SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist, alleviates disturbances of novelty discrimination in a social context in rats, a putative model of selective attention deficit.

RATIONALE: Selective attention deficit, characterised by the inability to differentiate relevant from irrelevant information, is considered to underlie many cognitive deficits of schizophrenia, and appears to be only marginally responsive to treatment with current antipsychotics. OBJECTIVES: We compared the activity of the putative atypical antipsychotic SSR181507 (a dopamine D(2) receptor antagonist and 5HT(1A) receptor agonist) with reference compounds, on disturbances of novelty discrimination in a social context in rats, a behavioural paradigm that putatively models selective attention deficit. METHODS: A first (familiar) juvenile rat was presented to an adult rat for a period (P1) of 30 min. A second (novel) juvenile was then introduced at the end of P1 for a period (P2) of 5 min. The ability of the adult rat to discriminate between the two juveniles, presented at the same time, was evaluated by measuring the ratio of the time spent in interaction with the novel vs the familiar juvenile during P2. RESULTS: Adult rats spent more time exploring the novel than the familiar juvenile. This novelty discrimination capacity was disrupted by: (1) parametric modification of the procedure (reduction of time spent in contact with the familiar juvenile during P1); (2) acute injection of psychotomimetics that are known to induce schizophrenia-like symptoms in humans, such as phencyclidine (PCP; 3 mg/kg, i.p.) and d-amphetamine (1 mg/kg, i.p.) and (3) neonatal treatment with PCP (three injections of 10 mg/kg, s.c.), a model based on the neurodevelopmental hypothesis of schizophrenia. The potential atypical antipsychotic SSR181507 (0.03-3 mg/kg, i.p.) and the atypical antipsychotics clozapine (0.1-1 mg/kg, i.p.) and amisulpride (1-3 mg/kg, i.p.) attenuated deficits in novelty discrimination produced by parametric manipulation and by acute or neonatal treatment with PCP. The typical antipsychotic haloperidol (up to 0.3 mg/kg, i.p.) attenuated only deficits in novelty discrimination produced by parametric modification. CONCLUSION: Collectively, these results suggest that SSR181507 can alleviate disturbances of novelty discrimination in a social context in rats, and that this paradigm may represent a suitable animal model of selective attention deficits observed in schizophrenia.

Administration of amyloid beta-peptides in the rat medial septum causes memory deficits: reversal by SR 57746A, a non-peptide neurotrophic compound.

Different putative toxic amyloid beta (A beta) peptides, beta (1-42), beta (1-40) and beta (25-35), were infused (0.75, 1.5 or 3 nmol) in the rat medial septum. Memory deficits were then investigated using the social recognition test. A significant amnesia was observed 4, 7 and 14 days after intraseptal injection of 3 nmol of beta (1-42), beta-(1-40)- and beta (25-35). Lower amounts of beta (1-42) were inactive except 1.5 nmol that disrupted memory 7 days post-treatment. Used as control, the inverted peptide beta (40-1) and the scrambled beta (25-35) were inactive. Using the prolongation procedure, rats infused with 3 nmol of beta (1-40) were still able to recognize the same juvenile. Finally, a daily treatment with the non-peptide neurotrophic compound SR 57746A (10 mg/kg p.o.) over 21 days, prevented the deficits in short-term memory induced by the intraseptal infusion of 3 nmol of either beta (1-40) or beta (25-35). These findings suggest that A beta fragments could impair short-term memory when infused in the rat medial septum, an effect that is prevented by SR 57746A.

Improvement of memory in rodents by the selective CB1 cannabinoid receptor antagonist, SR 141716.

Social short-term memory in rodents is based on the recognition of a juvenile by an adult conspecific when the juvenile is presented on two successive occasions. Cannabimimetics are claimed to induce memory deficits in both humans and animals. In the brain, they mainly bind to CB1 receptors for which anandamide is a purported endogenous ligand. SR 141716, a specific antagonist of CB1 receptors, dose-dependently reverses biochemical and pharmacological effects of cannabimimetics. More particularly, it antagonizes the inhibition of hippocampal long-term potentiation induced by WIN 55,212-2 and anandamide, and it increases arousal when given alone. The present experiments study the ability of SR 141716 (from 0.03 to 3 mg/kg SC) to facilitate short-term olfactory memory in the social recognition test in rodents. SR 141716 improved social recognition in a long intertrial paradigm with a threshold dose of 0.1 mg/kg SC. At 1 mg/kg, it antagonized the memory disturbance elicited by retroactive inhibition. Scopolamine (0.06 mg/kg IP) partially reversed its memory-enhancing effect. Moreover, SR 141716 reduced memory deficit in aged rats (0.03-0.1 mg/kg) and mice (0.3-1 mg/kg). As SR 141716 is not known to exhibit any pharmacological activity which is not mediated by CB1 receptors, the results strongly support the concept that blockade of CB1 receptors plays an important role in consolidation of short-term memory in rodents and suggest there may be a role for an endogenous cannabinoid agonist tone (anandaminergic) in forgetting.

Inhibition of long-term potentiation in rat hippocampal slices by anandamide and WIN55212-2: reversal by SR141716 A, a selective antagonist of CB1 cannabinoid receptors.

It has been reported previously that delta 9-tetrahydrocannabinol and the synthetic cannabinoid agonist HU-210 [(--)-11-OH-delta 8-dimethylheptyl tetrahydrocannabinol] prevent long-term potentiation (LTP) induction in rat hippocampal slices. In this study we confirm that both WIN55212-2 ¿R-(+)-(2,3-dihydro-5-methyl-3-[¿4-morpholinyl¿ methyl] pyrol [1,2,3-de]-1,4-benzoxazin-6-yl) (1-naphtalenyl) methanone monomethanesulphonate¿ (3 and 10 microM), another synthetic cannabinoid agonist, and anandamide (10 microM), considered to be the endogenous ligand of cannabinoid receptors, inhibit LTP formation in the Schaffer collateral-CA1 field complex. In addition, we show that SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamide hydrochloride] at 0.1-10 microM, a potent and selective antagonist of CB1 cannabinoid receptors, concentration-dependently reversed the inhibition of LTP induced by both WIN55212-2 and anandamide. These data indicate that cannabinoid receptor agonists inhibit hippocampal LTP formation through CB1 receptor activation and that anandamide could be a candidate for an endogenous neuromessenger involved in memory processes.

Effects of SR 48692, a selective non-peptide neurotensin receptor antagonist, on two dopamine-dependent behavioural responses in mice and rats.

One major mechanism underlying the central action of neurotensin is an interaction with the function of dopamine (DA)-containing neurons. In addition, direct or indirect DA agonists have been reported to promote neurotensin release. We have found that SR 48692, a non-peptide neurotensin receptor antagonist (0.04-0.64 mg/kg orally), antagonizes (50-65%) yawning induced by apomorphine (0.07 mg/kg SC) or bromocriptine (2 mg/kg IP) in rats, and turning behaviour induced by intrastriatal injection of apomorphine (0.25 micrograms), (+) SKF 38393 (0.1 micrograms), bromocriptine (0.01 ng) or (+) amphetamine (10 micrograms) in mice. Other apomorphine-induced effects in mice and rats such as climbing, hypothermia, hypo- and hyper-locomotion, penile erections and stereotypies were not significantly modified by SR 48692. Taken together, these data suggest that neurotensin may play a permissive role in the expression of some but not all behavioural responses to DA receptor stimulation.

The nonpeptide neurotensin antagonist, SR 48692, used as a tool to reveal putative neurotensin receptor subtypes.

The nonpeptide neurotensin (NT) antagonist, SR 48692, was recently shown to inhibit NT binding to the cloned rat and human NT receptor and to antagonize NT effects in a variety of in vitro and in vivo assays. Here, we show that, in contrast to its antagonistic action on NT-induced hypomotility in the rat, SR 48692 failed to antagonize NT-induced hypothermia and analgesia in the mouse and rat. We suggest that these effects might be mediated through a subtype of SR 48692-insensitive NT receptor.

SR 48692, a non-peptide neurotensin receptor antagonist differentially affects neurotensin-induced behaviour and changes in dopaminergic transmission.

Unilateral microinjection of neurotensin in the ventral tegmental area of the rat (2.5 micrograms/0.5 microliter) produced behavioural excitation illustrated by contralateral circling. Given orally, SR 48692, a selective and potent non-peptide neurotensin receptor antagonist, significantly reduced these rotations with a triphasic dose-effect relationship. Inhibition occurred at 0.12 mg/kg; further increases in dose up to 2.5 mg/kg produced no significant antagonism, then at doses > or = 5 mg/kg, a second phase of antagonism was observed. Bilateral injection of neurotensin (0.5 microgram each side) into the nucleus accumbens antagonized the increase in locomotor activity following intraperitoneal injection of amphetamine. Given orally, SR 48692 reduced dose-dependently (0.1-1 mg/kg) these intra-accumbens neurotensin effects. Using high pressure liquid chromatography with electrochemical detection, we showed that microgram amounts of neurotensin injected into the ventral tegmental area increased dihydroxyphenylacetate/dopamine ratios in the nucleus accumbens. Using in vivo voltammetry techniques, we found that the injection of nanogram and picogram amounts of neurotensin in the ventral tegmental area stimulated dopamine efflux in the nucleus accumbens. None of these biochemical changes were affected by SR 48692 (0.1-10 mg/kg). These results indicate complex interactions between neurotensin and the mesolimbic dopamine system. More particularly, the differential ability of SR 48692 to affect neurotensin-evoked behavioural versus biochemical changes supports the concept of neurotensin receptor heterogeneity.

Social olfactory recognition in rodents: deterioration with age, cerebral ischaemia and septal lesion.

Social olfactory recognition in rodents has been shown to assess short-term memory and to be sensitive to cholinergic drugs. It is based on the investigation of a juvenile by an adult rat and is measured by a reduction in duration of exploration during the second of two successive exposures lasting 5min. The present experiments further characterize rodent social recognition in pathophysiological models known to impair memory. Social recognition was distrupted by ageing in both rats and mice, by vincristine-induced septal lesion and by damaging the CA1 hippocampal layer after cerebral ischaemia in rats. These memory deficits could be compensated by reducing the time interval between the two presentations of the juvenile and/or by prolonging the juvenile encounter. Similarly, muscarinic agonists (arecoline, SR 46559A) counterbalanced the memory impairment in the three models. The present results indicate that the hippocampus plays a key role in social recognition. They suggest that in the three pathophysiological models, memory ability is still present although it is of very short duration; however, it can still be improved by pharmacological treatments.

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.

SR 46559A: a novel and potent muscarinic compound with no cholinergic syndrome.

The cholinergic activities of SR 46559A, 3-[N-(2 diethyl-amino-2-methylpropyl)-6-phenyl-5-propyl] pyridazinamine sesquifumarate, have been investigated in vitro and in vivo, in rodents. Using rat brain cortical membranes, SR 46559A was a competitive ligand (Ki = 112 nM) at muscarinic M1 receptors, its affinity for muscarinic M2 (cardiac) and M3 (glandular) receptors being 6-7 times lower. SR 46559A did not interact with brain nicotinic receptors and high affinity choline uptake sites nor did it inhibit brain acetylcholinesterase activity. In contrast to reference muscarinic agonists, SR 46559A (1 mM) did not inhibit the forskolin-induced activation of cAMP synthesis nor did it stimulate phosphoinositides breakdown in various brain preparations. However, this compound enhanced (+67% at 1 mM) diacylglycerol formation in rat striatal miniprisms, an effect fully reversed by atropine. As shown with reference agonists, SR 46559A inhibited (IC50 = 10 microM) the K(+)-evoked release of [3H]GABA from rat striatal slices and reduced at 0.5 and 1 microM, the population spike amplitude of the CA1 pyramidal cells induced by stimulation of the Schaffer's collateral commissural pathway in rat hippocampal slices. In mice, SR 46559A at a near lethal dose (200 mg/kg PO) did not induce the typical cholinergic syndrome nor did it modify at 30 mg/kg PO the oxotremorine-induced hypothermia. Like muscarinic agonists, SR 46559A (1 mg/kg PO) potentiated haloperidol-induced catalepsy in rats and inhibited (ED50 = 0.12 mg/kg PO) rotations induced in mice by intrastriatal injection of pirenzepine.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholinomimetic activities of minaprine.

The cholinomimetic activities of the antidepressant drug minaprine have been investigated, in vitro and in vivo, in rodents. Minaprine, and its metabolite SR 95070B [3-(2-morpholinoethylamino)-4-methyl-6-(2-hydroxyphenyl) pyridazine hydrochloride] selectively displaced [3H]-pirenzepine from its cortical and hippocampal binding sites, and only weakly inhibited the binding of [3H]-N-methylscopolamine in either the rat cerebellum, heart and salivary glands, or the guinea-pig ileum. In mice, none of these drugs induced the typical cholinergic side-effects up to lethal doses. Minaprine and SR 95070B antagonized rotations induced by an intrastriatal injection of pirenzepine in mice, after intraperitoneal and/or oral administration. Minaprine also antagonized atropine-induced mydriasis in mice. Both minaprine and SR 95070B potentiated the tremorigenic effect of oxotremorine without inducing tremor when injected alone. Finally, minaprine and SR 95070B, after parenteral and/or oral injection, antagonized the scopolamine-induced deficit in passive avoidance learning, and enhanced short-term retention in the social memory test, in rats. The muscarinic agonists arecoline, oxotremorine and RS 86 [2-ethyl-8-methyl-2,8 diazaspiro-4,5 decan-1,3 dion hydrobromide], as well as the acetylcholine esterase inhibitors physostigmine and tacrine were active in most of these models. These results indicate that minaprine, and its metabolite SR 95070B, have cholinomimetic activities which could be, at least in part, mediated by their selective affinity for M1 muscarinic receptors. Thus minaprine could represent a potential useful drug for the treatment of senile dementias and cognitive impairments occurring in elderly people.

Specific modulation of social memory in rats by cholinomimetic and nootropic drugs, by benzodiazepine inverse agonists, but not by psychostimulants.

The recognition of an unfamiliar juvenile rat by an adult rat has been shown to imply short-term memory processes. In this study the effect of various psychotropic drugs on this investigatory behaviour was examined. The procedure was as follows: an unfamiliar juvenile rat was placed in the home cage of an adult rat for 5 min. The time spent by the adult rat in investigating the juvenile was recorded. The adult rat was then immediately treated with vehicle or test compounds, and was again exposed for 5 min to the same juvenile 2 h later. At this time point vehicle-treated rats no longer recognized the juvenile rat, i.e. the time of investigation was similar to that observed during the first presentation. Arecoline (1 and 3 mg/kg IP), physostigmine (0.05 and 0.1 mg/kg SC), RS86 (0.5 mg/IP) and nicotine (0.125 and 0.5 mg/kg IP) reduced in a dose-dependent fashion the time spent in investigating the juvenile during the second exposure. This result cannot be attributed to nonspecific effects, since it was not observed when a different juvenile was used for the second exposure. The effect of arecoline was reversed by scopolamine, but not by methylscopolamine. Aniracetam reduced investigatory behaviour at the dose of 50 mg/kg IP. FG 7142 (5 mg/kg IP) and beta-CCM (0.4 mg/kg IP) were also active and their effect was reversed by Ro 15-1788. DL-Amphetamine (0.5 and 1 mg/kg IP), nomifensine (1.25-10 mg/kg IP) and strychnine (0.25 and 0.5 mg/kg IP) were ineffective or reduced this behaviour unspecifically.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of intracerebroventricular pirenzepine on muscarinic discriminations in rats.

In rats, mixed M1/M2 muscarinic ligands induce a discrimination which is of central origin and selectively mediated by either one or both muscarinic receptor subtypes. In the present study we examined the effects of intracerebroventricular (i.c.v.) pirenzepine, a relatively selective M1 receptor antagonist which does not cross the blood-brain barrier, on muscarinic discriminations. Groups of six rats were trained to discriminate, in a two-lever operant task, either 0.062 mg/kg subcutaneous (s.c.) scopolamine or 0.075 mg/kg s.c. oxotremorine. When the rats had been well trained in the procedure, the discriminative effects of various i.c.v. muscarinic ligands were examined. Scopolamine (1.5-12 micrograms i.c.v.), but not pirenzepine (20-40 micrograms i.c.v.), generalized to s.c. scopolamine. Oxotremorine (0.75-6 micrograms i.c.v.) generalized to s.c. oxotremorine. Scopolamine (12 micrograms i.c.v.), but not pirenzepine (20-40 micrograms i.c.v.), antagonized the oxotremorine cue. These results suggest that activation of the M1 receptor is not the prominent component of muscarinic stimulus control.