Decrease In Sensitivity Of Receptors Research Articles

C-fos expression in the solitary nucleus medial region and reaction to acute hemorrhage in streptozotocin-stimulated diabetic rats

Examination of circulatory dynamics and autonomic nerve activity in acute hemorrhage in diabetic (DM) rats revealed that despite decreased receptor sensitivity to arterial blood pressure, the DM rats experienced a decline in the heart rate and acceleration of the parasympathetic nerve activity at the sympathoinhibitory phase in response to bleeding (Bezold–Jarisch [B–J] reflex). To elucidate the involvement of the B–J reflex as a reaction to acute hemorrhage in DM rats by assessing c-Fos-positive cell (c-Fos) expression in the nucleus of the solitary tract (SolM), the primary relay nucleus of the baroreflex, Streptozotocin-induced DM and non-DM rats underwent controlled-graded bleeding or continuous phenylephrine infusion under conscious state. Changes in hemodynamics and autonomous nervous system caused by acute hemorrhage and continuous phenylephrine infusion were examined by analyzing blood pressure–heart rate variability. Furthermore, effects of hemorrhage and phenylephrine infusion on the expression of c-Fos in SolM were examined. DM rats showed increased c-Fos expression in response to acute blood loss in the SolM. Non-DM rats showed the same phenomenon in response to continuous phenylephrine infusion in the SolM. Significant interactions between DM and Non-DM rats were observed among hemodynamic and autonomic response to acute hemorrhage and continuous phenylephrine infusion. DM rats were sensitive to acute blood loss, and the circulatory system easily collapsed with accelerating parasympathetic activity in the form of the B–J reflex.

Progesterone and Its Metabolites Play a Beneficial Role in Affect Regulation in the Female Brain.

Premenstrual dysphoric disorder is a female affective disorder that is defined by mood symptoms. The condition is linked to unstable progesterone concentrations. Progestin supplementation is given in cases of threatened or recurrent miscarriage and for luteal phase support. Progesterone is essential for implantation, immune tolerance, and modulation of uterine contractility. For a long time, the administration of progestins was associated with an unfavorable impact on mood, leading to negative affect, and, therefore, was contraindicated in existing mood disorders. Establishing the role of the natural progesterone derivative allopregnanolone in advances in the treatment of postpartum depression has shed new light on the general pathophysiology of mood disorders. Allopregnanolone directly interacts with gamma-aminobutyric acid type A (GABA-A) receptors even at nanomolar concentrations and induces significant anti-depressant, anti-stress, sedative, and anxiolytic effects. Postpartum depression is caused by a rapid drop in hormones and can be instantly reversed by the administration of allopregnanolone. Premenstrual dysphoric disorder can also be considered to result from insufficient neuroactive steroid action due to low progesterone derivative concentration, unstable hormone levels, or decreased receptor sensitivity. The decrease in progesterone levels in perimenopause is also associated with affective symptoms and an exacerbation of some psychosomatic syndromes. Bioidentical progesterone supplementation encounters several obstacles, including limited absorption, first-pass effect, and rapid metabolism. Hence, non-bioidentical progestins with better bioavailability were widely applied. The paradoxical, unfavorable effect of progestins on mood can be explained by the fact that progestins suppress ovulation and disturb the endocrine function of the ovary in the luteal phase. Moreover, their distinct chemical structure prevents their metabolism to neuroactive, mood-improving derivatives. A new understanding of progesterone-related mood disorders can translate the study results from case series and observational studies to cohort studies, clinical trials, and novel, effective treatment protocols being developed.

Disruption of Akt signaling decreases dopamine sensitivity in modulation of inhibitory synaptic transmission in rat prefrontal cortex

Akt is a serine/threonine kinase, which is dramatically reduced in the prefrontal cortex (PFC) of patients with schizophrenia, and a deficiency in Akt1 results in PFC function abnormalities. Although the importance of Akt in dopamine (DA) transmission is well established, how impaired Akt signaling affects the DA modulation of synaptic transmission in the PFC has not been characterized. Here we show that Akt inhibitors significantly decreased receptor sensitivity to DA by shifting DA modulation of GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in prefrontal cortical neurons. Akt inhibition caused a significant decrease in synaptic dopamine D2 receptor (D2R) levels with high-dose DA exposure. In addition, Akt inhibition failed to affect DA modulation of IPSCs after blockade of β-arrestin 2. β-arrestin 2-mediated interaction of clathrin with D2R was enhanced by co-application of a Akt inhibitor and DA. Taken together, the reduced response in DA modulation of inhibitory transmission mainly involved β-arrestin 2-dependent D2R desensitization.

Protons Potentiate GluN1/GluN3A Glycinergic NMDA Receptor Currents

GluN1 and GluN3 subunits of the N-methyl-D-aspartate receptor family form tetrameric cation-permeable channels that are gated by glycine alone and are insensitive to glutamate. They are expressed primarily during early development and their role in cellular physiology is unknown. One hypothesis states that their tonic activation by basal levels of brain glycine controls cellular excitability. Notably, GluN1/GluN3A receptors are selectively up-regulated following ischemia, while ‘classical’ GluN2A- and GluN2B-containing receptors are down-regulated and also strongly inhibited by ischemic acidification. We found that extracellular protons strongly potentiated peak glycine-elicited currents from recombinant GluN1/GluN3A receptors (Ipk, 10-fold at pH 6.8 versus pH 8.0) with a half maximal effect in the physiologic range (EC50 = pH 7.1 ± 0.03). The time-course of current desensitization was also significantly prolonged (2-fold at pH 6.8 versus pH 8.0) and the recovery from desensitization was accelerated (2-fold at pH 6.8 versus pH 7.4). In addition, extracellular protons decreased receptor sensitivity to the agonist glycine (EC50, 48 ± 6 µM at pH 7.4 versus 83 ± 3 µM at pH 6.8) and to the endogenous potentiator Zn2+ (EC50, 32 ± 3 µM at pH 7.4 versus 185 ± 26 µM at pH 6.8). Importantly, we found that extracellular acidification during glycine-elicited steady-state activity produced a large transient influx of positive charge (Ipk, 8-fold at pH 6.8 versus pH 7.4) and increased steady-state activity (Iss/Ipk, 0.03 ± 0.01 at pH 7.4 versus 0.5 ± 0.2 at pH 6.8) which depolarized the membrane substantially (−23 ± 5 mV at pH 7.4 versus −13 ± 3 mV at pH 6.8). Taken together, these results indicate that small pH fluctuations potently modulate GluN1/GluN3A receptor currents and that protons may play a novel positive modulatory role at GluN1/GluN3A receptors in vivo by increasing cellular excitability.

The role of insulin–thyroid hormone interaction on β-adrenoceptor-mediated cardiac responses

β-adrenoceptor-mediated responses are known to be attenuated in diabetic rat hearts, related to decreased receptor sensitivity and density. These impaired responses were improved with insulin in diabetic rats, but not in thyroidectomized diabetic rats. We aimed to investigate the possible interaction between insulin and thyroid hormones to restore diabetes-induced alterations on β-adrenoceptor-mediated responses. Male Sprague-Dawley rats were divided into seven groups: control (C), diabetic (D), insulin-treated diabetic (DI), thyroidectomized diabetic (TxD), insulin-treated thyroidectomized diabetic (TxDI), insulin+low dose 3,3′,5-triiodo-L-thyronine (T3) treated (TxDIT2.5) or insulin+high dose T3 (TxDIT5) treated thyroidectomized diabetic rats. Diabetes was induced with 38mg/kg streptozotocin. Cardiac function was assessed through pressure-volume analysis and papillary muscle experiments. QPCR and western blot experiments were performed to evaluate cardiac gene expressions. Hemodynamic parameters were impaired in diabetes, and were mostly corrected in DI and TxDIT5 groups. Isoprenaline- and BRL37344-induced contractile responses were also decreased in diabetes. Isoprenaline responses were improved significantly in DI and TxDIT5 groups, whereas BRL 37344-mediated responses were increased slightly. Reduced β1-adrenoceptor and SERCA 2A mRNA levels in diabetes were corrected in DI and TxDIT5 groups. Decreased SERCA 2A and increased β3-adrenoceptor protein levels in diabetes were improved in DI and TxDIT5 groups. No significant changes were found in phospholamban or endothelial nitricoxide synthase protein levels. These results show that the beneficial effects of insulin on β-adrenoceptor-mediated responses in diabetic rats are dependent upon adequate concentrations of thyroid hormones.

Familial hypocalciuric hypercalcemia: new mutation in the CASR gene converting valine 697 to methionine

Familial hypocalciuric hypercalcemia is an uncommon cause of hypercalcemia that arises from mutations in the calcium-sensing receptor gene. Inactivation of this receptor leads to a decreased receptor sensitivity to calcium, determining that higher concentrations of calcium are needed to inhibit the release of parathormone in the parathyroid glands. Patients usually are asymptomatic. Diagnosis is usually made casually after a routine blood analysis. The syndrome is characterized by mild or moderate hypercalcemia, hypocalciuria, and normal or slightly increased levels of parathormone. The degree of hypercalcemia depends on the type of mutation. The accurate diagnosis is important since it is a benign disorder that does not require medical or surgical treatment. We report a 9-year-old female with persistent hypercalcemia in several routine blood analyses, who was diagnosed with familial hypocalciuric hypercalcemia after genetic studies were performed. A new mutation determining a nucleotide change c.2089G>A in the calcium-sensing receptor gene (exon 7) was detected. This mutation was also found in the patient's mother and brother.

A 5-year longitudinal study of the relationships between stress, coping, and immune cell β 2-adrenergic receptor sensitivity

Caring for a spouse with Alzheimer's disease (AD) is associated with overall health decline and impaired cardiovascular functioning. This morbidity may be related to the effects of caregiving stress and impaired coping on β 2-adrenergic receptors, which mediate hemodynamic and vascular responses and are important for peripheral blood mononuclear cell (PBMC) trafficking and cytokine production. This study investigated the longitudinal relationship between stress, personal mastery, and β 2-adrenergic receptor sensitivity assessed in vitro on PBMC. Over a 5-year study, 115 spousal AD caregivers completed annual assessments of caregiving stress, mastery, and PBMC β 2-adrenergic receptor sensitivity, as assessed by in vitro isoproterenol stimulation. Heightened caregiving stress was associated with significantly decreased receptor sensitivity, whereas greater sense of personal mastery was associated with significanty increased receptor sensitivity. These results suggest that increased stress may be associated with a desensitization of β 2-receptors, which may contribute to the development of illness among caregivers. However, increased mastery is associated with increased receptor sensitivity, and may therefore serve as a resource factor for improved health in this population.

Ca influx shutdown in neutrophils induced by Fas (CD95) cross-linking.

In neutrophils, as in most other cell types, Ca(2+) signalling is important for a number of cellular activities. Although inositol(1,4,5)trisphosphate-mediated release of Ca(2+) from intracellular stores is a necessary prelude, it is the Ca(2+) influx that is responsible for many of the neutrophil responses. We report here that although elevations of cytosolic Ca(2+) do not accompany Fas-mediated apoptosis in neutrophils, the Ca(2+) influx component of the response to N-formyl-methionyl-leucyl-phenylalanine (FMLP) becomes selectively inactived as the neutrophils progress towards accelerated apoptosis induced by Fas (CD95) cross-linking. After 4 hr incubation at 37 degrees, untreated neutrophils display an exaggerated Ca(2+) influx phase in response to FMLP. This was absent in neutrophils that had been Fas-activated at the same time. No Ca(2+) influx component was demonstrable by the removal of extracellular Ca(2+) or by Ca(2+) channel blockade with Ni(2+) and no Mn(2+) influx was detectable. The defect could not be attributed to a decrease in receptor sensitivity, receptor coupling or receptor number because the release of stored Ca(2+) remained constant during incubation and was unaffected by Fas activation. Ca(2+) influx became uncoupled from store release before detectable gross morphological changes or phosphatidyl serine externalization and was also insensitive to caspase 3 and 8 inhibitors. These results suggest a mechanism other than caspase-mediated proteolytic damage to components important for Ca(2+) influx.

Effects of isoflurane on gamma-aminobutyric acid type A receptors activated by full and partial agonists.

Volatile anesthetics prolong inhibitory postsynaptic potentials in central neurons an allosteric action on the gamma-aminobutyric acid type A (GABA(A)) receptor, an effect that may underlie the hypnotic actions of these agents. Inhaled anesthetics such as isoflurane act to enhance responses to submaximal concentrations of GABA, but it is not clear whether their effect is mediated by an increase in the binding of the agonist or by changes in receptor gating behavior. To address this question, the authors studied the effects of isoflurane on a mutant GABA(A) receptor with a gating defect that decreases receptor sensitivity by lowering agonist efficacy. They then compared the effects of clinically relevant concentrations of isoflurane on the actions of GABA and piperidine-4-sulfonic acid (P4S), a partial agonist at the GABA(A) receptor. The authors created a mutant of the GABA receptor alpha subunit (L277A) by site-directed mutagenesis. The mutant subunit was coexpressed with beta(2) and gamma(2S) subunits in HEK293 cells, and responses to GABA and P4S were recorded using the whole-cell patch clamp technique. EC values were determined for the full agonist GABA and the partial agonist P4S. The authors also determined the relative efficacy (epsilon) of P4S. These measurements were then repeated in the presence of isoflurane. The concentration-response curve for GABA was shifted to the right (EC(50) = 278 microm) in the alpha(1)(L277A)beta(2)gamma(2S) mutant receptor, compared with the corresponding wild-type alpha(1)beta(2)gamma(2S) GABA(A) receptor (EC(50) = 16 microm). P4S is a partial agonist at both receptors, with a dramatically decreased relative efficacy at the mutant receptor (epsilon = 0.24). When the mutant receptor was studied in the presence of isoflurane, the concentration-response curves for both GABA and P4S were shifted to the left (EC(50) for GABA = 78 microm); the efficacy of P4S also increased significantly (epsilon = 0.40). By studying a mutant GABA receptor with impaired gating, the authors were able to demonstrate clearly that isoflurane can increase the efficacy of a partial agonist, as well as increase agonist potency. These data suggest that the volatile anesthetic isoflurane exerts at least some of its effects on the GABA(A) receptor via alterations in gating rather than simply changing binding or unbinding of the agonist.

Effect of the Bowman-Birk inhibitor (a soy protein) on in vitro bladder neck/urethral and penile corporal smooth muscle activity.

The Bowman-Birk inhibitor (BBI), is a serine protease inhibitor derived from soy beans, which is presently being evaluated in clinical trials for its ability to serve as a cancer preventive or anti-inflammatory agent. The form of BBI currently in clinical trials is known as Bowman-Birk inhibitor concentrate (BBIC). There have been anecdotal reports from patients of improved voiding and sexual functions in the ongoing BBIC trials. The objective of this study was to quantify the effect of BBI and BBIC on urethral and corporal smooth muscle activity. In vitro muscle strip studies of New Zealand White rabbit urethra/bladder neck and penile corpora in the presence or absence of BBI or BBIC incubation (5 mg/mL) were performed. In dose-response curves to alpha stimulation, BBI mediated a shift to the right (decreased receptor sensitivity in bladder/urethra as well as corpora with no change in the maximal response). Bladder base/ urethra contraction by field stimulation was significantly inhibited by BBI at higher frequencies (1-32 Hz) (12.2 + 0.8 g vs. 6.3 + 0.75 g, P < 0.05). BBI inhibited field stimulated relaxation of corporal muscle at lower frequencies. Muscarinic contraction of the bladder neck/urethra in alpha prestimulated tissue was significantly inhibited by BBI (5.3 + 0.2 g vs. 2.7 + 0.1 g, P < 0.05). BBI has an inhibitory effect on alpha adrenergic dose-response curves in bladder neck/urethral and corpora smooth muscle. BBI also significantly inhibited neurohumoral cholinergic release and in vitro muscarinic contraction of the urethra. The effects on corpora relaxation were less pronounced. The data suggest that the phytochemical BBI may promote physiologic effects of urethral relaxation and improved voiding by unique mechanisms and deserves further study as a pharmacologic agent for lower urinary tract symptoms.

Endurance training in Wistar rats decreases receptor sensitivity to a serotonin agonist

There is mounting evidence that increased brain serotonin during exercise is associated with the onset of CNS-mediated fatigue. Serotonin receptor sensitivity is likely to be an important determinant of this fatigue. Alterations in brain serotonin receptor sensitivity were examined in Wistar rats throughout 6 weeks of endurance training, running on a treadmill four times a week with two exercise tests per week to exhaustion. Receptor sensitivity was determined indirectly as the reduction in exercise time in response to a dose of a serotonin (1A) agonist, m-chlorophenylpiperazine (m-CPP). The two groups of controls were used to examine (i) the effect of the injection per se on exercise performance and (ii) changes in serotonin receptor sensitivity associated with maturation. In the test group, undrugged exercise performance significantly improved by 47% after 6 weeks of training (4518 +/- 729 to 6640 +/- 903 s, P=0.01). Drugged exercise performance also increased significantly from week 1 to week 6 (306 +/- 69-712 +/- 192 s, P = 0.04). Control group results indicated that the dose of m-CPP alone caused fatigue during exercise tests and that maturation was not responsible for any decrease in receptor sensitivity. Improved resistance to the fatiguing effects of the serotonin agonist suggests desensitization of central serotonin receptors, probably the 5-HT1A receptors. Endurance training appears to stimulate an adaptive response to the fatiguing effects of increased brain serotonin, which may enhance endurance exercise performance.

Endurance training in Wistar rats decreases receptor sensitivity to a serotonin agonist

There is mounting evidence that increased brain serotonin during exercise is associated with the onset of CNS‐mediated fatigue. Serotonin receptor sensitivity is likely to be an important determinant of this fatigue. Alterations in brain serotonin receptor sensitivity were examined in Wistar rats throughout 6 weeks of endurance training, running on a treadmill four times a week with two exercise tests per week to exhaustion. Receptor sensitivity was determined indirectly as the reduction in exercise time in response to a dose of a serotonin (1A) agonist, m‐chlorophenylpiperazine (m‐CPP). The two groups of controls were used to examine (i) the effect of the injection per se on exercise performance and (ii) changes in serotonin receptor sensitivity associated with maturation. In the test group, undrugged exercise performance significantly improved by 47% after 6 weeks of training (4518 ± 729 to 6640 ± 903 s, P=0.01). Drugged exercise performance also increased significantly from week 1 to week 6 (306 ± 69–712 ± 192 s, P = 0.04). Control group results indicated that the dose of m‐CPP alone caused fatigue during exercise tests and that maturation was not responsible for any decrease in receptor sensitivity. Improved resistance to the fatiguing effects of the serotonin agonist suggests desensitization of central serotonin receptors, probably the 5‐HT1A receptors. Endurance training appears to stimulate an adaptive response to the fatiguing effects of increased brain serotonin, which may enhance endurance exercise performance.

The evaluation of sympathetic system-related contractile activity of the rat vas deferens after ligation and intra-abdominal placement of the testis.

To evaluate the contractile response of the vas deferens in a model of stress, to determine any changes in sympathetic activity as a result of stress in the ipsilateral testis, which decreases blood flow to the contralateral testis. The study comprised two groups of six rats each; group 1 underwent a sham operation, and in group 2 the right testis was placed into the abdominal cavity and the vas deferens ligated. After 30 days, the vasa deferentia were resected bilaterally and their isometric contractions recorded. Electrical-field stimulation (EFS) was applied through a pair of platinum electrodes and concentration-response curves constructed for noradrenaline at 37 degrees C and to a solution containing 80 mmol/L K+. The vasa deferentia in both groups showed similar contractile responses to EFS, which were frequency-dependent and maximal at 80 Hz. Noradrenaline-induced contractile activity was lower in amplitude in the vasa deferentia of group 2 than in the contralateral and ipsilateral vasa deferentia of group 1, which were not significantly different from each other. All groups responded similarly to high K+. Intra-abdominal placement of the testes with vas deferens ligation decreased the contractile response to noradrenaline in the ipsilateral vas deferens without altering the contractile response to EFS and high K+. This difference could be caused by a reduction in the number of postjunctional alpha-adrenergic receptors or decreased receptor sensitivity. Both possibilities suggest that the vas deferens may initiate sympathetic activity, which may be responsible for contralateral testicular deterioration.

Modulatory and direct effects of propofol on recombinant GABA A receptors expressed in Xenopus oocytes: Influence of α- and γ2-subunits

Propofol (2,6-diisopropylphenol) is an intravenous general anaesthetic which can directly activate and positively modulate the GABA A receptor. The effects of propofol on human recombinant GABA A receptors were studied in Xenopus oocytes expressing either α 1 β 2, α 1 β 2 γ 2L, or α 2 β 2 γ 2L receptor isoforms. In all receptor isoforms tested, propofol was able to potentiate the GABA-activated currents in a concentration-dependent manner. Although propofol potentiated both α 1 β 2 and α 1 β 2 γ 2L receptor isoforms with equal affinity, the efficacy of propofol potentiation was markedly greater in the α 1 β 2 receptor isoform. In contrast, potentiation of the α 2 β 2 γ 2L receptor isoform by propofol occurred with higher affinity and lower efficacy than in the α 1 β 2 γ 2L receptor isoform. Propofol directly activated all three receptor isoforms in a concentration dependent manner. Addition of the γ 2L subunit subtype to the α 1 β 2 receptor isoform decreased receptor sensitivity to direct activation by propofol. Replacement of the α 1-subunit subtype with the α 2-subunit subtype increased receptor sensitivity to propofol's direct effects. These results suggest that the α-and γ 2L-subunit subtypes each have the ability to influence both the direct and modulatory actions of propofol on GABA A receptor function.

Effects of age on the pharmacodynamics of naproxen in the rat.

The pharmacodynamics of naproxen were evaluated in 5- and 24-month-old male Fischer 344 rats. Plasma naproxen concentrations and thromboxane B2 (TxB2) concentrations were measured as a function of time after intravenous administration of 25 mg/kg naproxen. Age-dependent alterations in naproxen pharmacokinetics were attributed to significant reductions in free plasma clearance (CLfree) and free steady-state volume of distribution (VSSfree), suggesting a decline in metabolic activity and naproxen binding to tissue components in aged rats, respectively. The time course of TxB2 production as a function of unbound naproxen concentrations was described by a sigmoid Emax model. Age had no significant effect on the pharmacodynamic parameter Emax, the maximum percent inhibition of TxB2 formation. Age also had no statistically significant effect on EC50, the drug concentration producing 50% of the maximum effect, however, average EC50 values were 35% higher in the aged rats. The duration of TxB2 inhibition was unaffected by age, possibly owing to similar relative decreases in receptor sensitivity (increased EC50) and increases in free naproxen concentrations (decreased free clearance and volume of distribution). Alternatively, the age-related changes in pharmacokinetic parameters were not of sufficient magnitude to produce a significant change in drug response, naproxen, pharmacokinetics, pharmacodynamics, age, rats, thromboxane B2, nonsteroidal anti-inflammatory drugs.

Interference with normal chemoreceptor activity by some sesquiterpenoid antifeedants in an herbivorous insect Pieris brassicae

The sesquiterpenoids polygodial, warburganal and muzigadial interfere with normal chemoreceptor function and thereby inhibit food uptake by fifth-instar larae of Pieris brassicae. Prolonged exposure to these compounds of different chemosensitive cells, including the deterrent receptor, decreases receptor sensitivity reversibly. Muzigadial is the weakest direct stimulus of the deterrent cell, but exerts the strongest inhibitory effect on this receptor. It is concluded that inhibitions by these dialdehydic sesquiterpenoids affect general receptor function, which is (to a large extent) unrelated to receptor specificity.

Effects of the pyrethroid cypermethrin on l-glutamate-induced changes in the input conductance of the ventrolateral muscles of the larval house fly, Musca domestica

Cypermethrin has been previously demonstrated to block neuromuscular transmission in larval house fly ventrolateral muscles (VLMs). Although the effect is consistent with a presynaptic depolarization as it involves an increase in miniature excitatory postsynaptic current frequency, and decrease in amplitude of evoked responses, the role of a postsynaptic action in the production of these responses has not yet been assessed. Thus, this study was undertaken to observe the effects of both cypermethrin and its solvent acetone upon the postsynaptic aspect of synaptic transmission. VLMs 6a and 7a had similar resting membrane potentials (−57.6 ± 8.0 mV and −59.2 ± 8.3 mV, respectively; n = 20 cells) and input conductances (3.08 ± 0.87 and 2.97 ± 1.00 × 10 −7 siemens, respectively; n = 12 cells). l-Glutamate produced a dose-dependent depolarization and increase in the sarcolemma input conductance. A Hill plot revealed that a minimum of one glutamate molecule was required to bind to each receptor to elicit a unit response. At concentrations of 1 ml liter −1 acetone and 10 n M cypermethrin, no effects were observed on the muscle resting membrane potential, the sarcolemma input conductance, or sensitivity to 10 m M l-glutamate (pretreated with 1 μ M concanavalin A to block glutamate receptor desensitization). However, at higher concentrations both acetone and cypermethrin had postsynaptic effects. Acetone (10 ml liter −1) caused a slight increase in muscle input resistance ( P < 0.05), although higher concentrations produced a decrease in input resistance (EC 50 at 4%) of up to 70% control values. A transient membrane depolarization was observed upon initial application of acetone (> 10 ml liter −1) which was followed by a sustained membrane hyperpolarization. Intense axonal repetitive firing was also noted with acetone concentrations above 10 ml liter −1. Cypermethrin (1 μ M), 30–90 min after application, blocked the l-glutamate induced increases in input conductance and caused substantial oscillations in the sarcolemma resting membrane potential. The initial membrane depolarizations induced by 10 m M l-glutamate in control preparations were still observed in muscles poisoned with 1 μ M cypermethrin. These data demonstrate that the block of neuromuscular transmission at larval house fly nerve terminals by 10 n M cypermethrin does not involve a change in muscle membrane input conductance or a decrease in receptor sensitivity to glutamate, and therefore is likely to be a consequence of its presynaptic action.

Behavioural and electrocortical changes induced by muscimol in rats withdrawn from chronic treatment with diazepam

In rats withdrawn from a chronic treatment with diazepam, the effects of muscimol, given into the III cerebral ventricle, on behaviour and spectrum power of activity in the electrocorticogram (ECoG) were studied. In comparison to control rats which received only muscimol, in rats pretreated with diazepam (1 mg/kg/day for 30 consecutive days) the behavioural and ECoG effects of muscimol were significantly reduced or abolished. In fact, in rats pretreated with diazepam a small dose (50 ng) of muscimol did not affect behaviour or ECoG activity, in contrast to control animals in which the same dose produced, after a period of locomotor stimulation and ECoG desynchronization, typical and long-lasting behavioural sedation or sleep accompanied by a significant increase in total voltage power and in the lower frequency bands in the ECoG. In addition, larger doses (100 and 200 ng) of muscimol, which in control rats produced a typical biphasic pattern of ECoG and behavioural changes, i.e. an initial period of ECoG desynchronization and behavioural stimulation, followed by a second period of behavioural and ECoG sleep, in animals pretreated with diazepam, produced only an increase in total voltage power and in the lower frequency bands in the ECoG resembling the effects of the smaller (50 ng) dose. The present experiments suggest that, after chronic stimulation of benzodiazepine receptors a decrease in sensitivity of receptors or γ-aminobutyric acid (GABA) occurs, since the effects of muscimol on behaviour and spectrum power were significantly reduced or abolished.

Obese male mice (ob/ob) are normally sensitive to the satiating effect of CCK-8

The ob/ob mouse has a defect in short-term satiety mechanisms because ob/ob mice eat larger meals than leans and have abnormal postprandial behaviors. We suggested that this defect involved a failure to release CCK normally in response to ingested nutrients and/or decreased receptor sensitivity to CCK [7]. McLaughlin and Baile [3] reported that female obese mice were less sensitive to the satiating effect of CCK-8, a result consistent with the hypothesis of decreased receptor sensitivity. To investigate this possibility further, we determined the sensitivity to exogenous CCK-8 of obese and lean male mice. Adult male C57B1/6J ob/ob and male +/+ controls were injected with CCK-8 (1,2,4 and 8 μg/kg, IP) 15 min prior to the presentation of solid food (Noyes pellets) after 4.5 hr food deprivation in the dark. Food intake (FI) was measured at 30 min and 150 min. CCK-8 decreased FI during the first 30 min in both obese and lean mice ( p < 0.01). The threshold dose for inhibition of FI was 2 μg/kg in obese and 4 μg/kg in lean. Since obese mice weighed approximately twice as much as lean mice, their total dose of CCK-8 was equal to that of lean mice. Thus, obese male mice were at least as sensitive to the satiating effect of CCK-8 as lean male mice. These results do not confirm McLaughlin and Baile's result in female mice eating in the light and they suggest that the defect in satiety in obese male mice is not the result of decreased sensitivity of CCK receptors.

Aging of the rat adrenocortical cell: response to ACTH and cyclic AMP in vitro.

To study intrinsic age-related changes in adrenocortical steroid production, cells isolated from rats of different ages (3 to 24 months) were used. Acute (2 hour) corticosterone production in response to stimulation by adrenocorticotrophic hormone (ACTH) and adenosine 3':5'-cyclic monophosphate (cAMP) was measured by radioimmunoassay. With age, adrenocortical cells lose much of their ability to produce corticosterone in the absence or presence of ACTH or cAMP. The loss is progressive from 6 to 24 months of age. Analysis of the data suggests that from 6 to 12 months, an intracellular steroidogenic lesion develops; in addition there may be a loss in ACTH receptors on the plasma membrane. After 12 months these defects increase and are accompanied by a decrease in receptor sensitivity to ACTH.