MK-801-induced deficits in social recognition in rats: reversal by aripiprazole, but not olanzapine, risperidone, or cannabidiol.
Deficiencies in social activities are hallmarks of numerous brain disorders. With respect to schizophrenia, social withdrawal belongs to the category of negative symptoms and is associated with deficits in the cognitive domain. Here, we used the N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) for induction of social withdrawal in rats and assessed the efficacy of several atypical antipsychotics with different pharmacological profiles as putative treatment. In addition, we reasoned that the marijuana constituent cannabidiol (CBD) may provide benefit or could be proposed as an adjunct treatment in combination with antipsychotics. Hooded Lister rats were tested in the three-chamber version for social interaction, with an initial novelty phase, followed after 3 min by a short-term recognition memory phase. No drug treatment affected sociability. However, distinct effects on social recognition were revealed. MK-801 reduced social recognition memory at all doses (>0.03 mg/kg). Predosing with aripiprazole dose-dependently (2 or 10 mg/kg) prevented the memory decline, but doses of 0.1 mg/kg risperidone or 1 mg/kg olanzapine did not. Intriguingly, CBD impaired social recognition memory (12 and 30 mg/kg) but did not rescue the MK-801-induced deficits. When CBD was combined with protective doses of aripiprazole (CBD-aripiprazole at 12 :  or 5 : 2 mg/kg) the benefit of the antipsychotic was lost. At the same time, activity-related changes in behaviour were excluded as underlying reasons for these pharmacological effects. Collectively, the combined activity of aripiprazole on dopamine D2 and serotonin 5HT1A receptors appears to provide a significant advantage over risperidone and olanzapine with respect to the rescue of cognitive deficits reminiscent of schizophrenia. The differential pharmacological properties of CBD, which are seemingly beneficial in human patients, did not back-translate and rescue the MK-801-induced social memory deficit.
aSchool of Medical Sciences, Institute of Medical Sciences, Foresterhill, Aberdeen, Scotland bGW Research Ltd, Sovereign House, Vision Park, Histon, Cambridgeshire, UK cQs' Research Institute, Otsuka Pharmaceutical Co. Ltd, Tokushima, Japan.
Serena
S
Deiana
Akihito
A
Watanabe
Yuki
Y
Yamasaki
Naoki
N
Amada
Tetsuro
T
Kikuchi
Colin
C
Stott
Gernot
G
Riedel
D000818:Animals; D000068180:Aripiprazole / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002185:Cannabidiol / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects*; D023421:Models, Animal; D000077152:Olanzapine; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D021641:Recognition, Psychology / Q000187:drug effects*; D018967:Risperidone / Q000494:pharmacology*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D012919:Social Behavior
D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists; D001569:Benzodiazepines; D002185:Cannabidiol; D016291:Dizocilpine Maleate; D000068180:Aripiprazole; D018967:Risperidone; D000077152:Olanzapine