[Hemodynamic consequences of endogenous hyperinsulinism in obese rats with lesions of the ventromedial hypothalamus]. / Conséquences hémodynamiques de l'hyperinsulinisme endogène chez les rats obèses ayant des lésions de l'hypothalamus ventro-médian.

The rat with ventromedian hypothalamus lesions (VMH) is characterized by massive obesity, hyperinsulinemia, increase in parasympathetic tonus and sympathetic depression. The aim of this study was to examine in this model the hemodynamic changes and the baroreflex response and to compare the data with the evaluation of beta adrenergic sensitivity. In VMH rats and Sham operated rats hemodynamic parameters were followed until 8 weeks after operation. Heart rate (HR) and blood pressure (BP) were monitored each week during 24 hours by a telemetric system, a catheter being implanted in aorta. In VMH, HR was significantly lower by the first week (p = 0.02) and until the last measurement. Systolic BP increased progressively in the two groups but was higher in VMH only at 8 weeks (p = 0.03). Compared with Sham rats, 5 days after operation, the percentage of HR acceleration in response to atropine and isoprenaline was significantly higher in VMH, whereas HR response to sodium nitroprussiate was similar in the two groups. Plasma epinephrine and norepinephrine levels were significantly higher in VMH rats. The density of cardiac beta receptors decreased from 15 days to 3 months after operation, similarly in VMH and Sham rats. The affinity of cardiac beta receptors remained stable during the same period and very similar in VMH and Sham rats. This study suggests that in VMH rats 1. bradycardia results mainly from an increase in parasympathetic tone; 2. the increase in reflex tachycardia described in normal rats after insulin infusion needs a normal activity of the sympathetic nervous system; 3. catecholamine levels may be increased despite sympathetic depression, probably as a result of an increase in adrenomedullary secretion possibly due to endogenous hyperinsulinemia; 4. the lack of hypertension in this model including a massive obesity is likely to result from the proper vasodilatory effect of insulin.

Rat uncoupling protein 2 (UCP2): expression in obese ventromedial hypothalamus (VMH)-lesioned animals.

BACKGROUND: The family of uncoupling proteins is thought to play an important role in the regulation of energy metabolism by uncoupling the respiratory chain reactions from ATP synthesis. The recently discovered uncoupling protein 2 (UCP2) is upregulated in genetically obese rodent models and during long term high fat feeding. AIM: We have examined the UCP2 mRNA levels in liver, heart and white adipose tissue (WAT) of obese ventromedial hypothalamus (VMH)-lesioned rats, during the dynamic and the early stage of the static phase of obesity, before the appearance of most of the metabolic perturbations associated with long term established obesity. RESULTS: The amount of UCP2 mRNA was not increased in any tissue of VMH-lesioned rats relative to control animals during the dynamic phase nor during the early static phase of obesity. CONCLUSION: These results indicate that in the rat, obesity does not necessarily lead to an increase in UCP2 expression and suggest that the up-regulation of UCP2 described in other models may be secondary to metabolic perturbations, rather than to a direct adaptative response to the increased adipose tissue content of the organism.

Pioglitazone-induced increase of insulin sensitivity in the muscles of the obese Zucker fa/fa rat cannot be explained by local adipocyte differentiation.

Thiazolidinediones are potent antidiabetic compounds, which act by enhancing peripheral insulin sensitivity. They are also activators of the peroxisome proliferator activated receptor gamma in adipose tissue. Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat and hence the capacity of adipose tissue to utilize glucose. Nevertheless, muscles are the major site for insulin-mediated glucose disposal. The increase of muscle glucose utilization under thiazolidinedione treatment could be secondary to local adipose tissue differentiation. This possibility is supported by the fact that a thiazolidinedione-induced myoblast conversion into adipocytes has been described in vitro. To address this problem, we have studied the in vivo effect of a pioglitazone treatment on insulin-induced glucose utilization and the expression of genes exclusively expressed in mature adipocytes in three muscles differing by their fibre composition in Zucker (fa/fa) rats. Whereas pioglitazone treatment increased insulin-stimulated glucose utilization to the same extent in all muscle types, an adipocyte differentiation was only present in the oxidative muscle, the soleus. Soleus muscle was also the only one in which the presence of genes specific for adipose tissue could be detected before the pioglitazone treatment. There was no detectable expression of adipocyte specific genes in the extensor digitorum longus or in the epitrochlearis muscles before or after the drug treatment. We conclude that pioglitazone effects on muscle glucose metabolism cannot be due to a local adipocyte differentiation, and that the conversion of myoblasts into adipocytes under thiazolidinedione stimulation observed in vitro is, if it exists, a marginal phenomenon in vivo.

Hormonal counterregulation failure in rats is related to previous hyperglycaemia-hyperinsulinaemia.

Hyperglycaemia and hyperinsulinaemia were induced in rats by a continuous 48-h infusion with glucose. Discontinuation of glucose infusion resulted in marked, persistent hypoglycaemia. To further delineate the mechanism underlying this condition, we measured counterregulatory hormone levels, in vivo glucose kinetics (glucose production = rate of appearance = Ra; glucose utilization = rate of disappearance = Rd), and in vitro gluconeogenesis during the 48-h postinfusion period. Prior to cessation of glucose infusion, Rd was increased 6-fold when compared to control rats, whereas Ra was totally abolished. During the first hour after the end of glucose infusion, Ra increased and Rd decreased (but was still higher than Ra), inducing hypoglycaemia which stabilized after 1 h at ¿¿126¿¿3.5 mmol/l when both Ra and Rd became equal. Despite hypoglycaemia, plasma glucagon and catecholamine levels did not increase during the 3-to 36-h time interval. The increase in Ra during the first hour post-infusion was not related to changes in counterregulatory hormone response. The increase in glucose production was accounted for by glycogenolysis, as shown by total depletion in liver glycogen within 6 h and thereafter by gluconeogenesis. In vitro experiments using isolated hepatocytes suggested that gluconeogenesis was supported during the first 24 h by substrates entering the pathway beyond the step catalysed by the PEPCK enzyme. Thereafter, lactate became the major substrate, and this condition was associated with a progressive rise in glucagon concentration. It is concluded that 48 h of hyperglycaemia/hyperinsulinaemia resulted in a failure of counterregulatory hormonal response to hypoglycaemia. Yet, despite this lack of counterregulatory response, hepatic gluconeogenesis was stimulated in response to hypoglycaemia.

Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat.

Thiazolidinediones are potent antidiabetic compounds, in both animal and human models, which act by enhancing peripheral sensitivity to insulin. Thiazolidinediones are high-affinity ligands for peroxisome proliferator-activated receptor-gamma, a key factor for adipocyte differentiation, and they are efficient promoters of adipocyte differentiation in vitro. Thus, it could be questioned whether a thiazolidinedione therapy aimed at improving insulin sensitivity would promote the recruitment of new adipocytes in vivo. To address this problem, we have studied the in vivo effect of pioglitazone on glucose metabolism and gene expression in the adipose tissue of an animal model of obesity with insulin resistance, the obese Zucker (fa/fa) rat. Pioglitazone markedly improves insulin action in the obese Zucker (fa/fa) rat, but doubles its weight gain after 4 weeks of treatment. The drug induces a large increase of glucose utilization in adipose tissue, where it stimulates the expression of genes involved in lipid metabolism such as the insulin-responsive GLUT, fatty acid synthase, and phosphoenolpyruvate carboxykinase genes, but decreases the expression of the ob gene. These changes are related to both an enhanced adipocyte differentiation, as shown by the large increase in the number of small adipocytes in the retroperitoneal fat pad, and a direct effect of pioglitazone on specific gene expression (phosphoenolpyruvate carboxykinase and ob genes) in mature adipocytes.

Glucagon-like peptide-1(7-36)-amide confers glucose sensitivity to previously glucose-incompetent beta-cells in diabetic rats: in vivo and in vitro studies.

The effects of glucagon-like peptide-1(7-36)-amide (GLP-1) on cAMP content and insulin release were studied in islets isolated from diabetic rats (n0-STZ model) which exhibited impaired glucose-induced insulin release. We first examined the possibility of re-activating the insulin response to glucose in the beta-cells of the diabetic rats using GLP-1 in vitro. In static incubation experiments, GLP-1 amplified cAMP accumulation (by 170%) and glucose-induced insulin release (by 140%) in the diabetic islets to the same extent as in control islets. Using a perifusion procedure, GLP-1 amplified the insulin response to 16.7 mM glucose by diabetic islets and generated a clear biphasic pattern of insulin release. The incremental insulin response to glucose in the presence of GLP-1, although lower than corresponding control values (1.56 +/- 0.37 and 4.53 +/- 0.60 pg/min per ng islet DNA in diabetic and control islets respectively), became similar to that of control islets exposed to 16.7 mM glucose alone (1.09 +/- 0.15 pg/min per ng islet DNA). Since in vitro GLP-1 was found to exert positive effects on the glucose competence of the residual beta-cells in the n0-STZ model. we investigated the therapeutic effect of in vivo GLP-1 administration on glucose tolerance and glucose-induced insulin release by n0-STZ rats. An infusion of GLP-1 (10 ng/min per kg; i.v.) in n0-STZ rats enhanced significantly (P < 0.01) basal plasma insulin levels, and, when combined with an i.v. glucose tolerance and insulin secretion test, it was found to improve (P < 0.05) glucose tolerance and the insulinogenic index, as compared with the respective values of these parameters before GLP-1 treatment.

Dose related sequence of effects induced by the DA agonist 2-(N,N-dipropyl)-amino-5,6-dihydroxytetralin.

2-N,N-dipropylamino 5,6-dihydroxytetralin (nPr2 ADTN), a potent dopaminergic agonist, induces the same polyphasic effects observed with apomorphine by Protais et al., (1983). The dose related sequence of behaviours in mice can be summed up as followed: to 0.9 to 3.9 micrograms.kg-1, a decrease in motor activity without any other effects; to 7.8 to 15.6 micrograms.kg-1, a return to control level or an increase in motility alone according to experimental conditions; to 31 to 62.5 micrograms.kg-1, a second phase of hypomotility when hypothermia develops; above 125 micrograms.kg-1, a second phase of hypermotility when both stereotypies and climbing behaviour appear. Hypothermia moreover, disappears. The effects of the nPr2 ADTN were compared with those of apomorphine obtained in others studies (Puech et al., 1974; Protais et al., 1983). The tetralin derivative differs from apomorphine in that the first phase of hypermotility it induces is greater, and that hypothermia disappears at high doses.

Anticonvulsant activity of diphenylhydantoin: pharmacological evidence for an alpha-adrenergic mechanism of action.

Several studies have shown that the noradrenergic system, or more precisely the alpha-adrenergic system, is implicated in the mechanism of action of DPH (Rudzik et al., 1966). In the present study we have demonstrated that prazosin, a relatively specific blocker of post-synaptic alpha-adrenergic receptors, antagonized the anticonvulsant activity of DPH on 3 models of convulsions: convulsions in the quaking mouse, convulsions induced by pentylenetetrazol, convulsions provoked by electroshock. The psychotropic properties of DPH have not been clearly demonstrated in man. It would, therefore, be of interest to perform controlled clinical studies in order to predict possible consequences of treatment in epileptics who are treated at the same time with antagonists of alpha-post-synaptic receptors.

Evidence against the involvement of a noradrenergic mechanism in the release by diazepam of novelty-induced hypophagia in rats.

The involvement of noradrenergic processes in both the behavioral suppression and release of food intake induced by diazepam, was investigated using the novelty-induced inhibition of food consumption model. Clonidine (7.5-60 micrograms/kg i.p.) and another alpha 2-noradrenergic receptor agonist, guanfacine (0.25-1 mg/kg i.p.), increased the food intake of rats placed in an unfamiliar situation. The effects of clonidine (15 micrograms/kg) were antagonized by yohimbine (0.5-2 mg/kg i.p.). Clonidine (7.5 micrograms/kg) was unable to enhance the efficacy of diazepam (0.5 and 1 mg/kg i.p.) in stimulating food consumption, whereas yohimbine (0.5-2 mg/kg) did not reduce and even increased the potency of diazepam (2 mg/kg) to facilitate food intake. These findings suggest that although noradrenergic processes (and in particular alpha 2-adrenoreceptors) are involved in the hyponeophagia model they do not mediate the releasing effect exerted by benzodiazepines on novelty-induced suppression of food intake.

[Antidepressive effects of 3 endogenous monoamines: psychopharmacologic profiles of noradrenaline, octopamine and phenethylamine]. / Effet "antidépresseur" de 3 monoamines endogènes: profils psychopharmacologiques de la noradrénaline, de l'octopamine et de la phényléthylamine.

Norepinephrine (NE), octopamine (OA) and phenethylamine (PEA) are easily destroyed by M.A.O. but we could show, even injected intraperitoneally that they are active upon tests used generally to reveal an "antidepressant" effect. This effect is especially studied by using antagonism of apomorphine, reserpine, oxotremorine-induced hypothermia. The psychopharmacological spectra of NE and OA are close to the one of salbutamol and the observed effects correspond to alpha- and beta-adrenergic stimulations. The PEA spectrum is similar to the one of amphetamine and the observed effects correspond to adrenergic stimulations and to a dopaminergic stimulation. The mechanisms involved in the tests realized to show an "antidepressant" effect could reflect an activity not only through endogeneous NA but also possibly through endogeneous OA and PEA.

U 43,465F: a benzodiazepine with antidepressant activity? Interaction with Ro 15-1788 and d,1-propranolol.

U-43,465F (8-chloro-1-[2-(dimethylamino)ethyl]-6-phenyl-4H-s-triazolo [4,3-a][1,4]benzodiazepine p-toluene sulfonate) showed two fold activity at 32 mg/kg i.p.: antipunishment activity inhibited by the benzodiazepine receptor antagonist Ro 15-1788, and an antidepressant-like reversal of apomorphine-induced hypothermia, antagonized by the beta-adrenergic receptor blocker d,1-propranolol. U-43,465F hence produced effects not mediated by benzodiazepine receptors and these effects might be related to antidepressant activity.

[Unexpected interactions of some psychotropic drugs with barbital and pentobarbital effects in mice (author's transl)]. / Interactions imprévues de divers psychotropes avec les effets du barbital et du pentobarbital chez la souris.

Some of the substances studied modified the effects of the two barbiturates as expected and in the same direction: --chlorpromazine and diazepam increased the effects; --amphetamine and caffeine decreased them. Barbital, unlike pentobarbital, undergoes almost no metabolic transformation. This explains why pentobarbital is potentiated in the presence of proadifen, an inhibitor of liver microsomial enzymes, whereas the effect of barbital is unchanged, and probably explains similar results obtained with iproniazide and imipramine. For the same reason, rifampicine, an enzyme inducer, antagonizes the effect of pentobarbital without affecting that of barbital. The dissociated effects obtained with other substances are more difficult to explain: --increased effects of barbital without modification of the effects of pentobarbital (sulpiride); --decreased effects of barbital without modification of the effects of pentobarbital (methylphenidate, nomifensine, amineptine, oxolinic acid, methysergide); --decreased effects of barbital with increased effects of pentobarbital (viloxazine). Two hypotheses may be considered: 1. The study of barbital and pentobarbital concentrations in blood and brain would allow to exclude a pharmacokinetic interaction; 2. Barbital does not act through the same mechanism as pentobarbital.

Effects of drugs affecting the noradrenergic system on convulsions in the quaking mouse.

Handling-induced convulsions in the quaking mouse can be blocked by: phenobarbital, pentobarbital or phenytoin; postsynaptic alpha-adrenoceptor agonists (noradrenaline, phenylephrine, CRL 40028); presynaptic alpha-adrenoceptor blockers (yohimbine, mianserine); catecholamine liberating agent (amphetamine); noradrenaline reuptake inhibitors (cocaine, imipramine, desipramine). Moreover, the protective effect of yohimbine was antagonized by clonidine, prazosin or alpha-methylparatyrosine, and the protective effect of CRL 40028 was antagonized by prazosin but not by alpha-methyltyrosine. Drugs acting by other mechanisms (pilocarpine, atropine, trihexyphenidyl, (--)-5-HTP, methysergide, pimozide, clonidine, alpha-methyl DOPA, prazosin, isoprenaline, salbutamol) did not protect against convulsions. A slight protection was obtained with high doses of apomorphine and also with (+/-)-propranolol. This effect is probably not related to blockade of beta-adrenoceptors because the same effect was obtained with (+)propranolol. In young quaking mice, where susceptibility to convulsions is low, both postsynaptic alpha-adrenoceptor blockers and presynaptic alpha-adrenoceptor antagonist lowered the convulsive threshold. Thus, this seems to constitute an interesting model for the in vivo study of substances which affect the central alpha-adrenoceptors either pre- or postsynaptically.

[The new versus the old antidepressant drugs: a comparative study of their psychopharmacological profiles (author's transl)]. / Profils psychopharmacologiques des nouveaux antidépresseurs comparés aux antidépresseurs classiques.

We studied 13 known or potential antidepressants, choosen in different pharmacological classes: desipramine, imipramine, nialamide, dexamphetamine, AHR 1118, amineptine, iprindole, mianserine, nomifensine, salbutamol, TRH viloxazine, zimelidine. Each of these compounds was studied on 8 psychopharmacological tests: motor activity, reserpine induced hypothermia, reserpine induced ptosis, oxotremorine induced hypothermia, oxotremorine induced tremors, high doses apomorphine induced hypothermia, potentiation of toxic effects of yohimbine, behavioural despair. Clinical active compounds are efficient on yohimbine test and at least on one model of hypothermia; with a few exceptions, easy to explain, substances with a clearly demonstrated antidepressant activity in human have some common effects; these common effects can be used to predict, from animal experiments, an antidepressant effect in man.

Antagonism of hypothermia and behavioral response to apomorphine: a simple, rapid and discriminating test for screening antidepressants and neuroleptics.

The antagonism of hypothermia induced by two doses of apomorphine (1 to 16 mg/kg) is proposed as an improved screening test for both neuroleptics and antidepressants. Low dose apomorphine-induced hypothermia (1 mg/kg) differentiates sulpiride-like neuroleptics (which better antagonize this effect of apomorphine than other effects such as stereotyped behavior) from haloperidol-like drugs. The latter equally antagonize the two effects of apomorphine. The effects of sulpiride are also distinct from those of chlorpromazine-like drugs which strongly antagonize stereotyped behavior, but not hypothermia induced by apomorphine. Hypothermia induced by a high dose of apomorphine (16 mg/kg) is not antagonized by neuroleptics, but is strongly antagonized by antidepressants (imipramine-like drugs, amineptine, amoxapine, nomifensine, viloxazine) and potential antidepressants (beta-adrenergic stimulants). The use of these two tests rapidly screens both antidepressants and neuroleptics and classifies neuroleptics according to their profile of action on the dopaminergic system.