Experimental evidence indicates that cannabis or ?9-tetrahydrocannabinol (THC) use precipitates psychotic symptoms and is associated with a greater risk to develop schizophrenia and worsen its outcome. These observations led to the formulation of the cannabinoid hypothesis of schizophrenia, which postulates that over-activity of the brain endocannabinoid system may contribute to the etiology of this pathology. Recent studies, however, have challenged this hypothesis: for example, drugs aimed at blocking cannabinoid CB1 receptor activity have failed as antipsychotics in clinical trials. Paradoxically, the endocannabinoid anandamide has been found elevated in the cerebrospinal fluid of drug-nave schizophrenics and negatively correlated with the severity of psychotic symptoms, suggesting that endocannabinoids may have a protective role in schizophrenia. In keeping with this hypothesis, our preliminary experiments carried out in phencyclidine (PCP)-treated rats, an animal model of schizophrenia, showed that systemic administration of URB597 (a drug that elevates brain anandamide by inhibiting its inactivation) reverses PCP-induced behavioral deficits and increases coordinated neuronal activity in the prefrontal cortex (PFC), which is deficient in schizophrenia. The divergent effects of THC versus endocannabinoid-enhancing drugs may be attributable to their distinct properties (i.e., brain-wise versus localized activation of CB1 receptors, respectively). In addition, anandamide has the ability to activate other non-CB1 targets. In this proposal we will use behavioral, electrophysiological and biochemical approaches to test the hypothesis that elevation of endocannabinoid tone alleviates PCP-induced behavioral deficits that model schizophrenic symptoms. We will also investigate whether CB1 receptors are necessary and/or sufficient for the expression of the antipsychotic action of anandamide. There are three specific aims.
In AIM 1, we will assess how THC and endocannabinoid-enhancing drugs affect behaviors relevant to schizophrenia (working memory, social interaction and motor activity) in PCP-treated and normal rats, and analyze their underlying pharmacological mechanisms.
In AIM 2, we will study the effects of these drugs on the activity of coordinated neuronal ensembles and single neuron activity in the PFC of saline- and PCP-treated rats using in vivo electrophysiology.
In AIM 3, we will investigate the effects of the above drugs in the same experimental groups on: (1) endocannabinoid levels, (2) expression and function of CB1 and non-CB1 endocannabinoid-sensitive receptors, and 3) expression and function of endocannabinoid inactivating enzymes, in brain areas relevant to schizophrenia. This study will allow reformulating the cannabinoid hypothesis of schizophrenia to take into account the protective role of endocannabinoids in this disorder, and provide a rationale to design more effective pharmacotherapies for the treatment of psychoses.

Public Health Relevance

Preclinical and clinical studies indicate that cannabis use precipitates psychosis in vulnerable individuals. Paradoxically, the endogenous activators of cannabinoid receptors (endocannabinoids) reduce schizophrenic symptoms. By investigating the mechanisms of action of drugs that elevate endocannabinoid levels in the brain, this proposal will identify new and more effective therapeutic strategies for the treatment of psychoses.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Winsky, Lois M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center
Schools of Medicine
San Antonio
United States
Zip Code
Perez, Stephanie M; Donegan, Jennifer J; Boley, Angela M et al. (2018) Ventral hippocampal overexpression of Cannabinoid Receptor Interacting Protein 1 (CNRIP1) produces a schizophrenia-like phenotype in the rat. Schizophr Res :
Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J (2018) Adolescent Synthetic Cannabinoid Exposure Produces Enduring Changes in Dopamine Neuron Activity in a Rodent Model of Schizophrenia Susceptibility. Int J Neuropsychopharmacol 21:393-403
Seillier, Alexandre; Giuffrida, Andrea (2017) Anxiety does not contribute to social withdrawal in the subchronic phencyclidine rat model of schizophrenia. Behav Pharmacol 28:512-520
Perez, Stephanie M; Aguilar, David D; Neary, Jennifer L et al. (2016) Schizophrenia-Like Phenotype Inherited by the F2 Generation of a Gestational Disruption Model of Schizophrenia. Neuropsychopharmacology 41:477-86
Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J (2016) THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the subchronic PCP model of schizophrenia. J Psychopharmacol 30:169-81
Seillier, Alexandre; Giuffrida, Andrea (2016) Disruption of social cognition in the sub-chronic PCP rat model of schizophrenia: Possible involvement of the endocannabinoid system. Eur Neuropsychopharmacol 26:298-309
Matricon, Julien; Seillier, Alexandre; Giuffrida, Andrea (2016) Distinct neuronal activation patterns are associated with PCP-induced social withdrawal and its reversal by the endocannabinoid-enhancing drug URB597. Neurosci Res 110:49-58
Aguilar, David D; Chen, Li; Lodge, Daniel J (2014) Increasing endocannabinoid levels in the ventral pallidum restore aberrant dopamine neuron activity in the subchronic PCP rodent model of schizophrenia. Int J Neuropsychopharmacol 18:
Seillier, Alexandre; Dominguez Aguilar, David; Giuffrida, Andrea (2014) The dual FAAH/MAGL inhibitor JZL195 has enhanced effects on endocannabinoid transmission and motor behavior in rats as compared to those of the MAGL inhibitor JZL184. Pharmacol Biochem Behav 124:153-9
Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea (2013) Phencyclidine-induced social withdrawal results from deficient stimulation of cannabinoid CB? receptors: implications for schizophrenia. Neuropsychopharmacology 38:1816-24

Showing the most recent 10 out of 12 publications