THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the subchronic PCP model of schizophrenia.
Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the cerebrospinal fluid levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid-enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared with THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach.
Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center San Antonio, San Antonio, TX, USA aguilardd@livemail.uthscsa.edu.
David D
DD
Aguilar
Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center San Antonio, San Antonio, TX, USA.
Andrea
A
Giuffrida
Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center San Antonio, San Antonio, TX, USA.
Daniel J
DJ
Lodge
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D004195:Disease Models, Animal; D013759:Dronabinol / Q000008:administration & dosage / Q000494:pharmacology*; D063388:Endocannabinoids / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010622:Phencyclidine / Q000633:toxicity; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000503:physiopathology*; D015854:Up-Regulation / Q000187:drug effects
D001095:Arachidonic Acids; D001549:Benzamides; D002219:Carbamates; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; D013759:Dronabinol; D010622:Phencyclidine; C078814:anandamide
THC; electrophysiology; endocannabinoids; prefrontal cortex; schizophrenia; ventral hippocampus