Antidipsogenic role of the E-prostaglandins.

Prostaglandin E? (PGE?) is antidipsogenic when administered into the lateral cerebral ventricle of the rat. In 8 experiments with a total of 211 male Sprague-Dawley rats, PGE?, at a dose of 1 μg, suppressed water intake induced by centrally administered angiotensin II (AII) or carbachol, sc administered polyethylene glycol, and water deprivation. Even at this high dose, PGE? did not reduce water intake due to cellular dehydration. As the dose of PGE? was reduced, its suppressant effects became more specific to AII-induced drinking, with a dose of 10 ng yielding a significant suppression only in the case of AII-induced drinking. Even at a high dose (1 μg), the PGE? suppression of ingestion was specific to water intake. Although PGE?-treated Ss reduced food intake if they were not hydrated prior to access to food, no reduction in food intake was seen when they received water by gavage before food presentation. Since PGE?-like substances are synthesized in the brain, these data suggest the possibility that the prostaglandin may be involved in the regulation of water balance as a component of a reciprocal system in which water intake initiated by the activation of the renin-angiotensin system is halted by the synthesis and release of PGE. (29 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

An evaluation of dipsogenic stimuli in the African Green monkey.

In Exp I, elevations in the concentration of plasma angiotensin II (AII) and decline in plasma aldosterone (Ald) were noted in 6 female African Green monkeys at 48 hrs of water deprivation but not subsequent to an equivalent duration of food deprivation, compared with nondeprived levels. In Exp II, drinking was initiated following treatment with AII, hypertonic saline, and the beta-adrenergic stimulator isoproterenol. Concomitant elevations in plasma AII concentrations were measured following isoproterenol injection, but not after AII or hypertonic saline injection, when compared with isotonic saline treatment. Elevations in plasma Ald levels were noted following AII injection. Exp III evaluated dipsogenic additivity of stimuli by comparing the volumes of water consumed following isoproterenol or hypertonic saline injection with the intake resulting from combined treatment with isoproterenol and hypertonic saline. Additivity was tested under ad lib conditions and following adaptation to a daily water deprivation regimen. Results of the first 2 experiments generally agree with predictions based on the respective contributions by intracellular dehydration and extracellular fluid volume depletion to thirst. However, additivity of thirst stimuli was not demonstrated in Exp III. (50 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The naming impairment of living and nonliving items in Alzheimer''s disease

The role of the renin-angiotensin system (RAS) in the control of blood pressure and drinking was investigated in fresh water (FW)- and seawater (SW)-adapted eels, Anguilla anguilla, by comparing the effects of pharmacological manipulation through the use of papaverine (stimulator) and captopril (inhibitor) on the endogenous system. In SW eels basal blood pressure levels were lower (23.3 +/- 0.8 mm Hg) with correspondingly higher basal drinking rates (0.51 +/- 0.07 ml/kg/hr) and plasma AII concentrations (32.89 +/- 4.19 fmol/ml) compared to FW eels (33.8 +/- 1.3 mm Hg, 0.06 +/- 0.02 ml/kg/hr, 9.72 +/- 0.60 fmol/ml, respectively). In FW eels papaverine caused immediate hypotension with full recovery, decrease in plasma osmolality, and increase in drinking rate and plasma AII concentration, but in SW eels, hypotension with full recovery and an increase in plasma osmolality, drinking rate, and plasma AII concentration occurred. In FW eels captopril had no effect on the parameters measured, but in SW eels it caused a sustained decrease in blood pressure and a decline in the basal drinking rate and plasma AII concentration. Papaverine was also administered 15 min after captopril. In FW eels this manipulation caused hypotension only after the papaverine injection, followed by a partial recovery. Osmolality was unaffected, the previously observed papaverine-induced dipsogenic response was blocked, and the rise in plasma AII concentrations was smaller than with papaverine only. In SW eels there was an immediate hypotension after captopril administration with full recovery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ovarian steroid manipulation of the antidipsogenic and thermogenic responses of rats to central administration of prostaglandin E?.

A study by the 1st and 4th authors (1983) showed that intracerebroventricular (icv) injection of prostaglandin E? (PGE?) increased arterial pressure, suppressed water intake, and elevated the core temperature of rats. Treatment of ovariectomized (OVX) rats with estradiol or progesterone resulted in an attenuation of the pressor response to PGE?. The present study examined the effects of daily subcutaneous injection of estradiol benzoate (1 μg), progesterone (5 mg), or oil vehicle on the antidipsogenic and thermogenic response to icv PGE? of OVX Long-Evans rats. The change of core temperature induced by the PGE treatment was significantly correlated with antidipsogenesis for OVX Ss receiving daily oil injections. Although neither the suppression of water intake nor the increase of core temperature in response to icv PGE? was significantly affected by ovarian steroid treatment, the linear relation between the thermogenic and antidisogenic actions of the icv PGE? was abolished by either estradiol or progesterone administration. Thus, although the pressor, antidipsogenic, and thermogenic effects of icv PGE? tend to occur together, they may be differentially affected by ovarian steroid administration, suggesting that the mechanisms underlying these varied effects of icv PGE? may be independent. (12 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of salt intake, ANG II synthesis and SFO lesion on thirst and blood pressure during sodium depletion. Subfornical organ

Water intake was elevated in sodium-depleted rats during a daytime salt appetite test, but other rats drank a similar amount of water when saline was not available for drinking during the test. This water intake stimulated by sodium depletion was blocked by an inhibition of angiotensin (ANG) II synthesis with a high dose of captopril (100 mg/kg, sc). Captopril did not reduce water intake by causing hypotensive shock or uremia, because water and saline intakes were increased rather than decreased after a low dose of captopril (5 mg/kg) that also reduced blood pressure and elevated blood urea nitrogen. The water intake, but not salt appetite, induced by sodium depletion was greatly reduced by a lesion of the subfornical organ (SFO) in one-bottle tests, and this was not clearly related to any effects of the lesion on blood pressure. A physiological role for ANG II in water intake induced by sodium depletion has recently been disputed, but the simplest explanation for the data remains that elevated levels of circulating ANG II bind to receptors in the SFO to generate daytime water drinking during sodium depletion.     

Cerebral prostaglandin biosynthesis and angiotensin-induced drinking in rats.

Male Sprague-Dawley rats received 2.8, 28 or 280 pmoles of alprostadil (ALP [prostaglandin E?]) 30–60 sec prior to 1.0 pmole of angiotensin II (AII). ALP suppressed drinking induced by AII when both were injected into Ss' cerebral ventricles. This antidipsogenic effect of ALP was correlated with its known pyrexic actions. Administration of 1.5, 15, or 150 pmoles of icv arachidonic acid (AA) 10 min prior to 1.0 pmole of AII also suppressed AII-induced drinking. This antidipsogenic effect of AA was similarly correlated with pyrexia and was dependent upon conversion of the precursor to an ALP within the brain. Observations are consistent with the hypothesis that newly synthesized cerebral ALPs, in response to elevated AII levels, contribute to the cessation of drinking by opposing the dipsogenic action of AII. However, blockade of cerebral ALP biosynthesis by central injection of indomethacin did not enhance drinking elicited by AII even at doses that completely eliminated antidipsogenic and pyrexic actions of AA. (31 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Angiotensin and salt appetite: Physiological amounts of angiotensin given peripherally increase salt appetite in the rat.

In 2 experiments, adrenalectomized male Sprague-Dawley rats were maintained ad lib on distilled water, 3% saline, and sodium-free food. In Exp I, 45 Ss were given desoxycorticosterone acetate (DOCA [.1–2 mg/kg/day, intramuscularly]) for 5 days to determine the dose of DOCA that would produce the lowest voluntary saline intake, and 800 μg/kg/day was found to produce the nadir in saline intake. In Exp II, 40 Ss were placed ad lib on distilled water, saline, and sodium-free food as described above, maintained on 800 μg/kg/day DOCA, and infused with 4, 25, or 100 μg/kg/day angiotensin II (AII) or 0.9% saline. The 3 AII groups showed significant percentage changes in their saline intake above pre-AII levels; the saline control group showed no change in saline intake from pre-AII level. Results demonstrate the production of salt appetite in rats by peripheral administration of physiological doses of AII. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Histamine H3 receptors contribute to drinking elicited by eating in rats

A role for endogenous histamine and its H3 receptor subtype for mediating drinking elicited by eating was examined in adult male Sprague-Dawley rats. The i.p. injection of the H3 agonist R-alpha-methylhistamine (Ramh, 2.5 mg/kg) shortened the latency to initiate drinking and increased 1-h water intake in nondeprived rats freely eating pellets and drinking water. The ICV injection (through a surgically implanted chronic cannula) of 10 micrograms Ramh increased water intake; this Ramh-induced drinking was abolished by previous ICV injection of the H3 antagonist thioperamide (Th, 60 micrograms). For rats drinking and eating after 24-h food deprivation, s.c. Th inhibited drinking behavior: for example, 10 mg/kg Th s.c. delayed the latency to initiate drinking and inhibited 1-h water intake without inhibition of food intake. In contrast, 60 micrograms Th ICV failed to inhibit food-related drinking in rats eating after food deprivation. For nondeprived rats eating a small cracker, 10 mg/kg Th s.c. delayed the latency to initiate drinking and abolished water intake without effect of eating, and 60 micrograms Th ICV had similar effects upon drinking elicited by ingestion of cracker. The IG infusion (through a surgically implanted gastric catheter) of 2 ml 600 or 900 mOsm/kg NaCl, a treatment that is subthreshold for increase in systemic plasma osmolality at the initiation of drinking, elicited drinking that was abolished by 10 mg/kg Th s.c. and attenuated by 60 micrograms Th ICV. The IG infusion of 2 ml 1800 mOsm/kg NaCl, a treatment that is above threshold for increase in systemic plasma osmolality, elicited drinking that was attenuated by 10 mg/kg s.c. or 60 micrograms Th ICV. These results demonstrate that peripheral and central H3 receptors for histamine have a role in drinking elicited by eating and the postprandial gastrointestinal osmotic consequences of eating. These findings extend the evidence demonstrating a histaminergic contribution to food-related drinking in rats.     

The incidence of K-ras codon 12 mutations in cholangiocarcinoma detected by polymerase chain reaction technique

Urine samples from three daytime periods were collected from 545 5-50-year-old residents of three different Brazilian cities: Gar?a had fluoridated drinking water since 1973, Bauru since 1975 and Itápolis was not fluoridated. Dental fluorosis was examined in 985 5-24-year-olds using the Thylstrup-Fejerskov index (TF). The subjects were asked to estimate their daily intake of liquids and frequency of beverage consumption. The analysis of 94 water samples showed high variations in the fluoride content of the drinking water. The mean fluoride concentration of the water samples in Gar?a was 0.9 mg/L (range 0.75-1.2), in Bauru 0.64 mg/L (range 0.01-1.3), and in Itápolis 0.02 mg/L. Mean urinary fluoride concentration was 1.31 mg/L (s 0.61) in Gar?a, 0.88 mg/L (s 0.49) in Bauru, and 0.39 mg/L (s 0.21) in Itápolis. Self-reported daily liquid intake was not related to urinary fluoride concentration. The mean prevalence of fluorosis was 13.3% in Gar?a, 6.8% in Bauru, and 1.7% in Itápolis, with mainly categories TF 1 and TF 2 being recorded. Subjects with dental fluorosis tended to show a higher mean urinary fluoride concentration but the difference was not statistically significant. The study showed that fluoride exposure measured by urinary fluoride excretion was within the range expected for the level of fluoride concentration in the drinking water. However, enamel fluorosis tended to be markedly lower than expected. This study revealed that fluoride levels in the two cities with fluoridated drinking water were variable. To optimise anticaries benefits and minimise the risk of fluorosis greater control of the fluoride dosing of the drinking water is required.     

Localization of receptors for the dipsogenic action of angiotensin II in the subfornical organ of rats.

Investigated the proposal that the subfornical organ (SFO) is a site of receptors for drinking induced by angiotensin II (AII). A total of 159 male albino Holtzman rats was used. Intracranial injections of physiological doses of AII elicited drinking if and only if applied directly to the SFO (Exp I). Ablation of the SFO selectively (Exp II) and permanently (Exp IV) eliminated drinking elicited by physiological doses of iv infused AII. Animals in which SFO had been ablated responded normally to cellular dehydration but reduced responding to the extracellular thirsts of beta-adrenergic activation and hyperoncotic colloid dialysis (Exp III). Infusion of saralasin, an AII antagonist, directly into the SFO selectively and reversibly antagonized iv AII drinking (Exp V). The hypothesis that the SFO contains dipsogenic receptors for circulating AII was supported. (2 p ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mutual interactions between HIV-1 and cytokines in adherent cells during acute infection

Intracerebroventricular (i.c.v.) infusions of angiotensin II (AII) reliably induced c-fos expression in the supraoptic (SON) and paraventricular (PVN) nuclei, as well as other areas of the basal forebrain including the OVLT, subfornical organ (SFO), and bed nucleus (BNST). Double-labelling showed that AII-induced c-fos was observed in both vasopressin (AVP-) and oxytocin (OXY)-containing neurons of the SON and PVN in male rats. Allowing rats to drink water after AII infusions suppressed c-fos expression both AVP- and OXY-stained magnocellular neurons. Intragastric infusions of water were also effective, showing that oro-pharyngeal stimuli were not critical. Maximal suppression occurred in rats in whom water had been infused intragastrically about 5 min before i.c.v. AII infusions, suggesting that changes in osmolarity were responsible. i.c.v. AII also induced c-fos expression in a number of brainstem structures, including the solitary nucleus (NTS), lateral parabrachial nucleus (LPBN), locus coeruleus (LC), and the area postrema (AP). These results indicate that AVP and OXY-containing neurons in the magnocellular parts of the SON and PVN alter their immediate-early gene response to AII after water intake, and that this does not depend upon oro-pharyngeal factors. Furthermore, AII can induce c-fos expression in a number of brainstem nuclei associated with autonomic function, and these do not respond to water intake.     

Daily variations of platelet aggregation in relation to blood and plasma serotonin in diabetes

INTRODUCTION: An increase in digitalis-like substances has been reported in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We hypothesized that the role of saline and unilateral nephrectomy in DOCA hypertension may be due to stimulation of endogenous digitalis-like substances. METHODS: We investigated the effects of digoxin and DOCA alone and in combination in intact rats drinking water. Forty male Sprague-Dawley rats were used (body weight 223-298 g). RESULTS: Neither digoxin (40 micrograms/kg per day, by gavage, for 35 days, n = 10) nor DOCA (30 mg/kg twice a week, subcutaneously, for 5 weeks, n = 10) caused a consistent increase in blood pressure in intact rats drinking water. In contrast, combined digoxin and DOCA administration (n = 10) increased systolic blood pressure from day 18 of treatment onwards, to a maximum at day 34 compared with sham-treated rats (n = 10). There were no consistent changes in water intake, urine volume, urinary sodium or potassium excretion, or plasma sodium or potassium concentration with digoxin treatment. DOCA increased water intake and urine volume, and caused an initial decrease in urinary sodium excretion, but no change in urinary potassium excretion or plasma sodium concentration. Plasma potassium excretion was lower in DOCA- than sham-treated rats. CONCLUSION: Combined digoxin and DOCA administration in intact rats drinking water increased blood pressure significantly compared with either drug alone, raising the possibility that the mechanism by which nephrectomy and salt loading contribute to DOCA hypertension in the rat might be through stimulation of endogenous digitalis-like substances.     

Angiotensin III-induced dipsogenic and pressor responses in rodents.

Three experiments examined responses to angiotensins in 64 male Sprague-Dawley rats, 64 male Mongolian gerbils, and 40 Octodon degus—a South American rodent. In Exp I, injections of [des-Asp–1]-angiotensin I ([des-Asp–1]-AI), angiotensin II (AII), and angiotensin III (AIII), at doses of .001–2 mg/kg (sc), induced drinking in the rat and degus, but not in the gerbil. In Exp II, pretreatment with captopril (50 mg/kg), an angiotensin converting enzyme inhibitor, prevented the endogenous conversion of sc injected [des-Asp–1]-AI to AIII and prevented drinking in rats and degus. The pharmacological artifact of hypovolemia caused by angiotensin-induced increases in vascular permeability was not observed in members of these species. In Exp III, blood pressure changes resulting from injections of AII and AIII in rats and gerbils were measured. Significant pressor elevations were seen following the administration of both analogs, although AII was more potent. Results demonstrate that AIII is dipsogenic in rats and degus and serves as a pressor agent in rats and gerbils. No explanation was found for the gerbil's relative lack of dipsogenicity to the presently tested angiotensins. (54 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Subfornical organ: forebrain site of pressor and dipsogenic action of angiotensin II

Intracranial injection of angiotensin II (AII) at three brain sites elicited near simultaneous dipsogenic and pressor effects in rats. Both effects were maximal, occurred with the shortest latencies, and at the lowest doses of AII when the cannula terminated precisely within the parenchyma of the subfornical organ (SFO). Pressor effects were produced by SFO injection of a dose of AII (0.1 pg) which approximates plasma AII concentrations at the high end of the physiological range. Both the drinking and pressor effects were blocked by saralasin. Injections of AII at sites immediately adjacent to SFO produced smaller effects with longer latencies. These results ruled out the possibility that SFO injections were effective via leakage to alternative sites. The pressor effect of AII at the SFO remained in animals under chloralose anesthesia, demonstrating that it is not an artifact of drinking behavior. These results indicate that the SFO is a site of AII pressor action, and confirm previous demonstrations that the structure is a site of AII drinking action.     

Self-administered intravenous infusion of hypertonic solutions and sodium appetite of sheep.

Studied the effects of self-administered iv infusion of hypertonic NaCl, mannitol, glucose, urea, or isotonic NaCl on Na appetite. 22 Merino-Cross sheep were trained to barpress to replace Na deficits of 300–500 mmol. During basal conditions, each delivery to a drinking cup was 15 ml of .6 M NaHCO? (9 mmol). In the experimental situation, an iv infusion was given automatically with each delivery to the drinking cup. Ingestion of NaHCO? solution was significantly reduced by all hypertonic solutions, the largest decrease being caused by hypertonic NaCl or mannitol. The decreased intake was observed within 10 (with infusion of hypertonic NaCl, mannitol, or glucose) or 20–40 (with urea infusion) minutes, irrespective of whether water was concurrently available to drink. At 20 min, plasma Na was increased by hypertonic NaCl, decreased by mannitol or glucose, and not changed by urea. CSF Na concentration was increased by all hypertonic solutions. In regard to the "turn-off" of Na appetite by systemic infusion, data are consistent with the theory of neural cells within the blood–brain barrier responsive to changes of Na concentration or osmolality in their environment. In contrast, water intake was stimulated by hypertonic NaCl or mannitol but not by urea or glucose. Results suggest that the sensors involved in thirst (e.g., osmoreceptors) are in an area of the brain lacking the blood–brain barrier. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Relation between food and water intake in the pigeon (Columba livia).

In 4 experiments with 40 male White Carneaux pigeons, continuous monitoring of feeding and drinking activity under ad-lib conditions showed that food and water intake were closely associated temporally with 70.0% of water intake occurring just prior to, during, and immediately following a meal. There was a significant positive correlation between 24-hr food and water intake. However, the association between food and water intake varied temporally during ad-lib and food-restriction schedules. Under ad-lib conditions, there was a significant correlation between food and water intake during a 2-hr period in the morning but not the afternoon. Likewise, when food was restricted for a 2-hr period in the morning, water intake was significantly correlated with food intake. During total food deprivation, drinking was primarily confined to the light portion of the light–dark cycle. Data suggest that the amount of water ingested as well as the temporal pattern of water intake is not solely dependent on food intake and may be determined by an underlying temporal rhythm of drinking. (28 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of subchronic metformin treatment on macronutrient selection in genetically obese Zucker rats

Metformin has been particularly recommended to be used in obese type 2 diabetic patients because of its weight decreasing and serum lipid profile normalizing effects. In the present study the effects of subchronic metformin treatment on macronutrient selection, weight gain and plasma insulin and glucose were investigated in 20 genetically obese male Zucker rats which were maintained on a free-feeding self-selection paradigm with three pure macronutrient diets of carbohydrate, fat and protein. Half of the rats were given metformin hydrochloride 320 mg/kg/day up to 18 days in drinking water. The other half of the animals received normal drinking water as a control. Metformin treatment significantly reduced 24 hr carbohydrate (P < 0.01), fat (P < 0.001) and protein (P < 0.01) intake. The proportion of fat of the total consumed energy was significantly increased by metformin (P < 0.01) while the proportion of protein was decreased (P < 0.05). In hunger stimulated feeding experiment metformin decreased selectively protein intake (P < 0.01). Changes in macronutrient selection were associated with reduced body weight gain in metformin treated rats (P < 0.001). Metformin markedly reduced the hyperinsulinaemia (P < 0.01) and plasma glucose levels (P < 0.05), which suggests improved glucose tolerance after metformin treatment. It is concluded that subchronic metformin treatment can modify the composition of energy intake in a macronutrient selective manner.     

Prognostic markers in pheochromocytoma

Annexin II (AII) belongs to a family of glycoproteins that bind negatively charged phospholipids in the presence of calcium. The annexins exert various biological functions. We have previously shown that soluble AII suppresses mitogen-induced lymphoproliferation in vitro. In this study we address the question of whether soluble AII may also affect immunoglobulin secretion. Mononuclear cells from peripheral blood were stimulated with pokeweed mitogen in vitro and immunoglobulin-secreting cells were quantified using an ELISPOT assay. Retroplacental serum and soluble AII significantly inhibited secretion of IgG and IgM when added at concentrations that did not affect lymphoproliferation or cell viability. The inhibitory effect was dose- and time dependent. Significant suppression was observed when soluble AII was added at concentrations of 0.1 and 0.01 microg/ml. The strongest inhibition was observed when soluble AII or retroplacental serum was added initially. The data demonstrate that soluble AII can suppress immunoglobulin secretion in vitro. AII seems to be a potent immunosuppressive substance. The presence of high levels of soluble AII in retroplacental serum may indicate a possible immunomodulatory role in normal pregnancy.     

Human endometrial stromal cells generate uncombined alpha-subunit from human chorionic gonadotropin, which can synergize with progesterone to induce decidualization

Prostaglandin E2 (PGE2) is an endogenous hormone of adrenal zona glomerulosa cells and is released in response to stimulation by agonists such as angiotensin II (Ang II). It stimulates the release of aldosterone from cultured bovine adrenal zona glomerulosa cells. These studies were designed to determine whether this steroidogenic effect of PGE2 was mediated by an EP1, EP2, or EP3 receptor. Prostaglandin E2 and 11-deoxy PGE1, an EP2-selective agonist, stimulated aldosterone release in a concentration-related manner with an ED50 of 300 nmol/L for PGE2 and 2 micromol/L for 11-deoxy PGE1. The maximal effect of PGE2 was less than that of angiotensin II. 17-Phenyl trinor PGE2, an EP1-selective agonist, required concentrations of 100 micromol/L to stimulate aldosterone release and sulprostone, an EP3/EP1-selective agonist, failed to alter aldosterone release. The EP1-selective antagonist SC19220 failed to alter basal or PGE2-stimulated aldosterone release over a range of concentrations. PGE2 and 11-deoxy PGE1 also stimulated an increase in both intracellular and extracellular cAMP. This increase was time- and concentration-related. The ED50 for PGE2 was 9.8 micromol/L. 17-Phenyl trinor PGE2 and sulprostone were without effect. Using fura-2 loaded cells, PGE2 (2 micromol/L), dibutyryl cAMP (2 mmol/L), and Ang 11 (2 micromol/L) increased intracellular calcium over basal concentrations by 5.5-fold, 3-fold, and 6.2-fold, respectively. Like PGE2, dibutyryl cAMP also stimulated aldosterone release. PGE2- and dibutyryl cAMP-induced aldosterone release were blocked by the calcium channel inhibitor diltiazem. These studies indicate that PGE2 is a potent stimulus for aldosterone release and that the effect is mediated by EP2 receptors. Both cAMP and calcium appear to mediate the steroidogenic effect of PGE2 and calcium seems to be distal to cAMP.     

The role of cholecystokinin (CCK), CCK-A or CCK-B receptor antagonists in the spontaneous preference for drugs of abuse (alcohol or cocaine) in naive rats

A "free choice" two-bottle drinking test paradigm was implemented in naive adult male Wistar rats, resulting in a clear identification of rats drinking mainly water (water-preferring, WP rats) and rats spontaneously drinking also a consistent amount of a solution of cocaine (0.5 mg/ml water, cocaine-drinking, CD rats) or ethanol 10% v/v (ethanol-drinking, ED rats). Low, selective doses (5 micrograms/kg) of the specific cholecystokinin (CCK)-A receptor antagonist L-364,718 largely reduced the intake of ethanol 10% of ED rats only. In contrast, low, selective doses of GV-150013 (5 micrograms/kg) reduced significantly the consumption of cocaine of CD rats only. These results indicate that the CCK-A or B receptors are selectively involved in the modulation of alcohol or cocaine intake, respectively, and suggest an involvement of the CCKergic system in the drug-seeking behavior. WP rats and CD rats were then prepared for ex vivo electro-neurochemical analysis by means of differential pulse voltammetry (DPV) with micro-biosensors to monitor catechol, 5-hydroxyindole and peptidergic oxidation signals in the nucleus accumbens (nAcc). In this area, the peptidergic signal appeared to be related to the oxidation of endogenous CCK, which basal levels resulted higher in ED and CD rats than WP rats. Thus, the hypothesis that the endogenous tone of the CCK system is higher in the ED and CD rats than in the WP rats is proposed, and is supported by the observation that treatment with CCK-5 (CCK receptor agonist) selectively induced the WP rats to drink alcohol or cocaine. The selective effect of the CCK-antagonists on reducing the drug intake of ED or CD rats further supports this view, as it suggests that CCK antagonists may modify the individual sensitivity towards drugs of abuse set by the stimulating effect of high endogenous CCKergic tone over CCK-B or CCK-A receptors in spontaneous ED or CD rats, respectively. Therefore, the present data indicate that: i) Free-choice models may reveal the presence of individual sensitivity to alcohol or cocaine in naive rats; ii) the dopaminergic system is involved within the reward state, while peptidergic (CCKergic) activities modulate the drug-seeking state (craving state); iii) the CCK system could be a new target in the study of the drug dependency phenomenon. In particular, the data imply a CCK-A receptor mechanism in the regulation of individual sensitivity towards ethanol and a CCK-B receptor mechanism in the regulation of individual sensitivity towards cocaine. Thus, a potential therapeutic role for CCK-A antagonists in the treatment of ethanol abuse and for CCK-B antagonists in the treatment of cocaine abuse is proposed.