Cariprazine, a dopamine D(3)-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse.
BACKGROUND
A major challenge in the pharmacological treatment of psychotic disorders is the effective management of the associated cognitive dysfunctions. Novel concepts emphasize a potential benefit of partial agonists acting upon dopamine D(2)-like receptors in ameliorating these cognitive deficits, and pre-clinical studies suggest that D(3)-receptor-preferring compounds can exert pro-cognitive effects.


OBJECTIVE
The objective of the study was to use acute phencyclidine (PCP) treatment to model the cognitive deficits of schizophrenia in mice, and to test the efficacy of the novel, dopamine D(3)-receptor-preferring drug cariprazine in ameliorating the severity of PCP-triggered cognitive deficits.


METHODS
One group of wild-type or D(3)-receptor knockout mice was acutely treated with either saline or phencyclidine (PCP, 1 mg/kg). A separate group of mice was treated with cariprazine prior to PCP administration. Both groups were then tested in three cognitive tasks: social interaction/recognition and recognition memory, spatial working memory, and attention-set-shifting.


RESULTS
PCP effectively disrupted social recognition and social recognition memory, spatial working memory, and extradimensional attention set-shifting. Cariprazine pretreatment significantly attenuated the emergence of these cognitive deficits in PCP-treated wild-type mice, but not in PCP-treated D(3)-receptor knockout mice.


CONCLUSIONS
In an animal model of PCP-induced cognitive impairment, cariprazine pretreatment significantly diminished PCP-triggered cognitive deficits, and studies on knockout mice show that dopamine D(3) receptors contribute to this effect.
Department of Psychiatry, Columbia University, New York, NY, USA.
Ross
R
Zimnisky
Gloria
G
Chang
István
I
Gyertyán
Béla
B
Kiss
Nika
N
Adham
Claudia
C
Schmauss
D000704:Analysis of Variance; D000818:Animals; D001288:Attention / Q000187:drug effects*; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D054333:Drug Partial Agonism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D061212:Memory, Episodic; D008570:Memory, Short-Term / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010622:Phencyclidine / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects*; D012718:Set, Psychology
D010879:Piperazines; D050637:Receptors, Dopamine D3; C533287:cariprazine; D010622:Phencyclidine