guanosine-5--o-(3-thiotriphosphate) and Body-Weight

This study examined whether chronic Δ(9)-THC during early adulthood would produce the same hormonally-dependent deficits in learning that are produced by chronic Δ(9)-THC during adolescence. To do this, either sham-operated (intact) or ovariectomized (OVX) female rats received daily saline or 5.6 mg/kg of Δ(9)-THC i.p. for 40 days during early adulthood. Following chronic administration, and a drug-free period to train both a learning and performance task, acute dose-effect curves for Δ(9)-THC (0.56-10 mg/kg) were established in each of the four groups (intact/saline, intact/THC, OVX/saline and OVX/THC). The dependent measures of responding under the learning and performance tasks were the overall response rate and the percentage of errors. Although the history of OVX and chronic Δ(9)-THC in early adulthood did not significantly affect non-drug or baseline behavior under the tasks, acute administration of Δ(9)-THC produced both rate-decreasing and error-increasing effects on learning and performance behavior, and these effects were dependent on their hormone condition. More specifically, both intact groups were more sensitive to the rate-decreasing and error-increasing effects of Δ(9)-THC than the OVX groups irrespective of chronic Δ(9)-THC administration, as there was no significant main effect of chronic treatment and no significant interaction between chronic treatment (saline or Δ(9)-THC) and the dose of Δ(9)-THC administered as an adult. Post mortem examination of 10 brain regions also indicated there were significant differences in agonist-stimulated GTPγS binding across brain regions, but no significant effects of chronic treatment and no significant interaction between the chronic treatment and cannabinoid signaling. Thus, acute Δ(9)-THC produced hormonally-dependent effects on learning and performance behavior, but a period of chronic administration during early adulthood did not alter these effects significantly, which is contrary to what we and others have shown for chronic administration during adolescence.

Topics: Animals; Behavior, Animal; Benzoxazines; Body Weight; Dronabinol; Female; Guanosine 5'-O-(3-Thiotriphosphate); Morpholines; Naphthalenes; Organ Size; Ovariectomy; Rats; Rats, Long-Evans; Sodium Chloride; Uterus

Rats display persistent behavioural phenotypes of low (LE) versus high (HE) exploratory activity in the exploration box paradigm. LE rats that prefer passive coping strategies show differential dopaminergic activity in the striatum. The main hypothesis of this study was that chronic variable stress (CVS) would have a higher impact on LE rats.. Animals were submitted to a CVS regimen lasting 32 days that was followed by a behavioural test battery. The functional states of their dopamine D(1) and D(2) receptors were measured in the striatum and nucleus accumbens (NAcc). Cerebral oxidative metabolism was assessed via cytochrome c oxidase histochemistry in 65 brain regions.. CVS decreased weight gain, to a higher extent in LE rats, and lowered the sucrose preference after the first week, but habituation to the anhedonic effect had developed by the end of the experiment. CVS did not change the behavioural phenotypes initially assigned. No effect of stress on D(2) receptor function was found. Chronically stressed animals exhibited higher levels of social interaction and D(1) receptor-mediated cAMP accumulation in the NAcc, but not in the striatum. CVS was associated with higher oxidative metabolism levels in the anteroventral thalamus, median raphe nuclei and central periaqueductal grey matter. These changes after stress did not depend upon the exploratory phenotype.. This study revealed changes in brain biochemistry after habituation to CVS that might be implicated in successful adaptation to chronic stress.

Topics: Analysis of Variance; Animals; Body Weight; Choice Behavior; Chronic Disease; Cyclic AMP; Disease Models, Animal; Electron Transport Complex IV; Exploratory Behavior; Food Preferences; Guanosine 5'-O-(3-Thiotriphosphate); Male; Maze Learning; Nucleus Accumbens; Protein Binding; Rats; Rats, Wistar; Reaction Time; Receptors, Dopamine D1; Social Behavior; Stress, Psychological; Sucrose; Sulfur Isotopes; Swimming; Time Factors

μ-Opioid receptor (MOR) agonism induces palatable food consumption principally through modulation of the rewarding properties of food. N-{[3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine (GSK1521498) is a novel opioid receptor inverse agonist that, on the basis of in vitro affinity assays, is greater than 10- or 50-fold selective for human or rat MOR, respectively, compared with κ-opioid receptors (KOR) and δ-opioid receptors (DOR). Likewise, preferential MOR occupancy versus KOR and DOR was observed by autoradiography in brain slices from Long Evans rats dosed orally with the drug. GSK1521498 suppressed nocturnal food consumption of standard or palatable chow in lean and diet-induced obese (DIO) Long Evans rats. Both the dose-response relationship and time course of efficacy in lean rats fed palatable chow correlated with μ receptor occupancy and the plasma concentration profile of the drug. Chronic oral administration of GSK1521498 induced body weight loss in DIO rats, which comprised fat mass reduction. The reduction in body weight was equivalent to the cumulative reduction in food consumption; thus, the effect of GSK1521498 on body weight is related to inhibition of food consumption. GSK1521498 suppressed the preference for sucrose-containing solutions in lean rats. In operant response models also using lean rats, GSK1521498 reduced the reinforcement efficacy of palatable food reward and enhanced satiety. In conclusion, GSK1521498 is a potent, MOR-selective inverse agonist that modulates the hedonic aspects of ingestion and, therefore, could represent a pharmacological treatment for obesity and binge-eating disorders.

Topics: Adiposity; Animals; Anti-Obesity Agents; Body Weight; Brain; Calibration; Conditioning, Operant; Data Interpretation, Statistical; Drinking Behavior; Feeding Behavior; Food Preferences; Guanosine 5'-O-(3-Thiotriphosphate); Indans; Injections, Intravenous; Male; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Satiety Response; Triazoles; Weight Loss

The endocannabinoid system plays a crucial role in the pathophysiology of obesity. However, the clinical use of cannabinoid antagonists has been recently stopped because of its central side-effects. The aim of this study was to compare the effects of a chronic treatment with the CB(1) cannabinoid antagonist rimonabant or the CB(1) inverse agonist taranabant in diet-induced obese female rats to clarify the biological consequences of CB(1) blockade at central and peripheral levels. As expected, chronic treatment with rimonabant and taranabant reduced body weight and fat content. Interestingly, a decrease in the number of CB(1) receptors and its functional activity was observed in all the brain areas investigated after chronic taranabant treatment in both lean and obese rats. In contrast, chronic treatment with rimonabant did not modify the density of CB(1) cannabinoid receptor binding, and decreased its functional activity to a lower degree than taranabant. Six weeks after rimonabant and taranabant withdrawal, CB(1) receptor density and activity recovered to basal levels. These results reveal differential adaptive changes in CB(1) cannabinoid receptors after chronic treatment with rimonabant and taranabant that could be related to the central side-effects reported with the use of these cannabinoid antagonists.

Topics: Amides; Analysis of Variance; Animals; Autoradiography; Benzoxazines; Body Weight; Brain; Cyclohexanols; Diet Fads; Disease Models, Animal; Eating; Female; Guanosine 5'-O-(3-Thiotriphosphate); International Cooperation; Morpholines; Naphthalenes; Obesity; Piperidines; Protein Binding; Pyrazoles; Pyridines; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Sulfur Isotopes; Time Factors; Tomography Scanners, X-Ray Computed; Tritium; Whole Body Imaging

Histamine affects homeostatic mechanisms, including food and water consumption, by acting on central nervous system (CNS) receptors. Presynaptic histamine H(3) receptors regulate release of histamine and other neurotransmitters, and histamine H(3) receptor antagonists enhance neurotransmitter release. A-331440 [4'-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile] is a histamine H(3) receptor antagonist which binds potently and selectively to both human and rat histamine H(3) receptors (K(i)<==25 nM). Mice were stabilized on a high-fat diet (45 kcal % lard) prior to 28-day oral b.i.d. dosing for measurement of obesity-related parameters. A-331440 administered at 0.5 mg/kg had no significant effect on weight, whereas 5 mg/kg decreased weight comparably to dexfenfluramine (10 mg/kg). A-331440 administered at 15 mg/kg reduced weight to a level comparable to mice on the low-fat diet. The two higher doses reduced body fat and the highest dose also normalized an insulin tolerance test. These data show that the histamine H(3) receptor antagonist, A-331440, has potential as an antiobesity agent.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Appetite Depressants; Behavior, Animal; Biphenyl Compounds; Body Composition; Body Weight; Calcium; Cloning, Molecular; Diagnostic Imaging; Diet; Dietary Fats; Fenfluramine; Guanosine 5'-O-(3-Thiotriphosphate); Histamine Antagonists; Humans; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Nitriles; Pyrrolidines; Radioligand Assay; Rats; Receptors, Histamine H3; Weight Loss

Emerging evidence suggests that the gamma subunit composition of an individual G protein contributes to the specificity of the hundreds of known receptor signaling pathways. Among the twelve gamma subtypes, gamma3 is abundantly and widely expressed in the brain. To identify specific functions and associations for gamma3, a gene-targeting approach was used to produce mice lacking the Gng3 gene (Gng3-/-). Confirming the efficacy and specificity of gene targeting, Gng3-/- mice show no detectable expression of the Gng3 gene, but expression of the divergently transcribed Bscl2 gene is not affected. Suggesting unique roles for gamma3 in the brain, Gng3-/- mice display increased susceptibility to seizures, reduced body weights, and decreased adiposity compared to their wild-type littermates. Predicting possible associations for gamma3, these phenotypic changes are associated with significant reductions in beta2 and alphai3 subunit levels in certain regions of the brain. The finding that the Gng3-/- mice and the previously reported Gng7-/- mice display distinct phenotypes and different alphabetagamma subunit associations supports the notion that even closely related gamma subtypes, such as gamma3 and gamma7, perform unique functions in the context of the organism.

Topics: Adenylyl Cyclases; Adipose Tissue; Animals; Body Weight; Brain; Female; Gene Targeting; GTP-Binding Protein beta Subunits; GTP-Binding Protein gamma Subunits; Guanosine 5'-O-(3-Thiotriphosphate); Heterotrimeric GTP-Binding Proteins; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Seizures; Signal Transduction

gamma-Hydroxybutyrate (GHB), a metabolite of gamma-aminobutyric acid (GABA), is proposed to function as a neurotransmitter or neuromodulator. gamma-Hydroxybutyrate and its prodrug, gamma-butyrolactone (GBL), recently received increased public attention as they emerged as popular drugs of abuse. The actions of GHB/GBL are believed to be mediated by GABAB and/or specific GHB receptors, the latter corresponding to high-affinity [3H]GHB-binding sites coupled to G-proteins. To investigate the contribution of GABAB receptors to GHB actions we studied the effects of GHB in GABAB(1)-/- mice, which lack functional GABAB receptors. Autoradiography reveals a similar spatial distribution of [3H]GHB-binding sites in brains of GABAB(1)-/- and wild-type mice. The maximal number of binding sites and the KD values for the putative GHB antagonist [3H]6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene acetic acid (NCS-382) appear unchanged in GABAB(1)-/- compared with wild-type mice, demonstrating that GHB- are distinct from GABAB-binding sites. In the presence of the GABAB receptor positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol GHB induced functional GTPgamma[35S] responses in brain membrane preparations from wild-type but not GABAB(1)-/- mice. The GTPgamma[35S] responses in wild-type mice were blocked by the GABAB antagonist [3-[[1-(S)-(3,4dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]-cyclohexylmethyl phosphinic acid hydrochloride (CGP54626) but not by NCS-382. Altogether, these findings suggest that the GHB-induced GTPgamma[35S] responses are mediated by GABAB receptors. Following GHB or GBL application, GABAB(1)-/- mice showed neither the hypolocomotion, hypothermia, increase in striatal dopamine synthesis nor electroencephalogram delta-wave induction seen in wild-type mice. It, therefore, appears that all studied GHB effects are GABAB receptor dependent. The molecular nature and the signalling properties of the specific [3H]GHB-binding sites remain elusive.

Topics: 4-Butyrolactone; Adjuvants, Anesthesia; Animals; Anticonvulsants; Autoradiography; Baclofen; Behavior, Animal; Benzocycloheptenes; Binding, Competitive; Body Weight; Brain; Cell Membrane; Chromatography, High Pressure Liquid; Dihydroxyphenylalanine; Dose-Response Relationship, Drug; Drug Interactions; Electrochemistry; Electroencephalography; GABA-B Receptor Agonists; gamma-Aminobutyric Acid; Guanosine 5'-O-(3-Thiotriphosphate); Mice; Mice, Inbred BALB C; Mice, Knockout; Motor Activity; Organophosphorus Compounds; Phenols; Radioligand Assay; Receptors, GABA-B; Sodium Oxybate; Time Factors

A1 adenosine receptors (A1ARs) are widely expressed in the brain during development. To examine whether A1AR activation can alter postnatal brain formation, neonatal rats from postnatal days 3 to 14 were treated with the A1AR agonist N6-cyclopentyladenosine (CPA) in the presence or absence of the peripheral A1AR antagonist 8-(p-sulfophenyl)-theophylline (8SPT). CPA or CPA + 8SPT treatment resulted in reductions in white matter volume, ventriculomegaly, and neuronal loss. Quantitative electron microscopy revealed reductions in total axon volume following A1AR agonist treatment. We also observed reduced expression of myelin basic protein in treated animals. Showing that functional A1ARs were present over the ranges of ages studies, high levels of specific [3H]CCPA binding were observed at PD 4, 7 and 14, and receptor-G protein coupling was present at each age. These observations show that activation of A1ARs with doses of CPA that mimic the effects of high adenosine levels results in damage to the developing brain.

Topics: Adenosine; Animals; Animals, Newborn; Body Weight; Cell Count; Cerebral Cortex; Cerebral Ventricles; Drug Combinations; Drug Interactions; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Hippocampus; Microscopy, Electron; Myelin Basic Protein; Nerve Degeneration; Nerve Fibers, Myelinated; Neuroglia; Neurons; Presynaptic Terminals; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Telencephalon; Theophylline

We have recently reported enhanced levels of G(i)alpha proteins in genetic and other experimentally induced models of hypertension, whereas the levels of G(s)alpha were decreased in hypertensive rats expressing cardiac hypertrophy. The present studies were undertaken to investigate whether the decreased levels of G(s)alpha are associated with cardiac hypertrophy per se and used an aortocaval fistula (AV shunt; volume overload) rat model that exclusively expresses cardiac hypertrophy. Cardiac hypertrophy in Sprague-Dawley rats (200-250 g) was induced under anesthesia, and, after a period of 10 days, the hearts were used for adenylyl cyclase activity determination, protein quantification, and mRNA level determination. A temporal relationship between the expression of G(s)alpha proteins and cardiac hypertrophy was also examined on days 2, 3, 7, and 10 after induction of AV shunt in the rat. The heart-to-body-weight ratio (mg/g) was significantly increased in AV shunt rats after 3, 7, and 10 days of induction of AV shunt compared with sham-operated controls, whereas arterial blood pressure was not different between the two groups. Guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) stimulated adenylyl cyclase activity in a concentration-dependent manner in heart membranes from both groups; however, the degree of stimulation was significantly decreased in AV shunt rats. In addition, the stimulatory effects of isoproterenol were also diminished in AV shunt rats compared with control rats, whereas glucagon-stimulated adenylyl cyclase activity was not different in the two groups. The inhibitory effects of oxotremorine (receptor-dependent G(i) functions) and low concentrations of GTPgammaS on forskolin-stimulated adenylyl cyclase activity (receptor-independent G(i) functions) were not different in the two groups. In addition forskolin and NaF also stimulated adenylyl cyclase activity to a lesser degree in AV shunt rats compared with control rats. The levels of G(i)alpha-2 and G(i)alpha-3 proteins and mRNA, as determined by immunoblotting and Northern blotting, respectively, were not different in both groups; however, the levels of G(s)alpha(45) and G(s)alpha(47), and not of G(s)alpha(52), proteins were significantly decreased in AV shunt rats by days 7 and 10 compared with control rats, whereas no change was observed on days 2 and 3 after induction of AV shunt. These results suggest that the decreased expression of G(s)alpha proteins may not be the cause but the effec

Topics: Adenylyl Cyclases; Animals; Aorta, Thoracic; Arteriovenous Shunt, Surgical; Blood Pressure; Blotting, Northern; Body Weight; Cardiomegaly; Colforsin; Glucagon; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gs; Guanosine 5'-O-(3-Thiotriphosphate); Isoproterenol; Male; Myocardium; Organ Size; Protein Isoforms; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sodium Fluoride

Prenatal cocaine exposure increases mu-opioid receptor binding in dopaminergic terminal areas and enhances behavioral responsiveness to mu-opioid agonists. We investigated the influence of early postnatal cocaine treatment on in vitro mu- and delta-opioid receptor activation in male and female weanling rats. Pups received subcutaneous injections of either 20 mg/kg cocaine HCl or saline once daily on postnatal days 1 through 5. On postnatal day 25, animals were decapitated and their brains were removed and frozen for later sectioning. Opioid receptor activation was assessed in the striatum and the shell of the nucleus accumbens by autoradiographic analysis of agonist-stimulated [(35)S]GTP gamma S binding. Brain sections were incubated in the presence of [(35)S]GTP gamma S, GDP, and either the mu-opioid agonist [D-Ala(2)-N-MePhe(4)-Gly(5)-ol]enkephalin (DAMGO) or the delta-opioid agonist D-Pen(2)-D-Pen(5)-enkephalin (DPDPE). Baseline binding was assessed in the absence of agonist, and nonspecific binding was determined by the addition of unlabeled GTP gamma S. Film images were quantified using brain mash-calibrated [(14)C] standards. Neonatal cocaine treatment had no effect on either baseline or agonist-stimulated [(35)S]GTP gamma S binding. However, males exhibited significantly greater activation than females of delta-opioid receptors in both striatum and accumbens shell, regardless of neonatal treatment. These findings indicate a gender difference in delta-opioid receptor function that could mediate behavioral differences in response to opioid agonists.

Topics: Analgesics, Opioid; Animals; Animals, Newborn; Body Weight; Cocaine; Female; Guanosine 5'-O-(3-Thiotriphosphate); Male; Neostriatum; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, mu; Sex Factors; Sulfur Isotopes

The endogenous cannabinoid anandamide has been reported to produce well-defined behavioral tolerance, but studies on the possible mechanisms underlying this process are few and often contradictory. The present study was designed to survey the cellular events involved in anandamide tolerance, in terms of the effects on receptor number, coupling with G proteins, and activation of the cyclic AMP (cAMP) cascade. Chronic treatment of rats with anandamide (20 mg/kg i.p. for 15 days) resulted in behavioral tolerance without any change in cannabinoid receptor binding in the brain regions studied (striatum, cortex, hippocampus, and cerebellum), suggesting that receptor down-regulation was not involved in the development of anandamide behavioral tolerance. In contrast, prolonged exposure to anandamide significantly reduced agonist-stimulated guanosine 5'-O:-(3-[(35)S]thiotriphosphate) binding in the same areas, with losses of >50%, suggesting that receptor desensitization may be part of the molecular mechanism underlying this tolerance. Finally, concerning the cAMP cascade-the most well-known intracellular signaling pathways activated by CB(1) receptors-in the brain regions from rats tolerant to anandamide, we found no alteration in cAMP levels or in protein kinase A activity. We propose that anandamide, unlike Delta(9)-tetrahydrocannabinol and other cannabinoids, does not alter the receptor system at multiple levels but that desensitization of the CB(1) receptor might account for behavioral tolerance to the drug.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Behavior, Animal; Binding, Competitive; Body Weight; Brain; Cannabinoids; Cerebellum; Cerebral Cortex; Corpus Striatum; Dose-Response Relationship, Drug; Down-Regulation; Drug Tolerance; Endocannabinoids; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Hippocampus; Male; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Signal Transduction

During postnatal development, alpha-2 adrenergic receptors (A2AR) change in both density and distribution. In forebrain, receptor density increases about 4-fold over neonatal levels, reaching adult levels before postnatal day (P) 28, whereas in hindbrain, including cerebellum, there is a decrease in overall receptor density. We examined the coupling of A2AR to G proteins using agonist-stimulated [35S]GTPgammaS binding as a functional assay. In forebrain the A2AR agonist-stimulated [35S]GTPgammaS binding increases rapidly after P7, reaching its highest levels at P21 and then declining slightly to adult levels. This binding increases more slowly than receptor number, suggesting that the appearance of G proteins, rather than the A2AR, determines the developmental appearance of functional A2AR-G protein interactions in forebrain. Basal [35S]GTPgammaS binding and [35S]GTPgammaS binding stimulated by other neurotransmitter receptor systems (GABA-B, mu opiate, and muscarinic) increase with a time course similar to A2AR-stimulated [35S]GTPgammaS binding. In contrast, in hindbrain, A2AR-stimulated [35S]GTPgammaS binding decreases during postnatal development in parallel with the decrease in A2AR levels, whereas [35S]GTPgammaS binding stimulated by other neurotransmitter receptor systems increases in parallel with basal [35S]GTPgammaS binding. Functional receptor-G protein coupling in hindbrain appears to be dependent on the developmental appearance of G proteins for most neurotransmitter systems. However, for A2AR the decrease in receptor density is the overriding factor. These studies 1) demonstrate the functional measurement of A2AR-G protein coupling in native tissue for the first time, 2) demonstrate that A2AR are coupled to G proteins throughout postnatal development, and 3) describe developmental increases and decreases in functional A2AR in brain.

Topics: Age Factors; Animals; Animals, Newborn; Body Weight; Brain; Female; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Rhombencephalon

Previous studies have shown that stressors modify endogenous opioid systems. However, the consequences of social stress on the function of endogenous opioid systems is not well documented. The present studies investigated the effect of rank and housing condition on response to SNC-80, a delta receptor agonist. Triad-housed rats were assessed for dominance status by their behavior and alteration in body weights. At 3 and 50 days, triad- and individually housed rats were injected with SNC-80 (35 mg/kg i.p.) or saline, and evaluated using a test battery consisting of open field behaviors, rectal temperature, analgesia, and air-puff-induced ultrasonic vocalizations. After 50 days of housing, plasma corticosterone, adrenal catecholamines, and the density of cyclic[D-penicillamine2-D-penicillamine2]enkephalin-stimu lat ed guanylyl 5'-[gamma[35S]thio]-triphosphate binding in the prefrontal cortex, the amygdala, nucleus accumbens, thalamus, arcuate, and median eminence were also determined. The first 24 h of triad housing resulted in loss of body weight in subdominant (betas and gammas) but not dominant alpha rats. SCN-80-induced hypothermia was smaller, and there was no depression of headpoke and locomotor behavior in the periphery and the center of the field of alpha rats, in contrast to subdominant and singly housed rats. Rank status did not influence SNC-80's analgesic effect or its inhibition of air-puff-induced ultrasonic vocalizations. Plasma corticosterone levels of alphas and gammas were lower compared with betas and singly housed rats. Agonist stimulation of delta receptor guanylyl 5'-[gamma[35S]thio]-triphosphate binding was lateralized in prefrontal cortex and amygdala, but not nucleus accumbens. Binding was highest in all brain areas of singly housed rats and lowest in the thalamus of beta and of gamma rats. Lateralized binding in amygdala, high locomotor activity, and sensory sensitivity correlated positively with greater sensitivity to SNC-80-induced depression in these measures. Higher binding in the right amygdala correlated with higher plasma corticosterone levels. These findings indicate that dominant rats displayed stimulant rather than depressant responses to delta-opioid activation. Therefore in rodents rank-related stress can alter responsiveness of the endogenous opioid system, and dominance can increase the excitatory effects of delta agonists.

Topics: Adrenal Glands; Agonistic Behavior; Analgesia; Animals; Benzamides; Body Temperature; Body Weight; Brain; Catecholamines; Chronic Disease; Corticosterone; Defecation; Dominance-Subordination; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Guanosine 5'-O-(3-Thiotriphosphate); Male; Motor Activity; Piperazines; Rats; Rats, Long-Evans; Receptors, Opioid, delta; Social Environment; Stress, Psychological

The magnitude and kinetics of the L-type calcium current were compared in single left ventricular myocytes isolated from 8-mo-old (8M) and 19-mo-old (19M) genetically diabetic rats (WBN/Kob rats) and age-matched control rats. A diabetic state occurred at 19M but not at 8M. The left ventricular contractility was reduced in 19M WBN/Kob rats compared with age-matched control rats. The duration of the action potential was longer in 19M WBN/Kob rats than in the age-matched control rats. Peak inward current density was similar between diabetic rats and age-matched control rats. In addition, aging did not affect the current density at 8M or 19M. The various kinetic parameters of the L-type calcium current were not different between 19M diabetic and control cell types. The percent increase in the amplitude of the calcium current induced by isoproterenol was less in diabetic cells at the age of 19M, but not at the age of 8M, compared with age-matched control cells. Forskolin (10(-5) M), intracellularly applied adenosine 3',5'-cyclic monophosphate (5 x 10(-5) M), and guanosine 5'-[gamma-thio]triphosphate (10(-4) M) were equally effective in increasing the current in 19M diabetic and age-matched control cell types. The present study demonstrates that the basal calcium current density and kinetic parameters of the current were not altered. However, a decrease in response to beta-stimulation occurred in genetically diabetic rats compared with control rats.

Topics: Action Potentials; Animals; Blood Glucose; Body Weight; Calcium Channels; Colforsin; Cyclic AMP; Diabetes Mellitus, Experimental; Electric Conductivity; Guanosine 5'-O-(3-Thiotriphosphate); Heart; Heart Ventricles; Isoproterenol; Kinetics; Male; Myocardial Contraction; Rats; Rats, Wistar

Adenylate cyclase activity was determined in membranes of liver, muscle, white adipose tissue, and brown adipose tissue (BAT) of lean (Fa/) and obese (fa/fa) Zucker rats. Responses were monitored following beta-adrenergic receptor stimulation and addition of GTP, GTP gamma S, or forskolin. beta-Adrenergic responses in liver, white adipose tissue, and BAT were lower in obese than in lean animals. No such difference was observed in muscle membranes. Production of cAMP after addition of guanine nucleotides was lower in liver and white adipose tissue membranes from obese rats compared with their lean littermates. Synthesis of cAMP in muscle membranes of obese animals after addition of GTP was either not different, or slightly higher, than that observed in muscle membranes from lean animals. Furthermore, production of cAMP after forskolin addition to muscle membranes of obese rats was significantly higher than that observed from lean rats under the same conditions. Interestingly, BAT membranes of obese rats were significantly more sensitive to guanine nucleotide activation than those of lean animals. The results confirm recent findings indicating inferior function of G proteins in liver plasma membranes of obese Zucker rats, and extend this observation to adipose tissue. The present results further suggest that the "nonreceptor" components (e.g., G proteins) responsible for the activation of adenylate cyclase in BAT membranes of obese rats are more responsive to stimulation than those of lean animals. Such sensitivity may be related to and perhaps compensate for the reduced thermogenic activity in the obese Zucker rat during the development of obesity.

Topics: Adenylyl Cyclases; Adipose Tissue; Adipose Tissue, Brown; Animals; Body Weight; Colforsin; Cyclic AMP; Dose-Response Relationship, Drug; Female; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Triphosphate; Isoproterenol; Liver; Muscles; Norepinephrine; Obesity; Organ Size; Rats; Rats, Zucker; Receptors, Adrenergic, beta