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.
BACKGROUND
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.


OBJECTIVE
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.


CONCLUSIONS
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.
Terranova
J-P
JP
Sanofi-Synthelabo Recherche, CNS Research, 371 Rue du Pr Blayac, 34184 Montpellier, France. jean-paul.terranova@sanofi-aventis.com
Chabot
C
C
Barnouin
M-C
MC
Perrault
G
G
Depoortere
R
R
Griebel
G
G
Scatton
B
B
D000367:Age Factors; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects*; D003024:Clozapine / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D004146:Dioxanes / Q000008:administration & dosage / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects*; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008297:Male; D010622:Phencyclidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000502:physiology; D021641:Recognition, Psychology / Q000187:drug effects; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D012919:Social Behavior; D013619:Tacrine / Q000494:pharmacology; D014326:Tropanes / Q000008:administration & dosage / Q000494:pharmacology*
C480819:(3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride; D004146:Dioxanes; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists; D014326:Tropanes; D044282:Receptor, Serotonin, 5-HT1A; D013619:Tacrine; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol; D007099:Imipramine; D003913:Dextroamphetamine