Biomedical subjects

R Bergeron

Publications and source records attributed to R Bergeron.

At least 37 records · Page 2Linked to original sources

PubMed1999

Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR.

Insulin increases glucose uptake through the translocation of GLUT-4 via a pathway mediated by phosphatidylinositol 3-kinase (PI3K). In contrast, myocardial glucose uptake during ischemia and hypoxia is stimulated by the translocation of GLUT-4 to the surface of cardiac myocytes through a PI3K-independent pathway that has not been characterized. AMP-activated protein kinase (AMPK) activity is also increased by myocardial ischemia, and we examined whether AMPK stimulates glucose uptake and GLUT-4 translocation. In isolated rat ventricular papillary muscles, 5-aminoimidazole-4-carboxyamide-1-beta-D-ribofuranoside (AICAR), an activator of AMPK, as well as cyanide-induced chemical hypoxia and insulin, increased 2-[(3)H]deoxyglucose uptake two- to threefold. Wortmannin, a PI3K inhibitor, did not affect either the AICAR- or the cyanide-stimulated increase in deoxyglucose uptake but eliminated the insulin-stimulated increase in deoxyglucose uptake. Immunofluorescence studies demonstrated translocation of GLUT-4 to the myocyte sarcolemma in response to stimulation with AICAR, cyanide, or insulin. Preincubation of papillary muscles with the kinase inhibitor iodotubercidin or adenine 9-beta-D-arabinofuranoside (araA), a precursor of araATP (a competitive inhibitor of AMPK), decreased AICAR- and cyanide-stimulated glucose uptake but did not affect basal or insulin-stimulated glucose uptake. In vivo infusion of AICAR caused myocardial AMPK activation and GLUT-4 translocation in the rat. We conclude that AMPK activation increases cardiac muscle glucose uptake through translocation of GLUT-4 via a pathway that is independent of PI3K. These findings suggest that AMPK activation may be important in ischemia-induced translocation of GLUT-4 in the heart.

AMP-Activated Protein Kinases↗

PubMed1999

Glucose production during exercise in humans: a-hv balance and isotopic-tracer measurements compared.

The present study compared the arteriohepatic venous (a-hv) balance technique and the tracer-dilution method for estimation of hepatic glucose production during both moderate and heavy exercise in humans. Eight healthy young men (aged 25 yr; range, 23-30 yr) performed semisupine cycling for 40 min at 50.4 +/- 1.5(SE)% maximal O(2) consumption, followed by 30 min at 69.0 +/- 2.2% maximal O(2) consumption. The splanchnic blood flow was estimated by continuous infusion of indocyanine green, and net splanchnic glucose output was calculated as the product of splanchnic blood flow and a-hv blood glucose concentration differences. Glucose appearance rate was determined by a primed, continuous infusion of [3-(3)H]glucose and was calculated by using formulas for a modified single compartment in non-steady state. Glucose production was similar whether determined by the a-hv balance technique or by the tracer-dilution method, both at rest and during moderate and intense exercise (P > 0. 05). It is concluded that, during exercise in humans, determination of hepatic glucose production can be performed equally well with the two techniques.

Adult↗

PubMed1998

Modulation of N-methyl-D-aspartate receptor function by glycine transport.

The recent discovery of glycine transporters in both the central nervous system and the periphery suggests that glycine transport may be critical to N-methyl-D-aspartate receptor (NMDAR) function by controlling glycine concentration at the NMDAR modulatory glycine site. Data obtained from whole-cell patch-clamp recordings of hippocampal pyramidal neurons, in vitro, demonstrated that exogenous glycine and glycine transporter type 1 (GLYT1) antagonist selectively enhanced the amplitude of the NMDA component of a glutamatergic excitatory postsynaptic current. The effect was blocked by 2-amino-5-phosphonovaleric acid and 7-chloro-kynurenic acid but not by strychnine. Thus, the glycine-binding site was not saturated under the control conditions. Furthermore, GLYT1 antagonist enhanced NMDAR function during perfusion with medium containing 10 microM glycine, a concentration similar to that in the cerebrospinal fluid in vivo, thereby supporting the hypothesis that the GLYT1 maintains subsaturating concentration of glycine at synaptically activated NMDAR. The enhancement of NMDAR function by specific GLYT1 antagonism may be a feasible target for therapeutic agents directed toward diseases related to hypofunction of NMDAR.

2-Amino-5-phosphonovalerate↗

PubMed1998

Role of somatodendritic 5-HT autoreceptors in modulating 5-HT neurotransmission.

A very important element controlling serotonin (5-HT) release throughout the brain is the 5-HT1A autoreceptor present on the soma and dendrites of 5-HT neurons since it exerts a negative feedback influence on their firing activity. This 5-HT1A autoreceptor receives an increased activation by endogenous 5-HT at the beginning of a treatment with a selective 5-HT reuptake inhibitor (SSRI) and, consequently, a decreased 5-HT neuronal firing activity is obtained. As the SSRI treatment is prolonged, the 5-HT1A autoreceptor desensitizes and firing activity is restored in the presence of the SSRI. That this adaptive change underlies, at least in part, the delayed therapeutic effect of SSRI in major depression is supported by the acceleration of the antidepressant response by the concomitant administration of the 5-HT1A autoreceptor antagonist pindolol with SSRIs.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1998

Effect of hepatic portal injection of ouabain on the hepato-sympathoadrenal reflex.

The purpose of the present investigation was to evaluate the effects of an intraportal injection of ouabain (2 mg/kg), an inhibitor of the sodium-potassium pump, on plasma catecholamine response in unrestrained normally fed rats with and without an intact hepatic vagus nerve. Three groups of rats were submitted to two injection conditions each. Hepatic vagotomized (HV) rats were randomly injected with ouabain or saline (0.9%) in the portal vein. Sham-operated rats were either injected with ouabain or saline in the portal or jugular vein. Ouabain or saline were injected at 0 min and again at 20 min. Plasma catecholamines were measured before the first injection and 15 min after each injection. Blood glucose concentrations were significantly (p < 0.01) increased by the ouabain injection as compared with basal values and saline-injected groups. The hyperglycemic effect of ouabain was not affected by the hepatic vagotomy or the site of infusion. The injection of ouabain, either into the portal or the jugular vein and either after HV or the sham operation, resulted in a significant (p < 0.01) increase in epinephrine levels as compared with saline-infused rats. Plasma norepinephrine levels were significantly (p < 0.05) increased after the second intraportal injection of ouabain in both HV and sham-operated groups. However, the injection of ouabain into the jugular vein did not change the plasma norepinephrine levels. The latter observation indicates a specific action of ouabain in the liver on the sympathetic activity.

Adrenal Glands↗

PubMed1998

Lack of effects of an acute hepatic vagotomy on insulin and catecholamine responses in rats following exercise.

The purpose of the present investigation was to evaluate the effects of an acute hepatic vagotomy on hormonal responses to hyperglycemic and hypoglycemic challenges in rats previously submitted to an exercise protocol. Two experiments were conducted. In a first experiment, 8-week trained (TR) and untrained (UNTR) rats, subdivided into acutely hepatic vagotomized (HV) and sham-operated (SHM) groups, were submitted to an intraperitoneal glucose tolerance test (0.5 g/kg) under anesthesia. Training was associated with a tendency (P = 0.07) for blood glucose levels to be less elevated (at time point 10 min), and with a significant (P < 0.01) lower glucose/insulin ratio following the glucose injection. The HV did not have any effects on these responses. In a second experiment, non-exercised rats and a group of rats submitted to an acute bout of exercise (treadmill, 60 min, 26 m/min, 5% slope) 24 h before the experiment, each one of these two groups being subdivided into acutely HV and SHM groups, were submitted to an insulin-induced hypoglycemia protocol, under anesthesia. Blood glucose concentrations were decreased significantly (P < 0.01) to approximately 40 mg/dl in all groups 60 and 80 min after the insulin injection. Plasma adrenaline and noradrenaline levels were increased significantly (P < 0.01) in all groups. The catecholamine increase was not influenced by the HV or the acute exercise bout. The present results do not indicate an implication of the hepatic vagus nerve on hormonal responses to hyper and hypoglycemia following exercise.

Animals↗

PubMed1998

The use of pindolol to potentiate antidepressant medication.

Serotonin (5-HT) selective reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors are thought to have a delayed onset of antidepressant action attributable in part to the decrease in firing activity of 5-HT neurons they produce upon treatment initiation. As cell body 5-HT1A autoreceptors desensitize, 5-HT neuronal firing is restored. The agent pindolol, through its 5-HT1A receptor blocking property, has been shown to prevent the initial decrease in firing of rat 5-HT neurons associated with SSRI treatment. Four open-label studies put into evidence a significant acceleration of the antidepressant effect of SSRIs when combined with pindolol. Four of five placebo-controlled studies have confirmed this observation. Controlled trials indicate that a greater rate of response may be obtained by combining pindolol from the beginning of the SSRI treatment. The strategy of adding pindolol to the regimen of SSRI-resistant patients also appears to produce a therapeutic effect in a significant proportion of patients.

Animals↗

PubMed1997

Effects of low and high doses of selective sigma ligands: further evidence suggesting the existence of different subtypes of sigma receptors.

Several high affinity sigma (sigma) ligands, such as DTG, JO-1784, (+)-pentazocine, BD-737 and L-687,384, administered at low doses act as agonists by potentiating N-methyl-D-aspartate (NMDA)-induced activation of pyramidal neurons in the CA3 region of the rat dorsal hippocampus. This potentiation is dose-dependent at doses between 1 and 1000 micrograms/kg, IV but bell-shaped dose-response curves are obtained. Other sigma ligands like haloperidol, BMY-14802, (+)3-PPP and NE-100 administered at low doses act as sigma antagonists, since they do not modify the NMDA response but suppress the potentiation of the NMDA response induced by sigma agonists. Because high doses of the sigma agonists do not potentiate the NMDA response, the present experiments were undertaken to assess if, at high doses, these sigma ligands could also act as sigma antagonists and suppress the potentiation induced by low doses of sigma agonists. High doses of DTG, JO-1784, BD-737, and L-687,384, administered acutely, had an effect similar to that of low doses of haloperidol, by suppressing and preventing the potentiation induced by low doses of DTG, JO-1784, BD-737, L-687,384 and (+)-pentazocine. High doses of (+)-pentazocine suppressed the effect of a low dose of (+)-pentazocine but did not affect the potentiation induced by a low dose of the other sigma agonists. The potentiation induced by a low dose of a sigma 1 agonist was not further increased by the subsequent administration of another low dose of a sigma 1 agonist. All together, these results strongly suggest that more than two subtypes of sigma receptors exist in the CNS.

Animals↗

PubMed1997

Selective activation of postsynaptic 5-HT1A receptors induces rapid antidepressant response.

It has been reported that the 5-HT1A autoreceptor antagonist pindolol can accelerate the antidepressant response to the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine, presumably by preventing the initial decrease in firing activity of 5-HT neurons produced by the SSRI. The present study was aimed at further exploring this treatment strategy in three groups of 10 patients with unipolar major depression allocated sequentially to three treatment arms for 28 days. The administration of the selective 5-HT1A agonist buspirone (20 mg/day for 1 week and 30 mg/day thereafter) with pindolol (2.5 mg TID) was used to activate selectively postsynaptic 5-HT1A receptors. This combination produced a greater than 50% reduction of depressive symptoms in the first week in 8 of 10 patients and the response was sustained for the remainder of the trial. In contrast, the combination of tricyclic antidepressant drugs devoid of effect on the 5-HT reuptake process (desipramine or trimipramine, 75 mg/day for 1 week and 150 mg/day thereafter) with pindolol resulted in only one of ten patients achieving a 50% improvement after 28 days. The combination of the SSRI fluvoxamine (50 mg/day for 1 week and 100 mg/day thereafter) with pindolol produced a marked antidepressant effect but did not act as rapidly as the buspirone plus pindolol combination with none, four, and eight patients achieving a 50% amelioration after 7, 14, and 21 days of treatment, respectively. These results provide further evidence that pindolol may accelerate the antidepressant effect of drugs that alter the function of the 5-HT neurons and that the selective activation of postsynaptic 5-HT1A receptors may induce a rapid and robust antidepressant response.

Adult↗

PubMed1997

Effect of short-term and long-term treatments with sigma ligands on the N-methyl-D-aspartate response in the CA3 region of the rat dorsal hippocampus.

1. Long-term treatments with the sigma ligand haloperidol decrease the density of sigma receptors in mammalian CNS. We have shown that sigma ligands, such as di(2-tolyl)guanidin (DTG), potentiate dose-dependently, with bell-shaped dose-response curves, the neuronal response of pyramidal neurones to N-methyl-D-aspartate (NMDA) in the CA3 region of the rat dorsal hippocampus. sigma Ligands producing such a potentiation were denoted 'agonists'. This potentiation was suppressed by low doses of other sigma ligands denoted 'antagonists'. High doses of DTG and JO-1784 did not modify the NMDA response but acted as 'antagonists' by suppressing the potentiation induced by sigma 'agonists'. 2. Following a 21-day treatment with haloperidol as well as with high doses of DTG or JO-1784, after a 48 h washout, the acute administration of sigma 'agonists' failed to induce any potentiation of the NMDA response. Following a 21 day treatment with a low dose of DTG or JO-1784, after a 48 h washout, the neuronal response to microiontophoretic applications of NMDA was markedly increased. A 21 day treatment with low or high doses of (+)-pentazocine, after a 48 h washout, did not produce any change. 3. Following a two day treatment with a high dose of haloperidol, DTG, JO-1784 and (+)-pentazocine, after a 24 h washout, the potentiation of the NMDA response induced by the acute administration of the sigma 'agonists' was unchanged. 4. With the minipumps on board, with DTG and JO-1784, a dose-dependent enhancement of the NMDA response was seen but no effect was observed in the groups of rats treated at the same doses with haloperidol or (+)-pentazocine. 5. The present data suggest that long-term treatments with sigma 'antagonists' induce a desensitization of the th receptors, whereas long-term treatments with th 'agonists' induce a supersensitivity of the th receptors.

Animals↗

PubMed1997

Early onset of therapeutic action in depression and greater efficacy of antidepressant treatments: are they related?

Until recently, several weeks of treatment were required to obtain a clinically significant antidepressant response using pharmacotherapy. Now treatment strategies have been developed that appear to produce an early onset of action in major depression. In treatment-resistant depression, there are several agents that can be used to potentiate the therapeutic effect of the initial antidepressant drug. The question of whether such a rapid onset is related to greater efficacy of antidepressant treatments was examined on the basis of the putative mechanisms of action of these treatments, and on the clinical evidence available so far. Some approaches appear to have both a more rapid onset of action and greater efficacy, such as electroconvulsive shock treatment, venlafaxine and pindolol addition, whereas the addition of lithium does not produce a more rapid onset of action despite being effective in treatment-resistant depression. In contrast, amineptine exerts an early psychostimulant effect but is apparently as effective as other antidepressant drugs. We conclude that a treatment strategy producing a rapid onset often, but not invariably, has greater efficacy than a treatment producing a slower onset. These preclinical and clinical observations may help to devise rapid treatments for major depression that will be effective in a greater proportion of patients than at present.

Animals↗

PubMed1997

Effects of dietary manipulations and glucose infusion on glucagon response during exercise in rats.

The purpose of the present investigation was to test the hypothesis that blood glucose concentration is not always related to glucagon response during exercise. Three groups of rats were submitted to a prolonged (3-h) swimming exercise. Two groups of rats had their normal food intake restricted by 50% the night before the experiment. One of these two groups of rats was intravenously infused with glucose throughout exercise to maintain euglycemia. The third group of rats swam while under normal dietary conditions. Plasma glucose, sampled in arterial blood, was reduced (P < 0.05) at 75, 105, 150, and 170 min of exercise (from approximately 130 to 110 mg/dl) in the food-restricted animals without glucose infusion, whereas a significant (P < 0.05) increase was measured in the two other groups during exercise. A significant (P < 0.01) difference in the mean integrated areas under the glucose-concentration curve was found only between the fed and the two food-restricted groups. Plasma insulin concentrations decreased (P < 0.05) similarly in all groups during exercise, whereas plasma epinephrine and norepinephrine concentrations increased significantly (P < 0.01) in all groups. Despite differences between groups in plasma glucose response during exercise, and despite the absence of any decrease in exercising blood glucose levels in at least two of the three groups, plasma glucagon responses were increased (P < 0.05) similarly in all groups (from approximately 250 to 550 pg/ml) at the end of the exercise period. The increase in glucagon was significant after 90 min of exercise in the food-restricted groups, with or without glucose infusion, but only after 140 min in the fed group. These results indicate that the glucagon response during exercise is not always linked to the decrease in plasma glucose.

Animals↗

PubMed1996

Potentiation of neuronal NMDA response induced by dehydroepiandrosterone and its suppression by progesterone: effects mediated via sigma receptors.

We have shown previously that low doses of selective sigma (sigma)-receptor ligands potentiate the excitatory response of pyramidal neurons to NMDA in the CA3 region of the dorsal hippocampus in the rat. Because progesterone competitively displaces the binding of the ligand N-[3H]allyl-normetazocine (SKF-10,047), the present studies were undertaken to determine in vivo the effect of neuroactive steroids on NMDA-induced excitation of rat CA3 pyramidal neurons. Low doses of dehydroepiandrosterone (DHEA) potentiated the NMDA response selectively and dose-dependently. The effect of DHEA was reversed by the selective sigma antagonist N-dipropyl-2-(4-methoxy-3- (2-phenylethoxy)phenyl)-ethylamine monohydrochloride (NE-100) and by haloperidol, but not by spiperone. Progesterone had no effect by itself but reversed, at low doses, the potentiation of the NMDA response induced by DHEA as well as those induced by nonsteroidal sigma ligands. Neither pregnenolone nor pregnenolone sulfate had any effect on the NMDA response--nor did they antagonize the potentiation of the NMDA response induced by DHEA and by nonsteroidal sigma ligands. A pertussis toxin pretreatment, which inactivates Gi/o-proteins, abolished the potentiating effects of DHEA. Ovariectomy enhanced the potentiation of the NMDA response by the nonsteroidal sigma ligand di(2-tolyl)guanidine (DTG). There was a reciprocal occlusion of the effects of DHEA and DTG; DTG did not potentiate the NMDA response further after DHEA, and DHEA did not do so after DTG. These results suggest that some neuroactive steroids modulate the NMDA response via sigma receptors.

Animals↗

PubMed1996

Differential effects of sigma ligands on the N-methyl-D-aspartate response in the CA1 and CA3 regions of the dorsal hippocampus: effect of mossy fiber lesioning.

In the CA3 region of rat dorsal hippocampus, several sigma ligands, such as 1,3-di(2-tolyl)guanidine (DTG), (+)-pentazocine and (+)-N-cyclopropylmethyl-N-methyl-1, 4-diphenyl-1-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784), administered intravenously at low doses, potentiate selectively the pyramidal neuron firing activity induced by microiontophoretic applications of N-methyl-D-aspartate, without affecting those induced by quisqualate, kainate or acetylcholine. A similar potentiation of the N-methyl-D-aspartate response has also been found with microiontophoretic applications of neuropeptide Y, an effect exerted via delta receptors. The present experiments were carried out to determine the effects of these sigma ligands and of neuropeptide Y; in the CA1 and CA3 regions following unilateral destruction by a local injection of colchicine of the mossy fiber system, which is a major afference to CA3 pyramidal neurons. In the CA1 region, DTG, JO-1784 and neuropeptide Y did not potentiate the activation induced by microiontophoretic applications of N-methyl-D-aspartate. However, (+)-pentazocine potentiated the N-methyl-D-aspartate response, similarly to its effect in the CA3 region on the intact side. In the CA3 region, on the intact side, (+)-pentazocine, DTG, JO-1784 and neuropeptide Y induced a selective potentiation of N-methyl-D-aspartate-induced activation, in keeping with previous reports. On the lesioned side, the effect of (+)-pentazocine on the N-methyl-D-aspartate response was still present, but those of DTG, JO-1784 and neuropeptide Y were abolished. These results suggest that (+)-pentazocine, on the one hand, and DTG, JO-1784 and neuropeptide Y, on the other, are not acting on the same subtype of sigma receptors. Since (+)-pentazocine, JO-1784 and neuropeptide Y have been suggested to act on the sigma 1 subtype of receptors, these data suggest the existence of two subtypes of sigma 1 receptors. They also suggest that the receptors on which DTG, JO-1784 and neuropeptide Y are acting are located on the mossy fiber terminals in the CA3 region and are absent in the CA1 region.

Acetylcholine↗

PubMed1996

[Effect of removal of the adrenal medulla on the hormonal response induced by acute hepatic vagotomy].

The purpose of the present study was to determine the effects of an acute hepatic vagotomy on plasma insulin and catecholamines levels in fasted and fed rats with and without adrenodemedullation. Rats were first divided into two groups: adrenodemedullated (ADM) and non-adrenodemedullated rats, each group being subdivided into a normally fed and a fasted (14 hrs) group. Anesthetized rats were first ADM or sham operated, and a jugular catheter was inserted. The first blood sample was taken 30 min later (time 0). Rats were then hepatic vagotomized (HV) or sham operated, and the second blood sample was taken 30 min after the HV. Results (0 vs 30 min) indicate an increase in plasma glucose, epinephrine, and norepinephrine concentrations in rats non-adrenodemedullated. This effect was independent of the nutritional state and the integrity of the vagus nerve. A weakly significant (P < 0.07) effect of the HV on insulin response was found in ADM rats, independently of the fed or fast state (different levels of hepatic glycogen content). These results indicate the necessity of using ADM animals to study the effects of an acute HV. They also suggest that the hepato-pancreatic axis is not influenced by the level of hepatic glycogen.

Adrenal Medulla↗

PubMed1996

Sequential administration of augmentation strategies in treatment-resistant obsessive-compulsive disorder: preliminary findings.

Given that an important proportion of patients with obsessive-compulsive disorder (OCD) fail to respond adequately to serotonin (5-HT) reuptake inhibitors (SRI), augmentation strategies aimed at enhancing further 5-HT transmission by different mechanisms were attempted sequentially in 13 SRI-resistant patients. Addition of the 5-HT1A l beta-adrenergic antagonist pindolol did not alter OCD symptomatology but produced a rapid improvement of depressive symptoms. The 5-HT1A agonist buspirone as well as 5-hydroxytryptophan, the immediate precursor of 5-HT, added to the SRI-pindolol regimen, were not effective in attenuating the intensity of OCD. Tryptophan, added to the SRI-pindolol regimen, produced a significant improvement after 4 weeks, with further amelioration after 6 weeks (36% decrease of the Yale-Brown Obsessive Compulsive Score), which was maintained with treatment prolongation.

Adrenergic beta-Antagonists↗

PubMed1996

Potentiation by dehydroepiandrosterone of the neuronal response to N-methyl-D-aspartate in the CA3 region of the rat dorsal hippocampus: an effect mediated via sigma receptors.

We have previously shown in vivo that low doses of selective sigma (sigma) receptor ligands potentiate selectively and dose-dependently the excitatory response of pyramidal neurons to microiontophoretic applications of N-methyl-D-aspartate (NMDA) in the CA3 region of the rat dorsal hippocampus. As several neuroactive steroids such as progesterone and testosterone have a high affinity for sigma receptors, the effects of some neuroactive steroids on the NMDA-induced neuronal response were assessed using extracellular unitary recordings of CA3 dorsal hippocampus pyramidal neurons obtained in anesthetized Sprague-Dawley rats. Low doses of dehydroepiandrosterone (DHEA) potentiated selectively and dose-dependently the NMDA response without affecting those to acetylcholine or quisqualate. This potentiating effect of DHEA was suppressed by the selective sigma 1 antagonist NE-100 and by the non-selective sigma antagonist haloperidol. Low doses of progesterone and of testosterone did not modify the NMDA response, but reversed the potentiating effects of DHEA as well as those of the non-steroidal sigma ligands di-tolylguanidine (DTG), (+)pentazocine and JO-1784. The two neuroactive steroids with a low affinity for sigma receptors, pregnenolone and pregnenolone sulfate, had no effect on the NMDA response, and did not modify the potentiation of the NMDA response induced by DHEA and by non-steroidal sigma ligands. The potentiation of the NMDA response by DTG (1 microgram/kg i.v.) was significantly greater in ovariectomized rats than in males and non-ovariectomized females on either day one or three of the estrous cycle. These results suggest that some neuroactive steroids such as DHEA, progesterone and testosterone modulate the NMDA response via sigma receptors. Furthermore, they also indicate that endogenous progesterone and testosterone, by acting as non-selective sigma antagonists, may produce a tonic dampening of the function of sigma receptors and consequently a decrease in the NMDA receptor function.

Acetylcholine↗

PubMed1995

In vivo modulation of sigma receptor sites by calcitonin gene-related peptide in the mouse and rat hippocampal formation: radioligand binding and electrophysiological studies.

Possible interactions between sigma (sigma) receptor sites and calcitonin gene-related peptides (CGRP) were investigated using receptor subtype-related analogues and fragment in in vivo [3H](+)SKF 10 047/sigma binding in the hippocampus, and electrophysiological recording of the N-methyl-D-aspartate (NMDA)-induced activation of CA3 pyramidal neurons, two well-established sigma assays. In both paradigms, CGRP and the agonist [Cys(ACM)2,7]hCGRPalpha modulated sigma systems. In vivo binding experiments demonstrated that CGRP and [Cys(ACM)2,7]hCGRPalpha inhibited 25-40% of specific [3H](+)SKF 10 047 labelling in the mouse hippocampal formation while the purported antagonist hCGRP8-37 was inactive. The specificity of this modulation was demonstrated further by the lack of effect of other vasoactive peptides, including the atrial natriuretic peptide, substance P, and its N-terminal fragment, substance P1-7. In the CA3 subfield of the rat dorsal hippocampus, hCGRP alpha decreased (up to 61%) the NMDA-induced activation of the pyramidal neurons. Conversely, the linear analogue [Cys(ACM)2,7]hCGRP alpha enhanced (by 85%) the NMDA-induced activation of CA3 pyramidal neurons, while the antagonistic fragment hCGRP8-37 had no effect. Haloperidol, a high-affinity sigma receptor ligand, inhibited by 90% the in vivo [3H](+)SKF 10 047 labelling, and prevented the modulation of the NMDA-induced activation by hCGRP alpha and [Cys(ACM)2,7]hCGRP alpha. It thus appears that CGRP can modulate sigma-related systems in the hippocampal formation.

Animals↗