Project Summary

Pablo E. Castillo, M.D., Ph.D., (Independent Investigator 2006) of Albert Einstein College of Medicine of Yeshiva University, will study whether a dysfunction of the endocannabinoid (eCB) signaling system is involved in schizophrenia, as recent research indicates that defects in this system may contribute to the disorder, and other psychiatric disorders. Cannabinoid abuse (marijuana, hashish) is associated with psychotic symptoms and disorders, but the nature of this association remains unclear. Endocannabinoids suppress the release of other neurotransmitters by activating CB1-type cannabinoid receptors on nerve fiber terminals, which can induce short and long-term synaptic depression, with the effects occurring at both excitatory and inhibitory synapses. The main psychoactive component of marijuana, f’9-tetrahydrocannabinol (f’9-THC), produces its effects by activating this CB1 receptor, and these receptors are highly expressed in brain structures related to schizophrenia, such as the hippocampus, prefrontal cortex and ventral striatum. Increasing evidence suggests that marijuana use may induce psychotic states in normal individuals, worsen psychotic symptoms in patients with schizophrenia, and may contribute to the onset of schizophrenia in vulnerable individuals. Dr. Castillo hypothesizes that these actions might be due, at least in part, to a long-term alteration of eCB signaling triggered by exogenous activation of CB1 receptors. Using a rodent model, he will explore this possibility using standard electrophysiological techniques. He will investigate the role of the eCB system in synaptic transmission and plasticity in the prefrontal cortex, he will explore if f’9-THC exposure in young animals has a long-term impact on eCB signaling in the hippocampus and prefrontal cortex, as the earlier the age of first cannabis use, the greater the risk of psychotic outcomes, and he will examine the role of COMT, an enzyme whose mutation is linked to schizophrenia susceptibility, looking for any alteration in eCB signaling in a mouse model with deficient COMT activity. This project may enhance understanding of the pathology of schizophrenia and ultimately contribute to the development of novel treatments.

Program Area: MULTIPLE FOCUS\Mood Disorders/Schizophrenia\Substance Abuse

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