Martine Poncelet

Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors.

Abstract SR 141716, a selective central CB1 cannabinoid receptor antagonist, markedly and selectively reduces sucrose feeding and drinking as well as neuropeptide Y-induced sucrose drinking in rats. SR 141716 also decreases ethanol consumption in C57BL/6 mice. In contrast, blockade of CB1 receptors only marginally affects regular chow intake or water drinking. The active doses of SR 141716 (0.3–3u2005mg/kg) are in the range known to antagonize the characteristic effects induced by cannabinoid receptor agonists. These results suggest for the first time that endogenous cannabinoid systems may modulate the appetitive value of sucrose and ethanol, perhaps by affecting the activity of brain reward systems.

SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor.

SR 142801 is the first potent and selective non-peptide antagonist of the tachykinin NK3 receptor. It inhibited [MePhe7]NKB binding to its receptor from various species, including humans. SR 142801 was a competitive antagonist of [MePhe7]NKB-mediated contractions of guinea-pig ileum and inhibited the acetylcholine release following the activation of the guinea-pig ileum tachykinin NK3 receptor. In vivo, SR 142801 potently inhibited the turning behaviour induced by intrastriatal injection of senktide in gerbils, and appears as a powerful tool for investigation of the physiological and pathological role of NKB and its NK3 receptor.

Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic.

Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC50=18, 15, and 38u2009nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID50: 5u2009mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3u2009mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5u2009μM) and intrastriatal glycine-induced rotations in mice (MED: 1u2009mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB1 receptors): it reversed the decrease in electrically evoked [3H]acetylcholine release in hippocampal slices (MEC: 10u2009nM) and the reduction of PFC neurons firing (MED: 0.3u2009mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10–30u2009mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15u2009mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1–3u2009mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10u2009mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10u2009mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1u2009mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30u2009mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.

Overeating, alcohol and sucrose consumption decrease in CB1 receptor deleted mice.

Administration of the cannabinoid CB1 receptor antagonist SR141716 (3-10 mg/kg i.p.) abolished neuropeptide Y-induced overeating and significantly reduced ethanol and sucrose intake in CB1 wild-type (+/+) mice. In CB1 receptor knockout (-/-) mice, neuropeptide Y totally lost its capacity to increase food consumption. Similarly, sucrose and ethanol intakes were significantly lower in CB1-/- vs. CB1+/+ mice. In CB1 deficient mice, SR141716 had no effect in these models.

Targeted inactivation of the neurotensin type 1 receptor reveals its role in body temperature control and feeding behavior but not in analgesia.

Three subtypes of neurotensin receptor have been described, two members of the heptahelical transmembrane domain G protein-coupled receptor superfamily NT-1R and NT-2R, and NT-3R unrelated to this family. We have generated NT-1R deficient (NT-1R(-/-)) mice. NT-1R(-/-) mice were born at the expected Mendelian frequency without obvious abnormalities and they were fertile. The NT-induced analgesia on the writhing induced by phenyl-p-benzoquinone administration remained at wild-type levels in the NT-1R(-/-) mice demonstrating that the NT-1R is not implicated in the analgesic effect of NT in this test. The NT-1R(-/-) mice were hyperthermic; their body temperature was not affected by intracerebroventricular (i.c.v.) administration of NT, contrasting with the hypothermia induced in NT-1R(+/+) mice. NT-1R(-/-) mice showed a small significant increase in body weight compared to the NT-1R(+/+) congeners as early as 10 weeks after birth, correlated with a higher food intake. NT-1R(-/-) mice showed similar spontaneous locomotion to the control littermates, but did not respond to i.c.v. NT-induced hypolocomotion. I.c.v. injection of NT inhibited feeding in fasted wild-type mice, but had no effect on feeding of the NT-1R(-/-) mice. I.c.v. administration of the orexigenic neuropeptide Y (NPY) stimulated feeding to the same extent in both wild-type and NT-1R(-/-) mice. This analysis of NT-1R-deficient mice shows that the NT-1R does not play a role in NT-induced analgesia, but that it is clearly implicated in thermal and feeding regulation, weight control, and NT-induced hypolocomotion.

Intrastriatal injection of cannabinoid receptor agonists induced turning behavior in mice

When injected unilaterally into the mouse striatum, cannabinoid agonists such as Win 55212-2 (1-100 ng/mouse), CP 55940 (0.1-50 ng/mouse), and anandamide (0.5-50 ng/mouse), the putative endogenous ligand of CB1 receptor, dose-dependently induced turning behavior. SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H- pyrazole-3-carboxamide hydrochloride], the selective antagonist of CB1 receptor, antagonized the three cannabinoid receptor agonists-induced turning with similar ED50s (0.13-0.15 mg/kg, IP). Spiroperidol (a D2 receptor blocker), (+)-SCH 23390 (a D1 receptor blocker), or prior 6-OHDA lesions of the striatum blocked Win 55212-2- and CP 55940-induced turning, thus suggesting the involvement of DA transmission in cannabinoid-induced turning. Taken together, these findings reinforce the notion of a cannabinoid receptor-mediated control of nigrostriatal function.

Neuropharmacological characterization of SR 140333, a non peptide antagonist of NK1 receptors

SR 140333 (1-[2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl) piperidin-3-yl]ethyl]-4-phenyl-1-azonia-bicyclo[2.2.2]octane , chloride), a potent non peptide ligand of the substance P (SP) NK1 receptor subtype with high affinity for NK1 receptors from both rat cortical membranes and human IM9 cells (Ki = 0.02 nM and 0.01 nM, respectively) was studied in vivo on various effects induced by NK1 agonists in rats and mice. SR 140333 given intraperitoneally (i.p.) in mice antagonized dose-dependently and in a stereoselective manner the scratching responses induced by intracerebroventricular SP and septide (ID50 = 0.73 and 0.08 mg/kg, respectively) and the turning behavior elicited by intrastriatal SP and septide (ID50 = 0.07 and 0.06 mg/kg, respectively). This compound had little effect on the scratching responses and the turning behavior elicited by [Sar9, Met(O2)11]-SP. When SR 140333 was coadministered with the peptide agonist, the compound reduced the scratching responses elicited by SP, [Sar9, Met(O2)11]-SP and septide injected intrathecally (i.t.) in mice (ID50 = 72.0, 64.3 and 52.5 ng i.t., respectively). SR 140333 antagonized the salivation induced by SP, [Sar9, Met(O2)11]-SP and septide in rats (ID50 = 0.13, 0.18 and 0.09 mg/kg i.p., respectively). SR 140333 abolished the facilitation of the tail-flick reflex induced by noxious heat in rats (total reversal at 0.06 mg/kg, i.p.). This compound was also found to inhibit the turning behavior induced by intrastriatal apomorphine in mice (ID50 = 0.1 mg/kg, i.p.). In conclusion, these results indicate that SR 140333 behaves as a potent, selective and centrally active NK1 receptor antagonist.

Biochemical and pharmacological activities of SR 144190, a new potent non-peptide tachykinin NK2 receptor antagonist.

(R)-3-(1-[2-(4-benzoyl-2-(3,4-difluorophenyl)-morpholin-2-yl)- ethyl]-4-phenylpiperidin-4-yl)-1-dimethylurea (SR 144190) is a new non-peptide antagonist of tachykinin NK2 receptors. SR 144190 potently and selectively inhibited neurokinin A binding to NK2 receptors from various species, including humans. In in vitro functional assays, it was a potent, selective and competitive antagonist of NK2 receptors with apparent affinities (pA2 values) between 9.08 and 10.10. In vivo, SR 144190 blocked [Nle10]neurokinin A-(4-10)-induced bronchoconstriction in guinea pigs (ID50 = 21 micrograms kg-1 i.v. and 250 micrograms kg-1 i.d.) and [beta Ala8]neurokinin A-(4-10)-induced urinary bladder contraction in rats (ID50 = 11 micrograms kg-1 i.v. and 190 micrograms kg-1 i.d.). It prevented citric acid-induced cough and airway hyperresponsiveness to acetylcholine in guinea pigs (1 mg kg-1 i.p.) as well as castor oil-induced diarrhoea in rats (0.01-10 micrograms kg-1 s.c. or p.o). Finally, it blocked the turning behaviour induced by intrastriatal injections of [Nle10]neurokinin A-(4-10) in mice (ID50 = 3 micrograms kg-1 i.v. and 16 micrograms kg-1 p.o.).

Neuropharmacological profile of a novel and selective ligand of the sigma site: SR 31742A

The biochemical, electrophysiological and behavioural effects of SR 31742A, a novel and selective ligand of sigma sites in brain, labelled with (+)-[3H]3PPP (Ki = 5.3 +/- 0.3 nM), were investigated in rodents and compared with those of DA antagonists having (haloperidol) or not (spiroperidol) a high affinity for sigma sites. Like haloperidol but unlike spiroperidol, SR 31742A, (ED50 = 0.065 mg/kg, i.p., and 0.21 mg/kg, p.o.) antagonized sigma-dependent turning behaviour in mice and inhibited (0.5 mg/kg, i.v.) the spontaneous firing of hippocampal (CA3) neurones in urethane-anaesthetized rats. In chloral hydrate-anaesthetized rats, like classical antipsychotic compounds, SR 31742A (0.625-5 mg/kg, i.p.) increased the number of spontaneously active A9 and A10 DA cells after single administration and produced an opposite effect after repeated injections. The drug SR 31742A reduced (2.5, 5, 10 mg/kg, i.p.) the hyperactivity elicited by various drugs including that produced by injection of (+)-amphetamine into the nucleus accumbens and impaired avoidance responses at doses (5, 10 mg/kg, i.p.), sparing escape behaviour. SR 31742A lacked affinity for DA receptors and neither did the compound induce catalepsy nor antagonize such effects elicited by apomorphine as climbing, hypothermia, stereotypy or the inhibition of firing of DA neurones. SR 31742A did not affect the basal metabolism of DA but at 10 mg/kg (i.p.) it significantly reduced the amphetamine-induced rise in levels of 3-MT in the striatum of mice. Together, these results indicate a modulatory role for sigma sites upon the activity of hippocampal and DA systems and that sigma ligands exert effects, which suggest antipsychotic potential.

Turning behavior induced by intrastriatal injection of neurotensin in mice: sensitivity to non-peptide neurotensin antagonists

The intrastriatal injection of neurotensin (10 pg/mouse) elicited vigorous contralateral rotations which were not affected by disruption of dopaminergic transmission using 6-OHDA lesion of the striatum or systemic administration of spiroperidol (0.03 mg/kg). SR 48692, a selective non-peptide antagonist of neurotensin receptor, produced the following pattern of changes: a significant antagonism of rotations was observed at 0.04 and 0.08 mg/kg i.p. followed by a reinstatement of rotations at 0.16–0.64 mg/kg (at higher doses, a second antagonism occurred that lacked stereo selectivity). The reinstatement of rotations observed at 0.16 and 0.32 mg/kg of SR 48692 was abolished by spiroperidol and 6-OHDA lesions, suggesting the role of dopamine regulatory mechanisms.