Enhanced long-term potentiation in mice lacking cannabinoid CB1 receptors.

Marijuana is known to affect learning and memory in humans, and cannabinoids block long-term potentiation in the hippocampus, a model for the synaptic changes that are believed to underlie memory at the cellular level. We have now examined the physiological properties of the Schaffer collateral-CA1 synapses in mutant mice in which the CB1 receptor gene has been invalidated and found that these animals exhibit a half-larger long-term potentiation than wild-type controls. Other properties of these synapses, such as paired-pulse facilitation, remained unchanged.

Severe atherosclerosis and hypoalphalipoproteinemia in the staggerer mouse, a mutant of the nuclear receptor RORalpha.

Background: Hypoalphalipoproteinemia is the most common lipoprotein abnormality in patients with coronary artery disease, yet its causes are unknown.

Methods And Results: We show that the homozygous staggerer (sg/sg) mutant mouse, which carries a deletion within the nuclear receptor RORalpha gene, develops severe atherosclerosis when maintained on an atherogenic diet. In addition, sg/sg mice display a profound hypoalphalipoproteinemia, which is associated with decreased plasma levels of the major HDL proteins, apolipoprotein (apo) A-I and apoA-II.

Neuroprotective effects of riluzole on a model of Parkinson's disease in the rat.

The aim of the present study was to analyse whether riluzole, a compound that interacts with the voltage-dependent sodium channel and impairs glutamatergic transmission, would exhibit a neuroprotective activity in a model of Parkinson's disease in the rat. Impaired skilled forelimb use, circling behavior, and altered dopaminergic metabolism of the mesotelencephalic system were evaluated in unilaterally 6-hydroxydopamine-lesioned rats. Riluzole was administered twice 15 min before, and 24 h after, the lesion.

Protection against atherogenesis in mice mediated by human apolipoprotein A-IV.

Apolipoproteins are protein constituents of plasma lipid transport particles. Human apolipoprotein A-IV (apoA-IV) was expressed in the liver of C57BL/6 mice and mice deficient in apoE, both of which are prone to atherosclerosis, to investigate whether apoA-IV protects against this disease. In transgenic C57BL/6 mice on an atherogenic diet, the serum concentration of high density lipoprotein (HDL) cholesterol increased by 35 percent, whereas the concentration of endogenous apoA-I decreased by 29 percent, relative to those in transgenic mice on a normal diet.

[Current and future antithrombotic therapies].

In spite of progress, antithrombotic therapies involve the risk of haemorrhage. Thrombolytic agents have more or less fibrin specificity which is related to the risk of bleeding. These drugs have efficient antidotes which can be administered locally or by systemic route.

Primary structure control of recombinant proteins using high-performance liquid chromatography, mass spectrometry and microsequencing.

The conformity of two recombinant proteins (a von Willbrand factor fragment and human serum albumin, consisting of respectively 289 and 585 amino acids) has been examined by HPLC combined with mass spectrometry and microsequencing, on both intact material and fragment peptides obtained by proteolytic cleavage. These studies confirmed that the primary structure of the recombinant proteins corresponds to that predicted from their gene, particularly the integrity of their N and C termini, and, in the case of albumin, the agreement between the observed disulfide bond pattern and the published model. Furthermore, the structure of an albumin-related compound could be elucidated.

Pharmacological properties of ureido-acetamides, new potent and selective non-peptide CCKB/gastrin receptor antagonists.

We present here the pharmacological properties of 3 ureido-acetamide members of a novel family of non-peptide cholecystokinin-B (CCKB) receptor antagonists. RP 69758 (3-(3-[N-(N-methyl N-phenyl-carbamoylmethyl) N-phenyl-carbamoylmethyl] ureido)phenylacetic acid), RP 71483 ((E)-2-[3-(3-hydroxyiminomethyl phenyl) ureido] N-(8-quinolyl) N-[(1,2,3,4-tetrahydro 1-quinolyl)carbonylmethyl]acetamide) and RP 72540 ((RS)-2-[3-(3-[N-(3-methoxy phenyl) N-(N-methyl N-phenyl-carbamoylmethyl) carbamoylmethyl] ureido) phenyl] propionic acid) displayed nanomolar affinity for guinea-pig, rat and mouse CCKB receptors labelled with [3H]pCCK-8 or with the selective CCKB receptor ligand [3H]pBC264. RP 69758 and RP 72540 showed selectivity factors in express of 200 for CCKB versus CCKA receptors.

CCK-A and CCK-B receptors enhance olfactory recognition via distinct neuronal pathways.

We have previously reported that CCK-A receptor agonists and CCK-B receptor antagonists both enhance memory in an olfactory recognition test. Here, we report that the memory-enhancing effect of the CCK-B receptor antagonist L-365,260 (1 mg/kg i.p.

CCK-A and CCK-B selective receptor agonists and antagonists modulate olfactory recognition in male rats.

Modulation of learning and memory is one of the physiological roles that the neuropeptide cholecystokinin (CCK-8) may play. We have used a behavioural model of olfactory recognition among rats to test this hypothesis and to explore the relationship between CCK-A and CCK-B receptors and memory retention. Adult male rats form a transient memory of a juvenile congenere as indicated by a reduction in the duration of investigatory behaviour upon re-exposure 30 min after an initial exposure, but not when re-exposure is delayed until 120 min afterwards.

Predominant labeling of beta- over alpha-tubulin from porcine brain by a photoactivatable taxoid derivative.

An [(azidophenyl)ureido]taxoid (TaxAPU) was synthesized in a radiolabeled form by coupling an aminotaxoid to tritiated N-methyl-N-(chloroformyl)-p-azidoaniline. TaxAPU was used to photolabel polymerized porcine brain tubulin. This newly synthesized probe possesses taxoid properties as demonstrated by its effect, in the absence of light, on the kinetics of tubulin assembly and microtubule disassembly and on the critical concentration of tubulin.

Altered synaptic plasticity and memory formation in nitric oxide synthase inhibitor-treated rats.

Nitric oxide (NO) is a messenger molecule that is produced in the brain from the metabolism of L-arginine to L-citrulline. Growing evidence suggests a physiological role for NO in long-term potentiation (LTP). Since LTP is a form of synaptic plasticity thought to be involved in learning and memory, we have tested whether inhibition of endogenous NO production affects memory capacities of rats.

RP 59037 and RP 60503: anxiolytic cyclopyrrolone derivatives with low sedative potential. interaction with the gamma-aminobutyric acidA/benzodiazepine receptor complex and behavioral effects in the rodent.

This study describes the pharmacological properties of two novel cyclopyrrolone derivatives, RP 59037 [2-(7-chloro-2-naphthyridin-1,8-yl)-3-(5- methyl-2-oxohexyl)isoindolin-1-one] and RP 60503 [2-(7-chloro-2-naphthyridin-1,8-yl)isoindolin-1-yl-4- acetamidobutyrate], in the rodent. These compounds possess high affinity for the benzodiazepine binding site on the gamma-aminobutyric acidA receptor in rat cerebrocortical membranes with Ki values of 0.98 nM (RP 59037) and 1.

New indole derivatives as potent and selective serotonin uptake inhibitors.

A series of new indole derivatives (2-28) has been prepared in the search for novel 5-HT uptake inhibitors. These compounds were obtained by the condensation of N-(chloroalkyl) naphthalenesultam derivatives with the appropriate amine in presence of a base, at reflux of DMF or THF. The yields were moderate (12-56%), except for the piperazine derivative 20 (85%).

[Zopiclone. Data of experimental pharmacology and clinical use].

Zopiclone is the first of the cyclopyrrolones, a new class of psychotropic agents which is chemically different from the benzodiazepines (BZD). From an experimental point of view it has qualitatively the pharmacological profile of the tranquilizer-hyponotics, and activity quantitatively differs from hypnotic BZD by its lower myorelaxant. The electroencephalographic studies also demonstrated that its power spectrum is characteristic of a product having a tranquilizing hypnotic potential.

Comparison in different tissue preparations of the in vitro pharmacological profile of RP 67580, a new non-peptide substance P antagonist.

We describe the effects of RP 67580, a new non-peptide substance P (SP) antagonist, on tachykinin-induced contractions of guinea-pig ileum, trachea and urinary bladder, rabbit pulmonary artery and rat portal vein. All NK1 agonists tested (SP, Septide, SPOMe and [Pro9]SP) contracted guinea-pig ileum, trachea and urinary bladder (pD2 = 7.5 to 9.

[Cholecystokinins and their receptors. Functional aspects].

The term cholecystokinin (CCK) refers to a family of related peptides whose members play hormonal roles in the gastro-intestinal tract. The sulfated octapeptide CCK-8 [Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] is also abundant throughout the central nervous system where it satisfies the criteria for a neurotransmitter. CCK interacts with at least two types of receptor called CCK-A and CCK-B receptors.

Evidence for an endogenous cholecystokininergic balance in social memory.

The cholecystokinin (CCK) peptide family is involved in a variety of physiological processes, including neurotransmission in the brain. Pharmacological responses to CCK are mediated through at least two receptor subtypes termed CCK-A and CCK-B. Studies with CCK agonists suggest a possible role for CCK in cognition.

Enoxaparin (Clexane, Lovenox), a low molecular weight heparin, enhances t-PA-induced coronary thrombus lysis in anesthetized dogs without inducing hypocoagulability.

An occlusive coronary thrombus was obtained in barbiturate anesthetized dogs within 60 min following the angiographic placement of a copper coil into the left descending coronary artery. This thrombus persisted for the 60 min experimental period, within which the effects of i.v.