GABA Deficits and Vulnerability to Cannabinoid-Induced Psychosis Cannabinoids (CBs) induce transient psychotic symptoms and cognitive dysfunction in healthy individuals and exacerbate symptoms in schizophrenia patients. However, the latter are more vulnerable to the effects of cannabinoids. The enhanced cannabinoid sensitivity in schizophrenia might be driven by the well documented gamma-amino butyric acid (GABA) receptor deficits in schizophrenia. Converging preclinical evidence suggests important interactions between CB and GABA systems. CB1 receptors (CB1-Rs) are present on the axon terminals of cholecystokinin (CCK) containing GABA neurons that target pyramidal cells. These GABA neurons orchestrate the synchronization of neural activity which is believed to play an important rolein perceptual, memory and attentional processes. Activation of CB1-Rs on the axon terminals of CCK containing GABA neurons reduces GABA release, resulting in disinhibition of pyramidal cell activity. If this were to occur in the presence of a GABA deficit, as might be the case in schizophrenia, this could lead to further disinhibition and desynchronization of pyramidal cell activity, leading to perturbation of gating and associative functions, culminating in psychotic symptoms. Hypothesis: If GABA deficits increase the vulnerability of schizophrenic patients to the effects of cannabinoids, then inducing a GABA deficit in healthy subjects will potentiate the psychotomimetic, amnestic and neural synchrony deficits produced by ?9-THC. We have shown that in healthy individuals 1) ?9-THC induces transient psychosis and memory impairments, 2) both acute and chronic exposure to cannabinoids is associated with alterations in neural synchrony, and 3) GABA deficits produced by iomazenil, enhanced the psychotomimetic effects of a serotonergic agent. Methods: Healthy subjects will complete 4 test days during which they will receive intravenous iomazenil or placebo pretreatment, followed by intravenous ?9-THC or placebo, in a double-blind, randomized, counterbalanced design. Perceptual alterations, psychotic-like symptoms and memory will be assessed. Indices of neural synchrony will be assessed by measurement of EEG spectral power evoked by presentation of auditory click trains at 20, 30 and 40 Hz.

Public Health Relevance

The aim of this project is to evaluate whether a reduction in the principal inhibitory chemical messenger system in the brain, the GABA receptor system, enhances the vulnerability to the psychotomimetic effects of THC, the main active component of cannabis.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Meinecke, Douglas L
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Yale University
Schools of Medicine
New Haven
United States
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Sherif, Mohamed; Radhakrishnan, Rajiv; D'Souza, Deepak Cyril et al. (2016) Human Laboratory Studies on Cannabinoids and Psychosis. Biol Psychiatry 79:526-38
Radhakrishnan, Rajiv; Skosnik, Patrick D; Cortes-Briones, Jose et al. (2015) GABA Deficits Enhance the Psychotomimetic Effects of ?9-THC. Neuropsychopharmacology 40:2047-56
Sewell, R Andrew; Schnakenberg, Ashley; Elander, Jacqueline et al. (2013) Acute effects of THC on time perception in frequent and infrequent cannabis users. Psychopharmacology (Berl) 226:401-13
Spaderna, Max; Addy, Peter H; D'Souza, Deepak Cyril (2013) Spicing things up: synthetic cannabinoids. Psychopharmacology (Berl) 228:525-40