Uteroplacental hemodynamic disturbances in establishment of fetal growth retardation in streptozocin-induced diabetic rats.

This study examined the relationship between uteroplacental blood flow and fetal hypotrophy in streptozocin-induced diabetic rats (40 mg/kg body wt i.v.). Our results showed that, in diabetic rats, fetal hypotrophy was associated with a significant reduction in arterial blood velocity in the uterine artery (P less than 0.001), placenta (P less than 0.01), umbilical artery (P less than 0.01), and fetal aorta (P less than 0.05). This was not observed when diabetic rats were treated with insulin. Treatment of rats with the alpha 1-blocking vasodilator nicergoline restored fetal growth and arterial blood velocity to control values without affecting the degree of hyperglycemia. Nicergoline in control rats did not change fetal weight and caused only minor hemodynamic changes on presumably already maximally vasodilated arteries. We concluded that the uteroplacental hemodynamic disturbances observed in diabetic rats play a major role in the establishment of fetal growth retardation.

Acamprosate appears to decrease alcohol intake in weaned alcoholics.

Five hundred and sixty-nine alcoholics were included in a double-blind placebo-controlled randomized multicenter study of the effects of Acamprosate (calcium acetylhomotaurinate (CA), 1.3 g/day) on indicators of alcoholic relapse after withdrawal. One hundred and eighty-one patients in the CA group versus 175 in the placebo group completed the three-month study. The major efficacy criterion was plasma gamma-glutamyl transpeptidase (GGT), as an indicator of recent alcohol ingestion. This analysis was completed by criteria concordance analysis on a number of indicators of alcohol intake. Patients in both groups were similar initially. After 3 months of treatment, the patients in the CA group had significantly lower GGT (1.4 +/- 1.56 versus 2.0 +/- 3.19 times normal, P = 0.016). All significant differences (P less than 0.05) or trends (0.10 greater than P greater than 0.05) were in favor of a superior effect of CA over placebo. The major side-effect of CA was diarrhea (present in 13% of CA patients versus 7% of placebo, P = 0.04). CA proved superior to placebo on the evolution of markers of alcohol ingestion at three months, in this large-scale multicenter study. It could be a new modality in the drug therapy of alcoholism, not involving an antabuse effect, an antidepressant action, or conditioning.

Influence of an alpha-1-adrenoceptor antagonist, nicergoline, on placental prostanoid production in streptozotocin-induced diabetic pregnant rats.

The aim of this study was to determine if placental prostanoids could mediate the vasodilating action of an alpha-1-adrenoceptor antagonist, nicergoline (400 micrograms/kg i.p.), during late pregnancy in streptozotocin-induced diabetic rats (40 mg/kg i.v.). Placental prostanoid concentrations were evaluated by radioimmunoassay. Prostaglandin E2 levels showed a highly significant increase in diabetic and nondiabetic rats treated with nicergoline (p less than 0.001). 6-Keto-PGF1 alpha concentrations were slightly increased in diabetic rats compared to controls, and this increase was reversed by both nicergoline and insulin treatments. In all groups studied thromboxane B2 levels were comparable. It is concluded that prostaglandin E2 could mediate the vasodilating action of nicergoline on the placental irrigation and, therefore, improved the hemodynamic state of this organ in diabetic rats.

Alcohol and GABA: ethanol intake modifies hippocampal nipecotic acid binding in ethanol-preferring and non-preferring rats.

3H-nipecotic acid (3H-NIP) binding to GABA uptake recognition sites was studied in the hippocampus of 3 groups of male, Long Evans rats: Group 1: ethanol-naive rats (ENR); Group II: ethanol-preferring rats (DR) and non-preferring rats (NDR), which had consumed about 5 g.kg-1.d-1 and 1 g-1.d-1 of alcohol respectively in the form of a 12% ethanol solution prior to 3H-NIP binding analysis; Group III: DR and NDR who had had no access to ethanol for 21 d after the initial exposure of ethanol solution (28 d). Binding studies showed that ethanol drunk by both DR and NDR in Group II decreased 3H-NIP binding (Bmax decreased) with an enhancement of affinity (KD decreased). In rats subjected to withdrawal of ethanol (Group III), affinity of 3H-NIP for GABA uptake sites was higher than in controls (Group I), but lower than in Group II, Bmax in this group being higher than in the 2 other groups. In Group III, KD was higher in DR than in NDR. These results showed that ethanol intake, in a free-choice paradigm, altered 3H-NIP binding, and that differences in ethanol intake between DR and NDR were associated with differences in sensitivity of hippocampal GABA uptake sites. These differences in 3H-NIP binding could either precede ethanol intake, or be a direct result from it. The results, together with data from other laboratories suggest that: 1), 3H-NIP binding sites are involved in the regulation of ethanol intake; 2), 1 factor responsible for individual differences in ethanol response is reflected by the GABA uptake system.

Application of an analytical method to calcium acetylhomotaurinate determination in urine.

After urine purification, plasma and urine concentrations of calcium acetylhomotaurinate (Acamprosate, CaAOTA) were determined with a high-performance liquid chromatography method following i.v. administration of the drug in two dogs. Results obtained in serum were in good agreement with those found previously. The CaAOTA urine determination is a promising method to be used in healthy volunteers.

Increase in uterine prostaglandin E2, F2 alpha, prostacyclin and stability in thromboxane A2 production during late pregnancy in streptozotocin-induced diabetic rats.

This experiment was conducted to determine the effect of diabetes on uterine prostanoids production in near-term rats. The incidence of an insulin therapy was also studied. On the 21st day of pregnancy, uterine PGE2, PGF2 alpha and PGI2 levels showed a significant increase (respectively p less than 0.05, p less than 0.01 and p less than 0.05) in diabetic rats compared to controls whereas TxA2 production remained unchanged. The insulin therapy restored PGE2 levels, the most potent stimulatory factor of the myometrial fiber at control values, whereas it enhanced significantly PGI2 concentrations (p less than 0.05) and had no effect on PGF2 alpha production; TxA2 levels remaining always unchanged. It is suggested that the increase in uterine protanolds production during diabetes could induce a myometrial hypertonicity and play a role in the disturbances of the fetal development. The maintenance of PGE2 levels to control values by the insulin therapy might contribute to a normal delivery.

Lateralization of headache: possible role of an upper cervical trigger point.

An ipsilateral upper neck trigger point was found in 21 of 24 patients with unilateral headache. During the prodromic period this trigger point was detected as a tender protrusion on neck palpation. In 18 out of 24 patients it was also found during the headache-free period. On standard roentgenogram, this protrusion seemed to be a laterally developed C2 spinous process. The EMG study showed latent trapezius hypertonicity on the side of the headache, even during the headache-free period. The association of the painful protrusion and trapezius hypertonicity could create an autoreinforcing nociceptive loop, which in turn could be the cause of lateralization of the pain.

Pharmacokinetics of ambenonium chloride in dogs after intravenous and oral administration.

Plasma concentrations of ambenonium chloride (Mytélase) were studied, using a high pressure liquid chromatographic technique, in 11 dogs, after intravenous or oral administration of the drug. The results found suggest a complex multi-compartment storage with several periodical releases in general circulation.

Physicochemical, pharmacological and pharmacokinetic study of a new GABAergic compound, calcium acetylhomotaurinate.

It has been shown that calcium acetylhomotaurinate (Ca AOTA; Meram Patent, France) decreased voluntary ethanol intake in rats (1); this was antagonized by bicuculline. Homotaurine did not have this effect. We thought this was due to a different blood-brain barrier crossing ability for the two drugs. The present study was, therefore, planned to confirm blood-barrier crossing by Ca AOTA and to study the drug's physicochemical and pharmacokinetic characteristics. Both in vitro and in vivo (i.p.) administration of Ca AOTA increased the accumulation of [3H] GABA in rat striatal synaptosomal preparations. The chemical study confirmed Ca AOTA's great stability in biological and hydrophilic media, excluding a "homotaurine-dispensing" effect. The molecule was totally dissociated in such media, but the absence of any detectable acid form at any pH indicates that ion pairs are formed to cross barriers, and/or that a carrier system is used. The pharmacokinetic study showed short half-lives (5 and 30 min for the distribution and elimination phases) and small distribution volumes. However, the elimination phase distribution volume was dose-dependent, a further argument for a carrier transport system. From the present study it appears that Ca AOTA is an extremely stable drug, totally dissociated in hydrophilic media, which acts centrally as a GABA agonist after crossing the blood-brain barrier. It is not a precursor of homotaurine and presumably crosses barriers with the help of a transporter.

GABA transmission, but not benzodiazepine receptor stimulation, modulates ethanol intake by rats.

Adult male Long Evans were selected as ethanol preferring rats (DR) during 28 days. After this period, they were daily IP injected during 14 days with one of the next drugs: diazepam 1 mg.kg-1, alprazolam 1 mg.kg-1 (benzodiazepines), progabide 25 mg. kg-1 (GABA A and B agonist), nipecotic acid 150 mg.kg-1 (GABA uptake inhibitor), muscimol 0.2 mg.kg-1 (GABA A agonist), AOAA 10 mg.kg-1 (GABA decarboxylase inhibitor), baclofen 3 mg.kg-1 (GABA B agonist), or NaCl 0.9% (1 ml/200 g). During treatment, rats were isolated, had free access to food, and free choice between ethanol (12%) and water whose respective consumption were daily noted. Among treatments, only AOAA and baclofen were able to decrease significantly ethanol intake, without modifying total liquid intake. The action of these different drugs on GABA transmission and on ethanol intake was discussed. It was concluded that GABA A and benzodiazepine receptors were not implicated in ethanol intake, but that modulation of voluntary ethanol intake could be associated with a modification of GABA metabolism and/or stimulation of GABA B receptors. An intervention of GABA B receptors on noradrenergic pathways was also evoked.

[Diffusion of vancomycin in the cerebrospinal fluid, in the dog, in the absence of meningeal inflammation]. / Diffusion de la vancomycine dans le liquide céphalo-rachidien, chez le chien, en l'absence d'inflammation méningée.

The diffusion of vancomycin into the cerebro-spinal fluid was studied in 5 healthy dogs. Its appears that vancomycin does diffuse across the blood-brain barrier. Though the concentrations reached in the CSF are low, they are of the same order of magnitude as the minimal inhibitory concentrations of this antibiotic towards the germs usually treated. The usual pharmacokinetic parameters were determined.

Circling behaviour in rats with unilateral lesions of the nigrostriatum induced by 6-hydroxydopamine: changes induced by oral administration of cytidine-5'-diphosphocholine.

A unilateral administration of 6-hydroxydopamine into the nigrostriatal system of the rat was responsible for ipsiversive circling behaviour in response to administration and, in time, of contraversive circling behaviour in response to L-DOPA and apomorphine. This contraversive circling behaviour appears to be mediated by the development, on the lesioned side, of supersensitivity of postsynaptic dopamine receptors. Subchronic treatment with cytidine-5'-diphosphocholine (p.o.) by itself was devoid of behavioural effects. The CDP-choline did not modify the apomorphine-induced stimulant effect but potentiated the circling behaviour produced by L-DOPA and amphetamine. The data show that the effects of CDP-choline were mediated by a presynaptic mechanism: the potentiation of the effects of L-DOPA cannot be explained by an activation of tyrosine hydroxylase, but seems to be related to an improvement of release of newly synthesized dopamine from exogenous L-DOPA.

Circling in normoxic or hypoxic rats with unilateral 6-OHDA nigrostriatal lesion. Part 2. Effects of d-amphetamine.

Unilateral administration of 6-hydroxydopamine into the rat nigrostriatal system induces a unilateral damage of the dopamine (DA) containing neurons. In such lesioned animals, d-amphetamine (AMPH) induces circling behavior (ipsiversive circling) in relation to its DA releasing property in the non-lesioned side. A preexposition to hypoxia potentiates the behavioral effect of AMPH: this can be related to an increase in the amount of substrate available for release, dopamine. Hypoxia occurring just after the administration of AMPH does not initially modify the AMPH induced circling behavior. This suggests that tyrosine hydroxylase inhibition by hypoxia is not a limiting factor of the releasing effect of AMPH. After 20 min of hypoxia, circling decreases. This impairment could be mediated by a decrease of the amount of available DA and/or by a decrease of release.

Circling behavior in normoxic or hypoxic rats with unilateral 6-OHDA nigrostriatal lesion. Part 1. Effects of apomorphine and L-dopa.

Unilateral administration of 6-hydroxydopamine (6-OHDA) into the rat nigrostriatal system provokes circling behavior in response to apomorphine and L-dopa. This behavior appears to be mediated by the development in the lesioned side of a postsynaptic dopamine receptors supersensitivity. Acute hypobaric hypoxia does not modify the apomorphine-induced stimulant effects, but does oppose the L-dopa-induced circling behavior. Our data suggest that effects of hypoxia are mediated by a presynaptic mechanism. The antagonism of the effects of L-dopa cannot be explained by the inhibition of activity of the oxygen-dependent enzyme tyrosine hydroxylase, but seems to be related to an impairment of the release of newly synthesized dopamine from exogenous L-dopa.

Platelet affinity for serotonin is increased in alcoholics and former alcoholics: a biological marker for dependence?

The kinetics of 3H serotonin platelet uptake were studied in alcoholics and former alcoholics to see whether differences found between alcohol-preferring and non-preferring rats could be reproduced in man. Three groups of patients were studied: 10 dependent alcoholics on admission for treatment; 10 dependent alcoholics after 20 days of treatment; 8 former dependent alcoholics, abstinent for 1-11 years. Controls were non-alcoholics, matched for age and sex. The Km for 3H serotonin uptake in platelets was lower in patients from all three groups compared to 15 controls. This phenomenon could be congenital or induced by the previous excessive intake of alcohol. We believe that this increased platelet affinity for serotonin, in the absence of cirrhosis of the liver and/or depression could be a marker for alcohol dependence, enabling the therapeutic effort to be focussed on these patients.

Noradrenaline and GABA brain receptors are co-involved in the voluntary intake of ethanol by rats.

Stimulation of GABA brain receptors by calcium bis acetyl-homotaurine (a new GABAergic agent) or of noradrenergic brain receptors by metapramine reduces the voluntary intake of ethanol by rats. Bicuculline antagonizes the effects of both drugs. It is suggested that both GABA and noradrenaline are implicated in ethanol intake, and that there is a common final pathway of the two systems to modulate ethanol intake.

Effects of hypoxia and cytidine (5') diphosphocholine on the concentrations of dopamine, norepinephrine and metabolites in rat hypothalamus and striatum.

Experiments were performed in order to determine whether exogenous cytidine (5') diphosphocholine (CDP-choline) opposes the effects of an acute hypobaric hypoxia on the metabolism of catecholamines in rat striatum and hypothalamus. Hypoxia decreased striatal HVA, DOPAC, 3 MT, hypothalamic norepinephrine (NE), and increased both striatal and hypothalamic dopamine (DA). CDP-choline (1000 mg X kg-1 p.o.; 1 or 3 days) was devoid of effects in normoxia, but partially reversed 3 MT, NE and DA changes, potentiated the HVA and DOPAC decrease in hypoxic rats. Our results suggest that hypoxia could impair neurotransmitter release and that treatment with CDP-choline (acute, and especially subacute administration) opposes this impairment.