Biomedical subjects

L Rägo

Publications and source records attributed to L Rägo.

At least 19 recordsLinked to original sources

PubMed2000

Differential effects of melanocortin peptides on ingestive behaviour in rats: evidence against the involvement of MC(3) receptor in the regulation of food intake.

The pro-opiomelanocortin-derived peptides decrease food intake possibly via MC4 receptor. In this study we compared the effects of alpha-melanocyte-stimulating hormone (MSH), beta-MSH and gamma(1)-MSH (0.2, 1.0 and 5.0 microg, i.c.v.) on food intake. alpha-MSH and beta-MSH inhibited spontaneous food intake in a dose dependent manner, whereas the gamma(1)-MSH did not. alpha-MSH and beta-MSH but not gamma(1)-MSH (all 5.0 microg, i.c.v.) inhibited fasting-induced food intake about 50%. None of the three peptides inhibited fluid consumption in water-deprived (24 h) rats. It is suggested that MC(3) receptor, activated selectively by gamma(1)-MSH, is not involved in the regulation of food intake.

Animals↗

PubMed2000

Anorexigenic cocaine- and amphetamine-regulated transcript peptide intensifies fear reactions in rats.

An increasing number of appetite-regulating peptides are being discovered. The list of regulators inhibiting food intake is considerably longer than that of appetite stimulators. In many cases, the peptides inhibiting food intake facilitate fear reactions, whereas the majority of the agents reducing anxiety responses stimulate appetite. Cocaine- and amphetamine-regulated transcript (CART) cDNA was isolated from hypothalamic libraries and CART was reported to inhibit food intake and to mediate the anorectic effects of leptin. Here, we show that the active core fragment of CART (CART(89-103), 0.04-5.0 nmol) injected into lateral cerebral ventricle not only inhibits food intake, but also causes a dose-dependent increase in anxiety-like reactions in elevated plus-maze test. Intracerebroventricular administration of CART(82-103) (0.04-5.0 nmol) did not inhibit water intake and did not affect spontaneous locomotor activity in the open field test ruling out unspecific effects of the peptide. Our results suggest that CART could be an endogenous factor in the brain mediating the effects of stress on appetite.

Animals↗

PubMed2000

Differential effects of beta-carbolines and antidepressants on rat exploratory activity in the elevated zero-maze.

Present experiments were designed to compare the effects of antidepressants desipramine (10 and 20 mg/kg IP) and fluoxetine (5 and 10 mg/kg IP) with anxiogenic beta-carboline DMCM (0.5 and 1.0 mg/kg IP) in the elevated zero-maze test in rats. The second aim of this study was to assess the effects of pinoline (6-methoxy-1,2,3, 4-tetrahydro-beta-carboline) in the rat elevated zero-maze test in comparison with structurally unrelated beta-carboline DMCM and antidepressants. The time spent in the open part of the elevated zero-maze was not significantly affected by antidepressants, but was decreased by beta-carbolines pinoline and DMCM. The number of line crossings in the open parts and the number of head dips were also decreased more by beta-carbolines in comparison with antidepressants. Latency to enter the open part was statistically significantly increased only by DMCM. Measurement of locomotor activity in a separate experiment indicated that activity of the rats' time moving, distance traveled, and number of rearings were reduced by all four drugs studied. These results demonstrate that the effects of antidepressants in the elevated zero-maze test differ from the effects of the reference anxiogenic compound DMCM. The effects of pinoline and DMCM in the zero-maze test were similar, which suggests the involvement of mechanisms other than serotoninergic in the action of pinoline.

Animals↗

PubMed2000

Orexigenic effect of the melanocortin MC4 receptor antagonist HS014 is inhibited only partially by neuropeptide Y Y1 receptor selective antagonists.

Neuropeptide Y (NPY) and melanocortin (MC) peptides have opposite effects on food intake: NPY-like peptides and MC receptor antagonists stimulate feeding and increase body weight, whereas melanocortins and NPY antagonists inhibit food intake. In this study we tested whether the orexigenic effect of the selective MC4 receptor antagonist HS014 (1 nmol) could be inhibited by three different NPY antagonists, (R)-N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]D-argininam ide (BIBP3226), (R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N2(diphenyl acetyl)-argininamidetrifluoroacetate (BIBO3304), and decapeptide [D-Tyr(27,36)D-Thr32]NPY(27-36), after icv administration in freely feeding male rats. All three NPY receptor antagonists inhibited the orexigenic effects of HS014 partially and with markedly different potency. [D-Tyr(27,36)D-Thr32]NPY(27-36) was active only in subconvulsive dose. The NPY Y1 selective antagonist BIBP3226 was more effective in inhibiting the effect of HS014 than BIBO3304 despite in vitro data indicating that BIBP3226 is about 10 times less potent than BIBO3304 at NPY Y1 receptor. An enantiomer of BIBO3304, BIBO3457, failed to inhibit HS014-induced feeding, indicating that the effects of BIBO3304 were stereoselective. These results suggest that stimulation of food intake caused by weakening of melanocortinergic tone at the MC4 receptor is partially but not exclusively related to NPY Y1 receptor activation.

Animals↗

PubMed1999

Long-term administration of MC4 receptor antagonist HS014 causes hyperphagia and obesity in rats.

In this study we investigated the long term effects of a potent and selective melanocortin 4 (MC4) receptor antagonist (HS014) on food intake, body weight, body composition and blood glucose levels in adult rats. HS014 was injected i.c.v. either by twice-daily injections (2 x 1 nmol) for 6 days or administered by continuous infusion with osmotic minipumps (0.16 nmol/h) for 2 weeks. The results show a considerable increase in food intake and body weight after both of the treatments without any signs of tachyphylaxis. After 2 weeks of treatment with osmotic pumps, the HS014-treated rats (average weight 425g) had 20% higher body weight than the controls rats (average 360 g). When i.c.v. injections were terminated, the body weight of the twice-daily HS014-treated rats returned to the levels of control group, whereas the rats treated with continuous infusion of HS014 remained hyperphagic and still gained weight. Blood glucose levels in the rats treated with HS014 infusion were significantly increased. Analysis of body composition in HS014-infused rats indicated that body weight was increased due to fat deposits. These data show for the first time that chronic administration of exogenous MC4 receptor antagonist causes hyperphagia and severe obesity in rats. These data also indicate that the melanocortic control of food intake is very robust and suggest that changes induced by such treatment overcome negative feedback signals.

Animals↗

PubMed1999

Neuropeptide Y Y1 receptor antagonist BIBP3226 produces conditioned place aversion in rats.

1. Previous studies have shown that the blockade of the neuropeptide Y (NPY) Y1 receptors with N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]-D-arginine amide (BIBP3226) induces anxiogenic-like reaction in rats tested in elevated plus-maze test. 2. The present study examined whether such a treatment is aversive using place conditioning in a two-compartment apparatus. Locomotor activity was measured in open field test. 3. Pairings with potentially anxiogenic dose of BIBP3226 (5 micrograms/6.5 microliters, i.c.v.) produced a conditioned aversion for the drug-associated place, whereas the locomotor activity in the open field test was not affected by this dose of BIBP3226. 4. These data suggest that the blockade of central NPY Y1 receptors is aversive and provide additional evidence to the hypothesis that the NPY Y1 receptors are involved in the regulation of affective states.

Animals↗

PubMed1998

Evidence for involvement of the melanocortin MC4 receptor in the effects of leptin on food intake and body weight.

The hypothesis that the melanocortin MC4 receptor mediates the homeostatic effects of leptin was tested. Leptin (0.3 nmol, i.c.v.) lowered food intake at 4 and 24 h and body weight at 24 h. This effect was inhibited by pretreatment with an analogue of melanocyte stimulating hormone (MSH), the selective melanocortin MC4 receptor antagonist HS014 (cyclic [AcCys11,D-Nal14,Cys18,Asp-NH2(22)]-beta-MSH11-2 2, 0.3 nmol, i.c.v.). HS014 alone at this dose did not modify food intake or body weight. At a higher dose (1.0 nmol, i.c.v.) HS014 stimulated food intake and this orexigenic effect of HS014 was attenuated by leptin pretreatment (0.3 nmol, i.c.v.). These results confirm earlier findings that leptin inhibits food intake and lowers body weight via the melanocortin system and suggest that leptin affects signalling at the melanocortin MC4 receptor.

Analysis of Variance↗

PubMed1998

Anxiogenic-like effect of the NPY Y1 receptor antagonist BIBP3226 administered into the dorsal periaqueductal gray matter in rats.

Exogenous neuropeptide Y (NPY) administered intracerebroventricularly or into the central nucleus of amygdala has anxiolytic-like effects in animal models of anxiety. These effects are probably mediated by the NPY Y1 receptor. The role of the NPY Y1 receptor activation by endogenous NPY in this and other brain areas has not been fully elucidated. The selective NPY Y1 receptor antagonist (R)-N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]-D-arginine amide (BIBP3226) was microinjected into various brain sites implicated in the regulation of anxiety-related behaviour and resultant behavioural changes were assessed using the elevated plus-maze (EPM) and open-field test in rats. Intracerebroventricular application of BIBP3226 (5.0 microg) which caused an anxiogenic-like effect in the EPM did not affect exploratory activity in the open-field test. A decrease in EPM exploration was observed also when BIBP3226 (0.5 microg) was microinjected into the dorsal periaqueductal gray matter (DPAG). Intra-DPAG BIBP3226 did not change open-field behaviour suggesting that the effects of BIBP3226 in the EPM test were not related to changes in locomotor activity in general. Bilateral application of BIBP3226 into the central nucleus of amygdala (0.5 and 2.5 microg/side) and unilateral injections into the locus coeruleus and the paraventricular nucleus of the hypothalamus (both 0.5 microg) were ineffective in modifying the plus-maze exploration. These data suggest that endogenous NPY may regulate anxiety-related behaviour in rats by acting via the NPY Y1 receptors in DPAG.

Animals↗

PubMed1998

NPY Y1 receptors in the dorsal periaqueductal gray matter regulate anxiety in the social interaction test.

We have reported previously that the NPY Y1 receptor antagonist BIBP3226 applied into the dorsal periaqueductal gray matter (DPAG) has an anxiogenic-like effect in the elevated plus-maze test in rats. In the present study the effects of neuropeptide Y (NPY) Y1 receptor antagonists BIBP3226 (500 pmol) and 1229U91 (formerly also GR231118, GW1229 and EXBP68, 100 and 500 pmol) administered into the DPAG were investigated in the social interaction test in rats. BIBP3226 and 1229U91 (both 500 pmol) significantly decreased the time spent in active social interaction. These results provide additional evidence that NPY-ergic neurotransmission in the DPAG may be involved in the modulation of anxiety-related behaviour and suggest that endogenous NPY, released under stressful conditions in the DPAG, relieves anxiety via the NPY Y1 receptors. This is the first report demonstrating the effect of NPY receptor active agent on social behaviour.

Animals↗

PubMed1998

Evidence that orexigenic effects of melanocortin 4 receptor antagonist HS014 are mediated by neuropeptide Y.

Recent studies using melanocortin-4 receptor (MC4R) knockout mice and MC4R antagonists have shown that weakening of MC4R-ergic tone increases food intake and causes obesity. In this study, we used the newly discovered selective MC4R antagonist HS014 for increasing food intake in free-feeding rats and evaluated the effects of the NPY Y1 receptor antagonist 1229U91 and the selective serotonin uptake inhibitor fluoxetine on this increased feeding behavior. 1229U91 (12 nmol, i.c.v.), which alone does not affect food intake, significantly attenuated the orexigenic effects of HS014, whereas 1 and 3 nmol doses of 1229U91 were ineffective. Fluoxetine, which has been shown to inhibit NPY release, inhibited spontaneous food intake and completely blocked the stimulation of food intake by HS014. These data suggest that feeding induced by weakening of the MC4R-ergic tone may be mediated through activation of the NPY-ergic system. This is the first report showing that physiological feeding response evoked by MC4R blockage is influenced by NPY signalling.

Animals↗

PubMed1998

Selective antagonist for the melanocortin 4 receptor (HS014) increases food intake in free-feeding rats.

Recently, we discovered a cyclic analogue of MSH (melanocyte stimulating hormone), HS014, which is the first selective antagonist of the MC4 receptor. We have here studied the effects of this peptide on food intake in non-deprived male rats. Vehicle or five doses of HS014 (0.1-10 nmol) were administered ICV at midday. HS014 (0.33-3.3 nmol) significantly and in a dose-dependent manner increased food intake for the first 1 h. At 4 h after the injections, food intake was also significantly increased in rats treated with 1 and 3.3 nmol of HS014, whereas the lowest dose tested (0.1 nmol) was without effect. Cumulative food intake increased to 100% at 4 h after the injections. The highest dose of HS014 (10 nmol) induced sedation and inhibited feeding for first hour of testing. However, this dose also increased food consumption later. These data demonstrate that attenuation of central melanocortinergic tone with HS014 induces disinhibition of feeding and provides additional evidence for the hypothesis that activation of the MC4 receptor inhibits food intake. HS014 may be a useful tool for elucidating the role of the MC receptor subtypes in vivo. This is the first report demonstrating an increase in daytime food intake in free-feeding animals caused by a MC receptor active agent.

Animals↗

PubMed1998

Anxiolytic-like effect of neuropeptide Y (NPY) and NPY13-36 microinjected into vicinity of locus coeruleus in rats.

Neuropeptide Y (NPY, 1 and 10 pmol), NPY Y1 receptor agonist [Leu31, Pro34]NPY (10 pmol) and Y2 agonist NPY13-36 (100 pmol) were administered unilaterally into the region of the nucleus locus coeruleus (LC) in rats. NPY (10 pmol) and NPY13-36 increased the percentage of open arm entries, the percentage of time spent on open part, number of both open and closed arm entries and line crossings in the open part while [Leu31,Pro34]NPY failed to modify elevated plus-maze behavior. These data suggest that NPY applied close to LC has anxiolytic-like effects by acting on NPY Y2, not on Y1 receptors. Thus, NPY Y2 receptors in the vicinity of LC may be involved in the regulation of anxiety in rats.

Animals↗

PubMed1998

Drug use in Estonia in 1994-1995: a follow-up from 1989 and comparison with two Nordic countries.

OBJECTIVE: To determine the patterns of drug use in Estonia for the years 1989 and 1994 1995, i.e. for the years before and after the pharmaceutical services in the country changed from a state monopoly to a competitive market. METHODS: The wholesale data from Estonia and the defined daily doses methodology were used. For comparison, national statistics on medicines from Finland and Sweden for the years 1994-1995 are shown. RESULTS: The general sales of drugs in Estonia decreased almost twofold in all major pharmacological groups from 1989 to 1994 and subsequently increased by 10%-30% in 1995. Substantial differences in patterns of drug use between Estonia and the two Nordic countries were observed. The amount of prescription-only medicines used in Estonia was approximately 25% of that used in Finland and Sweden. The amount of over-the-counter drugs used was 61% of that used in Finland and 58% of that used in Sweden. In the drug use patterns in Estonia, some common trends can be noted: (1) persistent traditions, such as the low use of diuretics, beta-blockers, antithrombotics and inhalant anti-asthmatic drugs; (2) changes in prescription preferences--central anti-adrenergic drugs, pyrazolones, aminoglycosides and barbiturates are being replaced by calcium channel blockers and angiotensin-converting-enzyme inhibitors, propionic acid derivatives, cephalosporins and benzodiazepines, respectively; (3) rapidly increasing use of drugs not prescribed in the 1980s, such as hormonal contraceptives, opioids and antiulcer drugs, which strongly improves the quality of pharmacotherapy in Estonia. CONCLUSION: The general trends in Estonia and the two Nordic countries are similar--the use of newer and more effective drugs is increasing and that of older ones decreasing. The changes are more rapid in Estonia than in Finland and Sweden, but, because of a short observation period, the use of newer drugs not yet prevailing. The international differences in drug utilization observed in this study may possibly be related mainly to the prescription preferences (e.g. therapeutic traditions) and less dependent on the respective health care systems (e.g. reimbursement schemes) and economic state of the country.

Drug Prescriptions↗

PubMed1998

Evidence for involvement of neuropeptide Y receptors in the regulation of food intake: studies with Y1-selective antagonist BIBP3226.

1. Experiments were conducted to evaluate the effects of the novel non-peptide neuropeptide Y Y1 receptor antagonist, BIBP3226 (N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]-D-arginine amide) on spontaneous, fasting-induced and NPY-induced food intake in rats. In addition to consumption of regular chow, the effects of BIBP3226 on consumption of highly palatable sweetened mash were monitored in a 1 h test on first exposure and after familiarization with novel food. 2. BIBP3226 (10.0 nmol, i.c.v.) had no effect on the consumption of regular chow, but reduced significantly the intake of highly palatable diet and the food intake stimulated by fasting (24 h). Neuropeptide Y (NPY, 1.0 nmol, i.c.v.) significantly increased the consumption of regular rat chow. This orexigenic effect of NPY was blocked by BIBP3226 (10.0 nmol, administered i.c.v. 5 min before NPY) at 30 min and 4 h, but not at 1 and 2 h. When animals were pretreated with diazepam (0.5 mg kg(-1), i.p., 20 min before NPY), BIBP3226 failed to suppress NPY-induced feeding. 3. An NPY Y1 and Y3 receptor agonist, [Leu31,Pro34]NPY and a Y5 receptor agonist human peptide YY3-36 (hPYY3-36, both 30 pmol), microinjected into the paraventricular nucleus of the hypothalamus (PVN) increased the consumption of regular rat chow. BIBP3226 (0.4 nmol, into the PVN) completely blocked the stimulatory effect of [Leu31,Pro34]NPY but not that of hPYY3-36. BIBP3226 (0.4 nmol) alone failed to modify the consumption of the regular chow. Higher doses of BIBP3226 (1.0 and 2.0 nmol) injected into the vicinity of the PVN reduced the consumption of the sweetened mash. 4. These results suggest that both the NPY Y1 and Y5 receptors in the PVN are involved in the regulation of food intake. The stimulatory effect of exogenous NPY is probably mediated through an NPY receptor subtype that is not identical with the Y1 receptor (possibly Y5 receptor). However, the NPY Y1 receptors may mediate the effect of endogenous NPY in conditions of increased energy demand or on intake of highly palatable diets.

Animals↗

PubMed1998

Comparison of the antioxidant activity of melatonin and pinoline in vitro.

Several recent experiments have shown that melatonin is an efficient antioxidant and free radical scavenger. In the present study the antioxidative effect of melatonin was compared with that of pinoline. Pinoline (6-methoxy-tetrahydro-beta-carboline) can be formed in the mammalian body under physiological conditions from 5-hydroxytryptamine or as a tricyclic metabolite of melatonin. Both melatonin and pinoline inhibited lipid peroxidation and showed comparable activity in a total antioxidant status test. Melatonin and pinoline concentration-dependently scavenged hydroxyl radicals with IC50 11.4+/-1.0 microM for melatonin and 62.3+/-3.8 microM for pinoline. These results support the importance of the indolic part of the molecule and the 5-methoxy group common to both compounds in terms of the ability of these molecules to quench the hydroxyl radicals. As pinoline has been shown to exert an antidepressant-like effect in behavioral experiments and has been reported to have a low toxicity, this compound should be further studied as a potential antidepressant with pronounced antioxidative effects. These results further support the importance of pineal gland in antioxidative protection.

Antioxidants↗

PubMed1998

Discovery of a novel superpotent and selective melanocortin-4 receptor antagonist (HS024): evaluation in vitro and in vivo.

Several novel cyclic MSH analogs were synthesized, and their binding properties were tested on cells transiently expressing the human melanocortin-1 (MC1), MC3, MC4, and MC5 receptors. We discovered a novel substance (HS024) that showed about 20-fold selectivity and very high affinity (Ki = 0.29 nM) for the MC4 receptor. HS024 (cyclic [AcCys3,Nle4,Arg5,D-Nal7,Cys-NH2(11)]alpha-MSH-(3-11)) has a 29-membered atom ring structure that includes an Arg in position 5. HS024 was found to antagonize an alphaMSH-induced cAMP response in cells expressing the human MC1, MC3, MC4, and MC5 receptor DNAs. HS024 also caused a dose-dependent increase in food intake, with a maximum response (4-fold increase) at a 1-nmol dose injected intracerebroventricularly in free feeding rats. We also tested SHU9119, a previously described nonselective MC receptor antagonist, and found HS024 and SHU9119 to have similar potencies for increasing food intake, although SHU9119 appeared to induce more serious side-effects. HS024 increased the food intake of free feeding rats to levels comparable to those in food-deprived rats, indicating that blockade of the MC4 receptor is a highly effective way to increase feeding. Moreover, we tested the effects of intracerebroventricular injections of HS024 in elevated plus-maze and open-field experiments on rats. In these tests, HS024 did not appear to affect emotionality or locomotor activity, suggesting that the MC4 receptor does not mediate the anxiogenic-like and locomotor effects related to the melanocortic peptides.

Animals↗

PubMed1997

Alpha-helical CRF(9-41) prevents anxiogenic-like effect of NPY Y1 receptor antagonist BIBP3226 in rats.

We reported previously that the neuropeptide Y (NPY) Y1 receptor antagonist, N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]-D-arginine amide (BIBP3226) has an anxiogenic-like effect in the elevated plus maze test in rats. In this study we investigated the effect of the corticotropin-releasing factor (CRF) receptor antagonist, alpha-helical-CRF(9-41) (alpha-h-CRF) on this response. BIBP3226 (5 microg, i.c.v.) induced an anxiogenic-like effect, which was blocked by pretreatment with alpha-h-CRF at a concentration (1 microg, i.c.v.) which alone failed to affect the elevated plus maze performance. Thus, the anxiogenic effect of a selective Y1 receptor blocker was prevented by the blockade of CRF receptors, suggesting antagonistic effects of endogenous NPY and CRF in shaping the response to novelty.

Animals↗

PubMed1997

The effect of cholecystokinin tetrapeptide on respiratory resistance in healthy volunteers.

The effects of cholecystokinin tetrapeptide (CCK-4) on respiratory resistance were studied in 14 healthy volunteers by the registration of slow vital capacity and flow volume loop during forced respiration test. The administration of CCK-4 (50 micrograms) was performed in a double-blind and placebo-controlled design. Injections of CCK-4 induced prominent and time-limited paniclike symptoms in all healthy volunteers. Four volunteers (29%) experienced a panic attack. Subjective dyspnea was experienced by the majority of subjects at the peak of CCK-4 effect and seemed related to a diminution in vital capacity parameters; however, the forced respiration test did not reveal bronchoconstriction after CCK-4 challenge. Administration of CCK-4 also induced a short-lasting increase in heart rate and skin blood flow. This study suggests that dyspnea induced by CCK-4 is not related to changes in respiratory resistance.

Adult↗