Odile Piot

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. Using selective antagonists and a behavioural recognition test based on the olfactory discriminative capacities of rats, we found that endogenous CCK acting at CCK-A and CCK-B receptors modulates olfactory recognition positively and negatively, respectively. CCK-B receptor antagonists therefore have facilitatory potentialities on memory processes.

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. In the present study, rats were treated after the first contact with various compounds; inhibition and facilitation of olfactory recognition were evaluated as the persistence in investigation 30 min and the decrease in investigation 120 min after pharmacological manipulations, respectively. Systemic injection of CCK-8, of a selective CCK-A agonist, or of non-peptide CCK-B antagonists (CI-988 and LY-262691) enhanced olfactory recognition. In contrast, the CCK-B selective agonist BC 264 and the tetrapeptide CCK-4 both disrupted it. Taken together with previous evidence of the detrimental effect of the non-peptide CCK-A antagonist devazepide on olfactory recognition, these results confirm and extend the hypothesis that there is a balance between CCK-A-mediated facilitative effects and CCK-B-mediated inhibitory effects on memory retention.

Are 5-HT2 antagonists endowed with anxiolytic properties in rodents?

The precise role of serotonin (5-HT) in anxiety remains unclear. We report here on the effects of RP 62203, a new 5-HT2 antagonist, and ritanserin in different animal models of anxiety. In the elevated plus-maze in mice, RP 62203 increased dose-dependently the percentage of entries onto, and time spent on open arms, over the dose range 0.25-4 mg.kg-1 p.o. By contrast, ritanserin was ineffective up to the dose of 4 mg.kg-1 p.o. In addition, both compounds were tested against the anxiogenic compound FG 7142 (20 mg.kg-1, i.p.) in the plus-maze test in mice and via electrocorticographic recordings (ECoG) in rats. The anxiolytic effect of RP 62203 is antagonized by FG 7142 at a dose devoid of anxiogenic properties. A similar interaction between RP 62203 and FG 7142 is observed in ECoG studies. In contrast, ritanserin seemed to potentiate the anxiogenic and awakening activities of FG 7142. These results demonstrate that RP 62203, a selective 5-HT2 antagonist, possesses anxiolytic properties in rodents suggesting that 5-HT2 receptors are involved in the control of anxiety.

Pharmacological characterization of RP 62203, a novel 5-hydroxytryptamine 5-HT2 receptor antagonist

1 RP 62203 (2‐[3‐(4‐(4‐fluorophenyl)‐piperazinyl)propyl]naphto[1,8‐cd]isothiazole‐1,1‐dioxide) is a novel naphtosultam derivative which shows very high affinity for 5‐HT2 receptors in the rat cerebral cortex (Ki = 50.0 pm). 2 RP 62203 is relatively selective for this sub‐type of 5‐hydroxytryptamine (5‐HT) receptor, having lower affinity for the 5‐HT1A receptor and very low affinity for the 5‐HT3 receptor. RP 62203 displayed low to moderate affinity for α1‐adrenoceptors, dopamine D2 receptors and histamine H1 receptors. 3 In vivo binding experiments demonstrated that oral administration of low doses of RP 62203 led to a long‐lasting (> 6 h) occupation of cortical 5‐HT2 receptors (ID50 = 0.39 mg kg−1). 4 In cortical slices from the neonatal rat, RP 62203 potently inhibited inositol phosphate formation evoked by 5‐HT, with an IC50 of 7.76 nm. 5 The activity of neurones in the raphé and their responses to microiontophoretically applied 5‐HT were studied with extracellular recording electrodes in the anaesthetized rat. RP 62203 potently and dose‐dependently blocked excitations evoked by 5‐HT when administered at doses of 0.5–4.0 mg kg−1, i.p. In contrast, neither 5‐HT‐evoked depressions nor glutamate‐evoked excitations of raphé neuronal firing were blocked by RP 62203 at doses as high as 8.0 mg kg−1 i.p. 6 Head twitches induced by 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI) could be abolished by low doses of RP 62203 in mice (ED50 = 0.44 mg kg−1, p.o.) and in rats (ED50 = 1.54 p.o.). Similar results were obtained with mescaline and 5‐hydroxytryptophan (5‐HTP). 7 The potency of RP 62203 was compared with that of three other 5‐HT2 receptor antagonists, ritanserin, ICI 169,369 and ICI 170,809. In all models, RP 62203 showed similar activity to ritanserin, whilst either ICI 169,369 or ICI 170,809 was several fold less active. 8 It is concluded that RP 62203 is a potent and selective antagonist at 5‐HT2 receptors in the rodent central nervous system.

Cyclopyrrolones unlike some benzodiazepines do not induce physical dependence in mice

In a model of physical dependence in mice, treatment with cyclopyrrolones such as zopiclone and suriclone (from 4 to 400 mg/kg/day), did not modify the sensitivity of the gamma-aminobutyric acid (GABA) receptor complex to the partial inverse agonist FG 7142 following their withdrawal, whereas sensitivity changes were observed after treatment and withdrawal from some benzodiazepines (e.g. lorazepam, diazepam, flunitrazepam and triazolam). These data suggest that, in contrast to some benzodiazepines, zopiclone and suriclone may not produce physical dependence.

The mechanism of action of zopiclone

The mechanism of action of the cyclopyrrolone hypnotic drug zopiclone involves allosteric modulation of the GABAA receptor. Zopiclone displaces the binding of [(3)H]-flunitrazepam with an affinity of 28 nM, and enhances the binding of the channel blocker [(35)S]-TBPS. The binding of zopiclone, unlike that of hypnotic benzodiazepines, is not facilitated by GABA. Zopiclone does not distinguish between GABAA receptors containing different alpha-subunits (BZ(1) and BZ(2) phenotype). Studies with protein-modifying agents (eg diethylpyrocarbonate) and photoaffinity labelling suggest that cyclopyrrolones bind to a domain on the GABAA receptor different from the benzodiazepine binding domain. The consequence of this interaction with the GABAA receptor is to potentiate responses to GABA, as can be demonstrated by electrophysiological methods. Subchronic treatment of mice with high doses of zopiclone does not produce the changes in sensitivity of the GABAA receptor that are observed with hypnotic benzodiazepines.

Comparative behavioural profile of centrally administered tachykinin NK1, NK2 and NK3 receptor agonists in the guinea‐pig

1 The NK, tachykinin receptor agonists, septide, [Sar9, Met(O2)11]SP and [Pro9]SP produced locomotor hyperactivity (10–20 min) when injected intracerebroventricularly (i.c.v.) in the guinea‐pig. Producedlocomotor The most potent in eliciting this hyperactivity was septide (from 0.63 to 5 μg), compared to [Sar9, Met(O2)11]SP, which was active at 2.5 and 5 μg and [Pro9]SP which induced a non‐significant increase even at 10 μg. 2 Wet‐dog shakes were elicited by septide, [Sar9, Met(O2)11]SP and [Pro9]SP injected by the i.c.v. route in the guinea‐pig. [Sar9, Met(O2)11]SP, active from 0.16 to 2.5 μg was more potent than septide (active at 1.25 μg) and [Pro9]SP (active at 0.63 μg) in eliciting such behaviour. To a lesser extent, grooming was also observed after injection of these agonists. 3 The NK2 tachykinin receptor agonist, [Lys5, MeLeu9, Nle10]NKA(4–10), up to the dose of 10 μg i.c.v. had no effect in the guinea‐pig. It neither modified locomotor activity nor induced a characteristic behavioural response. At higher doses (20μg), some toxic effects were noted. 4 The NK3 tachykinin receptor agonist, senktide, contrasts with the NK1 receptor agonists in that it elicited only wet‐dog shakes, at doses ranging from 0.32 to 1.25 μg. It neither modified locomotor activity (1 pg) nor induced grooming (up to 5 μg) in the guinea‐pig. 5 To our knowledge, these results are the first demonstration that the guinea‐pig could be useful to differentiate tachykinin agonists on the basis of their behavioural profile, distinct from those obtained in mice and rats.

Synthesis, anticonvulsant and neuroprotective activities of RP 66055, a riluzole derivative

Abstract RP 66055, a riluzole derivative, has been characterized as a potent anticonvulsant and in vivo neuroprotective agent.

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%). The affinity of the compounds for uptake site and 5-HT2, alpha 1, and D2 receptors was measured. Some compounds were studied in vivo by their potentiating effect of 5-HTP-induced symptomatology. The most potent and selective (uptake, 5-HT2 versus alpha 1, D2 sites) compounds contain a 3-[(4-piperidinyl)methyl]indole moiety. 5-Fluoro-3-[(4-piperidinyl)methyl]indole itself (compound 1) displayed a high affinity for the uptake site but was devoided of in vivo activity. N-Methylation of this compound abolished the affinity. In contrast N-substitution by a two-carbon chain linked to a naphthalenesultam or related heterocycle led to compounds exhibiting high affinity for the uptake site. One of them, 1-[2-[4-((5-fluoro-1H-indol-3-yl)methyl-1- piperidinyl]ethyl]-5,6-dihydro-1H,4H-1,2,5-thiadiazolo[4,3,2- ij]quinoline 2,2-dioxide (compound 24), was found as active as fluoxetine in vivo.

1,1-diphenyl-3-dialkylamino-1-silacyclopentane derivatives: A new class of potent and selective 5-HT2A antagonists

Abstract A new series of 1,1-diphenyl-3-dialkylamino-1-silacyclopentanes was synthesized, and most compounds demonstrated moderate to high affinity for the 5-HT2A receptor. A member of this series, compound 1p displays potent antagonist activity after oral administration against both mescaline and DOI-induced head-twitches in mice and rats, with a long duration of action. The dextrorotatory isomer (+)-1p is highly more potent than the levorotatory isomer (−)-1p in in vitro and in in vivo assays.