrindole had no effect on the initiation of responding but suppressed it later during the session, whereas CTOP also affected initiation. In Wistar rats, naltrindole microinjections into both the nucleus accumbens and basolateral amygdala decreased ethanol responding, whereas CTOP was effective only in the amygdala. Injections of these antagonists into the ventral tegmental area had little effect on ethanol intake. CONCLUSIONS: The results confirm previous results which showed that both mu- and delta-opioid receptors are involved in the regulation of ethanol self-administration and indicate that genetic differences between AA and Wistar rats produced by selection do not modify the effects of opioid antagonists. The nucleus accumbens and the basolateral amygdala may be important central sites for the mediation of their suppressive effects.