Cysteamine exerts multiple effects on the endocrine cells of the rat pancreas

We have studied the effects by cysteamine in vitro and in vivo on hormone production and islet cell metabolism in isolated pancreatic islets and perfused pancreas of the rat. In isolated islets, cysteamine dose-dependently depleted somatostatin immunoreactivity by 50% after 60 min exposure to 1 mmol/l of the compound. This effect appeared to be independent of interaction of the drug with secretion of somatostatin from the pancreatic D-cells. Cysteamine, however, interacted acutely not only with the D-cells, but also markedly suppressed glucose-induced insulin release. Moreover, cysteamine inhibited islet glucose oxidation, an effect which reflects interference with the metabolism mainly of the B-cells. The effect of cysteamine on glucose-induced insulin release was prolonged, since it was still observed in the isolated rat pancreas perfused 24 h after in vivo treatment with cysteamine. In contrast to the effects on glucose-induced insulin release, the response to glibenclamide remained unaffected by a previous exposure to cysteamine in vivo. However, both glucose- and glibenclamide-induced somatostatin secretion was reduced by 50%, whereas basal glucagon secretion was significantly enhanced in pancreata from cysteamine-treated rats vs. control rats. We conclude that (1) cysteamine does not specifically affect the D-cells of the islets, and (2) the multiple effects by cysteamine on islet cell function, particularly on B-cell metabolism and secretion, renders the compound unsuitable for the study of paracrine interactions in the islets.     

Methamphetamine enhances paced mating behaviors and neuroplasticity in the medial amygdala of female rats

Methamphetamine (METH) is a psychomotor stimulant strongly associated with increases in sexual drive and behavior in women and men. Even though men and women are equally as likely to be addicted to or use METH, studies of sexual behavior often focus on male users. The paucity in studies examining the effect of METH in women is of great concern, when one considers the high correlation with sexually transmitted diseases such as HIV/AIDS and unplanned pregnancies. In fact, why METH so profoundly increases sexual drive is unknown. We have demonstrated that repeated exposure to METH enhances both receptivity and proceptivity in hormonally primed female rats. The current study examined whether a repeated exposure to METH enhanced female-initiated sexual behaviors in hormonally primed rats. In a paced mating paradigm, METH treatment significantly decreased the female's return latency following a mount (57%) and an ejaculation (44%), and the likelihood to leave the male following an intromission (37%) compared to controls. The METH-induced changes in paced mating behavior were accompanied by a 60% increase in spinophilin levels in the medial amygdala following hormonal priming and METH treatment. Taken together, these findings suggest that METH increases female sexual motivation and behavior in the rat potentially via changes in the neural substrate that require repeated exposure to the drug.     

Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence

Depression during pregnancy and the postpartum period is a growing health problem, which affects up to 20% of women. Currently, selective serotonin reuptake inhibitor (SSRIs) medications are commonly used for treatment of maternal depression. Unfortunately, there is very little research on the long-term effect of maternal depression and perinatal SSRI exposure on offspring development. Therefore, the aim of this study was to determine the role of exposure to fluoxetine during development on affective-like behaviors and hippocampal neurogenesis in adolescent offspring in a rodent model of maternal depression. To do this, gestationally stressed and non-stressed Sprague-Dawley rat dams were treated with either fluoxetine (5 mg/kg/day) or vehicle beginning on postnatal day 1 (P1). Adolescent male and female offspring were divided into 4 groups: 1) prenatal stress+fluoxetine exposure, 2) prenatal stress+vehicle, 3) fluoxetine exposure alone, and 4) vehicle alone. Adolescent offspring were assessed for anxiety-like behavior using the Open Field Test and depressive-like behavior using the Forced Swim Test. Brains were analyzed for endogenous markers of hippocampal neurogenesis via immunohistochemistry. Results demonstrate that maternal fluoxetine exposure reverses the reduction in immobility evident in prenatally stressed adolescent offspring. In addition, maternal fluoxetine exposure reverses the decrease in hippocampal cell proliferation and neurogenesis in maternally stressed adolescent offspring. This research provides important evidence on the long-term effect of fluoxetine exposure during development in a model of maternal adversity.     

Bombesin injection into the central amygdala influences feeding behavior in the rat.

The present study was performed to determine whether low doses (10 or 40 ng) of bombesin microinjected into the amygdala could modify solid food intake. Forty ng of bombesin in 24 h deprived rats caused transient inhibition of food intake. This inhibitory effect was eliminated by prior bombesin antagonist treatment. A series of quantitative behavioral tests indicated that low doses of bombesin application specifically reduced food intake without altering the behavioral pattern or influencing the body temperature. The present results suggest, that bombesin-like peptides may act as a satiety signal in the central part of the amygdala.     

Fluoxetine results in misleading conclusions on fish behavior

Fluoxetine is an antidepressant medicine causing relaxation and mood improvement in people, with silencing certain personality traits in some cases. The question arise if such phenomena can be observed in nontarget organisms such as fish. Fluoxetine affects fishes behavior; however, it is not known if the medicine affects its “personality.” This study aimed to evaluate the reaction of the invasive Neogobius fluviatilis and native Gobio gobio individuals to fluoxetine at environmental concentration of 360 ng/L. We prepared three variants of the experiments: (a) behavioral trials with unexposed fishes, (b) behavioral trials with the same fishes after 21 days of fluoxetine exposure, and (c) behavioral trials with the same fishes after 21‐day depuration period, that is, without fluoxetine. The fishes reaction time (RT), that is, difference in time spent on reaching food with and without the necessity of overcoming the obstacle, was analyzed. Additionally, the personality, bold or shy, traits of each fish individual, was assigned. The results indicated that environmental concentrations of the antidepressant influenced RT. The average RT of the fishes cultured with fluoxetine was by 7‐min shorter in comparison with the nonexposed control. Share of individuals exposed to fluoxetine assigned as bold raised to 71.4% in comparison with 46.4% in nonexposed control. This sheds new light on wild fishes behavior caught from freshwater. Environmental concentrations of the antidepressant influenced the time of fishes reaction and share individuals assigned as bold. Moreover, 21‐day recovery lasting might be not enough to get fluoxetine effect on fishes.     

IGF-1 modulation of rat cardiac fibroblast behavior and gene expression is age-dependent

The collagenous extracellular matrix (ECM) forms a stress-tolerant network that is essential for proper function of the vertebrate heart. Profound changes have been detected in the interstitial ECM concurrent with developmental and disease processes of the heart. These alterations in either the organization or accumulation of ECM components markedly affect myocardial function. Studies have shown that a number of biochemical factors, including angiotensin II, transforming growth factor-β, and insulin-like growth factors, modulate collagen expression by heart fibroblasts, however, few studies have examined the differential effects of these factors on fibroblasts from animals of different physiological backgrounds. The present studies were carried out to determine whether cardiac fibroblasts isolated from different aged animals (fetal, neonatal, and adult) have diverse responses to insulin-like growth factor-1 (IGF-1). Fibroblasts isolated from fetal, neonatal, and adult rat hearts were treated with IGF-1, and several downstream responses were measured, including collagen gel contraction, adhesion to ECM, and expression of interstitial collagen and integrins. IGF-1 affected these parameters to different degrees, depending on the age of the animal from which the fibroblasts were isolated. These experiments indicate that IGF-1 is a potent modulator of fibroblast behavior in general; however, significant differences are apparent in the responsiveness of cells to this growth factor depending on the age of the animal of origin. Future experiments will be directed at determining how the in vivo chemical and biomechanical environment affects the response of heart fibroblasts to growth factors such as IGF-1.     

PGE2 exerts dose-dependent opposite effects on net water and chloride absorption from the rat colon

This work investigated the effect of different doses of PGE2 on net water and Cl- absorption from the rat colon, using an in situ perfusion technique. PGE2 exerted opposite effects at different concentrations. Net water and Cl- absorption was significantly reduced at low doses with a minimum at 0.4 microg/100g BW, and significantly elevated at high doses with an observed maximal effect at 21 microg/100g BW. At low doses, PGE2 increased in superficial cells, the activity of the Na+-K+ ATPase and the protein expression of the Na+K+2Cl- cotransporter, but reduced them in crypt cells. Thus, the reduction in net water and Cl- absorption was ascribed to an increase in secretion by surface cells that masked absorptive processes. At high doses, PGE2 increased significantly the activity of the Na+-K+ ATPase in superficial cells only, and was without any effect on the protein expression of the cotransporter and the pump in both surface and crypt cells. The observed increase in net water and Cl- absorption was attributed in this case to an increase in absorptive processes with no effect on secretion.     

Platelet-derived growth factor exerts disparate effects on odontoblast differentiation depending on the dimers in rat dental pulp cells

Platelet-derived growth factor (PDGF) has recently been demonstrated to control the expression of alkaline phosphatase and proteoglycan synthesis of odontoblastic cells in dental pulp tissues. Although PDGF appears to be closely related to dentinogenesis, much about the mode of action of PDGF on odontoblast differentiation remains unclear. In this study, we examined the effects of three PDGF dimers (PDGF AA, AB, and BB) on odontoblastic differentiation of dental pulp cells in long-term mineralized cultures. Dental pulp cells isolated from rat lower incisors were continuously treated with each of PDGF AA, AB, and BB in separate cultures for 20 days. The three PDGF dimers suppressed alkaline phosphatase activity, osteocalcin and calcium content, and the formation of dentin-like nodules. The expression of mRNA for dentin sialoprotein (DSP) in the cells was inhibited by PDGF AA treatment, whereas PDGF AB and BB treatment stimulated the expression of DSP, even though the dentin-like nodule formation was inhibited. Although the effects of PDGF on odontoblastic differentiation varied among the dimers, the cells expressed both PDGF and receptors, whose quantities were similar. These results suggest that PDGF exerts diverse effects on odontoblastic differentiation depending on its dimeric form. These in vitro findings explain, at least in part, the in vivo action of PDGF in dentinogenesis during the repair process of damaged dental pulp.This work was supported in part by grants-in-aid from the Ministry of Science, Education, and Culture of Japan     

Sex-and age-dependent effects of prenatal exposure to caffeine on open-field behavior, emergence latency and adrenal weights in rats

Pregnant rats were provided with drinking water containing 0, 0.23 or 0.3 mg/ml of caffeine throughout gestation. These concentrations gave rise to daily doses of 0, 28 and 36 mg/kg. Open-field behavior and latencies to emerge from a darkened chamber were observed in offspring at regular intervals from 1 to 8 months after birth. The main results revealed increases in open-field locomotor and rearing activity with 28 but not 36 mg/kg/day. The opposite pattern characterized emergence latency. These changes were more typical of male rats particularly when older. Combining the present results with those of an earlier study by the authors strengthened the curvilinear trends observed and led to the conclusion that, low doses of prenatal caffeine increase activity and decrease emotionality. Higher doses may have the opposite effects to the point that the significant differences from control subjects reported earlier can occur. When 8 months old, female but not male rats prenatally exposed to 36 mg/kg/day of caffeine had significantly heavier adrenal glands than controls.     

Taurolithocholic acid exerts cholestatic effects via phosphatidylinositol 3-kinase-dependent mechanisms in perfused rat livers and rat hepatocyte couplets

Taurolithocholic acid (TLCA) is a potent cholestatic agent. Our recent work suggested that TLCA impairs hepatobiliary exocytosis, insertion of transport proteins into apical hepatocyte membranes, and bile flow by protein kinase Cepsilon (PKCepsilon)-dependent mechanisms. Products of phosphatidylinositol 3-kinases (PI3K) stimulate PKCepsilon. We studied the role of PI3K for TLCA-induced cholestasis in isolated perfused rat liver (IPRL) and isolated rat hepatocyte couplets (IRHC). In IPRL, TLCA (10 micromol/liter) impaired bile flow by 51%, biliary secretion of horseradish peroxidase, a marker of vesicular exocytosis, by 46%, and the Mrp2 substrate, 2,4-dinitrophenyl-S-glutathione, by 95% and stimulated PI3K-dependent protein kinase B, a marker of PI3K activity, by 154% and PKCepsilon membrane binding by 23%. In IRHC, TLCA (2.5 micromol/liter) impaired canalicular secretion of the fluorescent bile acid, cholylglycylamido fluorescein, by 50%. The selective PI3K inhibitor, wortmannin (100 nmol/liter), and the anticholestatic bile acid tauroursodeoxycholic acid (TUDCA, 25 micromol/liter) independently and additively reversed the effects of TLCA on bile flow, exocytosis, organic anion secretion, PI3K-dependent protein kinase B activity, and PKCepsilon membrane binding in IPRL. Wortmannin also reversed impaired bile acid secretion in IRHC. These data strongly suggest that TLCA exerts cholestatic effects by PI3K- and PKCepsilon-dependent mechanisms that are reversed by tauroursodeoxycholic acid in a PI3K-independent way.     

Antagonism between L-DOPA and apomorphine in their effects on rat behavior

The effect of simultaneous injections of apomorphine and l-DOPA on stereotypy, aggressiveness, on the exploratory motor activity, the threshold of emotional reactivity and aggressiveness elicited by painful electrical stimulation was studied in experiments on male albino rats. When injected separately, in control experiments, both compounds had similar effects on the exploratory-motor activity and the emotional behaviour, but when injected simultaneously in various doses a distinct antagonism between l-DOPA and apomorphine, according to all the behaviour tests, was noted (a decrease of sterotypy, aggressiveness and emotional reactivity). Against the background of l-DOPA apomorphine (5 mg/kg) increased the dopamine content in the forebrain and in the diencephalon even more. It is suggested that the increased level of the functionally active mediator suppressed the activity of postsynaptic receptors sensitive to it.     

The experience of maternity exerts a significant effect on the shaping of behavior in rat progeny in early postnatal ontogeny]

Maturation of specific behavioral reactions were studied in 13-24-day-old rats born by females with prior maternal experience (group A) and maternally naive females (group B). The rats of group B showed later eyes opening and earlier maturation of grooming and manipulation than the group A rats. The development of behavioral reactions was found to be related with eye opening in the rats of group A and maturation of manipulation in group B rats. The results suggest that the maternal influence is a significant environmental factor, which affects the early postnatal development of rat pups.     

Prey behavior, age-dependent vulnerability, and predation rates

Variation in the temporal pattern of vulnerability can provide important insights into predator-prey relationships and the evolution of antipredator behavior. We illustrate these points with a system that has coyotes (Canis latrans) as a predator and two species of congeneric deer (Odocoileus spp.) as prey. The deer employ different antipredator tactics (aggressive defense vs. flight) that result in contrasting patterns of age-dependent vulnerability in their probability of being captured when encountered by coyotes. We use long-term survival data and a simple mathematical model to show that (1) species differences in age-dependent vulnerability are reflected in seasonal predation rates and (2) seasonal variation in prey vulnerability and predator hunt activity, which can be associated with the availability of alternative prey, interact to shape seasonal and annual predation rates for each prey species. Shifting hunt activity from summer to winter, or vice versa, alleviated annual mortality on one species and focused it on the other. Our results indicate that seasonal variation in prey vulnerability and hunt activity interact to influence the impact that a predator has on any particular type of prey. Furthermore, these results indicate that seasonal variation in predation pressure is an important selection pressure shaping prey defenses.     

The effects of adrenalectomy and corticosterone replacement on maternal behavior in the postpartum rat

It is well known that the hypothalamic-pituitary-adrenal (HPA) axis is activated during stress. Recent work suggests it is also implicated in the regulation of "normal" behaviors. The present studies investigated the effects of adrenalectomy and of varying glucocorticoid concentrations on adult maternal behavior in primiparous rats. In two studies, rats in late pregnancy were adrenalectomized or given sham surgeries and were tested for maternal behavior. In the first study, primiparous rats were given 0, 25, 100, 300, or 500 microg/ml of corticosterone in their drinking water. In the second study, primiparous rats were given either control or corticosterone time-release pellets. Blood samples were taken to ensure that rats demonstrated levels of corticosterone in blood that were relative to doses received. In studies one and two, primiparous adrenalectomized rats showed slightly, but significantly, lower levels of some maternal behaviors, including licking and time in nest, than primiparous sham rats. Primiparous rats given higher doses of corticosterone replacement showed higher levels of these maternal behaviors than primiparous rats given lower doses of corticosterone. In conclusion, adrenalectomy decreases, but does not abolish, maternal behavior. Corticosterone replacement reverses these effects. Corticosterone is not necessary for the initiation or maintenance of maternal behavior but plays a role in the modulation of ongoing maternal behavior.     

Silybin exerts antioxidant effects and induces mitochondrial biogenesis in liver of rat with secondary biliary cirrhosis

The accumulation of toxic hydrophobic bile acids in hepatocytes, observed during chronic cholestasis, induces substantial modification in the redox state and in mitochondrial functions. Recent reports have suggested a significant role of impaired lipid metabolism in the progression of chronic cholestasis. In this work we report that changes observed in the expression of the lipogenic enzymes acetyl-CoA carboxylase and fatty acid synthase were associated with a decrease in the activity of citrate carrier (CIC), a protein of the inner mitochondrial membrane closely related to hepatic lipogenesis. We also verified that the impairment of citrate transport was dependent on modification of the phospholipid composition of the mitochondrial membrane and on cardiolipin oxidation. Silybin, an extract of silymarin with antioxidant and anti-inflammatory properties, prevented mitochondrial reactive oxygen species (ROS) production, cardiolipin oxidation, and CIC failure in cirrhotic livers but did not affect the expression of lipogenic enzymes. Moreover, supplementation of silybin was also associated with mitochondrial biogenesis. In conclusion, we demonstrate that chronic cholestasis induces cardiolipin oxidation that in turn impairs mitochondrial function and further promotes ROS production. The capacity of silybin to limit mitochondrial failure is part of its hepatoprotective property.     

C-peptide exerts cardioprotective effects in myocardial ischemia-reperfusion

Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac dysfunction. C-peptide, a cleavage product of proinsulin to insulin processing, induces nitric oxide (NO)-mediated vasodilation. NO is reported to attenuate cardiac dysfunction caused by PMNs after ischemia-reperfusion (I/R). Therefore, we hypothesized that C-peptide could attenuate PMN-induced cardiac dysfunction. We examined the effects of C-peptide in isolated ischemic (20 min) and reperfused (45 min) rat hearts perfused with PMNs. C-peptide (70 nmol/kg iv) given 4 or 24 h before I/R significantly improved coronary flow (P < 0.05), left ventricular developed pressure (LVDP) (P < 0.01), and the maximal rate of development of LVDP (+dP/dt(max)) compared with I/R hearts obtained from rats given 0.9% NaCl (P < 0.01). N(G)-nitro-L-arginine methyl ester (L-NAME) (50 micromol/l) blocked these cardioprotective effects. In addition, C-peptide significantly reduced cardiac PMN infiltration from 183 +/- 24 PMNs/mm(2) in untreated hearts to 44 +/- 10 and 58 +/- 25 PMNs/mm(2) in hearts from 4- and 24-h C-peptide-treated rats, respectively. Rat PMN adherence to rat superior mesenteric artery exposed to 2 U/ml thrombin was significantly reduced in rats given C-peptide compared with rats given 0.9% NaCl (P < 0.001). Moreover, C-peptide enhanced basal NO release from rat aortic segments. These results provide evidence that C-peptide can significantly attenuate PMN-induced cardiac contractile dysfunction in the isolated perfused rat heart subjected to I/R at least in part via enhanced NO release.     

Contrasting effects of Org 2766 and alpha-MSH on social and exploratory behavior in the rat

Intraperitoneal injection of Org 2766 (0.01-0.4 microgram/kg) produced a dose-related increase in the number of social contacts and in the time spent in active social interaction by pairs of male rats tested in arenas with which they were familiar, but had little effect when the rats were tested in unfamiliar arenas. The increased social interaction was not accompanied by any change in motor activity. In contrast, alpha-MSH (20-200 microgram/kg) decreased the time spent in active social dose-related. Both peptides reduced exploratory head-dipping only at high doses (4-8 microgram/kg for Org 2766 and 200 microgram/kg for alpha-MSH); this change was not accompanied by a reduction in motor activity.     

Role of the amygdala in the behavior of domesticated and aggressive foxes

Influence was studied of the bilateral electric coagulation of the basolateral part of the amygdala on the behaviour in unknown environment and on the attitude to the man of domesticated and aggressive foxes. Increase of exploratory behaviour with enhancing of motor activity was observed in all foxes after amygdala ablation. At the same time a decrease of positive emotional reactions to man was observed in the domesticated animals, while in the aggressive foxes defensive reactions to man and in unknown environment were weakened.