Involvement of the endocannabinoid system in phencyclidine-induced cognitive deficits modelling schizophrenia.
Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and schizophrenia. Our studies showed that chronic-intermittent phencyclidine (PCP) treatment of rats, an animal model of schizophrenia-like cognitive deficit, impaired recognition memory in the novel object recognition (NOR) test and induced alterations in CB1 receptor functionality and in endocannabinoid levels mainly in the prefrontal cortex. In this region, we observed a significant reduction in GTPgammaS binding (-41%) accompanied by an increase in the levels of the endocannabinoid 2-AG (+38%) in PCP-treated rats, suggesting that a maladaptation of the endocannabinoid system might contribute to the glutamatergic-related cognitive symptoms encountered in schizophrenia disorders. Moreover, we evaluated the ability of the main psychoactive ingredient of marijuana, Delta9-tetrahydrocannabinol (THC), to modulate the cognitive dysfunctions and neuroadaptations in the endocannabinoid system induced by PCP. Chronic THC co-treatment worsened PCP-induced cognitive impairment, without inducing any effect per se, and in parallel, it provoked a severe reduction in the levels of the other endocannabinoid, AEA, vs. either vehicle (-73%) or PCP (-64%), whereas it reversed the PCP-induced increase in 2-AG levels. These results point to the involvement of the endocannabinoid system in this pharmacological model of cognitive dysfunction, with a potentially different role of AEA and 2-AG in schizophrenia-like behaviours and suggest that prolonged cannabis use might aggravate cognitive performances induced by chronic PCP by throwing off-balance the endocannabinoid system.
Vigano
Daniela
D
DBSF and Neuroscience Center, University of Insubria, Busto Arsizio (VA), Italy.
Guidali
Cinzia
C
Petrosino
Stefania
S
Realini
Natalia
N
Rubino
Tiziana
T
Di Marzo
Vincenzo
V
Parolaro
Daniela
D
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism*; D004195:Disease Models, Animal; D063388:Endocannabinoids; D008297:Male; D010622:Phencyclidine / Q000633:toxicity*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism*
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D010622:Phencyclidine