GABA Deficits Enhance the Psychotomimetic Effects of Δ9-THC.

Abstract

Emerging evidence supports a number of associations between cannabis and psychosis/psychotic disorders, including schizophrenia. Acute exposure to both cannabis and synthetic cannabinoids (CBs) (including Spice and K2) can produce a range of transient psychotomimetic symptoms, cognitive deficits, and psychophysiological abnormalities that bear a striking resemblance to symptoms of schizophrenia (D'Souza et al, 2004; Radhakrishnan et al, 2014). Furthermore, epidemiologic studies suggest that early and heavy exposure to cannabis confers a higher risk for developing a psychotic disorder such as schizophrenia (Moore et al, 2007). However, only a minority of individuals exposed to CBs appear to be vulnerable to CB-related acute or persistent psychosis outcomes. In individuals with schizophrenia, CBs have been shown to transiently exacerbate symptoms (D'Souza et al, 2005), trigger relapse, and have negative consequences on the course of the illness (Linszen and van Amelsvoort, 2007). A number of lines of evidence suggest that schizophrenia patients are more vulnerable to some of the effects of CBs. In an experience sampling study, schizophrenia patients were more sensitive to the psychosis-inducing effects of cannabis than controls (Henquet et al, 2010). Epidemiologic studies also show that cannabis use is associated with greater negative consequences on the course and expression of schizophrenia (van Os et al, 2002). In an experimental study, despite receiving stable doses of antipsychotic medications and being clinically stable, 80% of schizophrenic patients, but only 25% of controls, experienced clinically significant psychosis (>3 points on the Positive and Negative Syndrome Scale (PANSS) positive subscale) with a low dose of delta-9-tetrahydrocannabinol (THC) (D'Souza et al, 2005). Finally, individuals who are psychosis prone as determined either psychometrically or by family history are more sensitive to the psychosis-inducing effects of cannabis (Arendt et al, 2008; GROUP, 2011). However, the basis of the enhanced vulnerability to the psychosis-inducing effects of CBs in schizophrenia patients is not clear. Several other mechanisms might explain vulnerability to THC effects including polymorphisms of genes for COMT (Henquet et al, 2006), AKT1, and DAT1 (Bhattacharyya et al, 2012, 2014), and γ-aminobutyric acid (GABA) deficits. Furthermore, it is conceivable that combinations of these factors may coexist and have additive or synergistic effects on increasing vulnerability to THC effects. GABA deficits have been observed in the dorsolateral prefrontal cortex in schizophrenia (Lewis et al, 2005), and furthermore, there is important interplay between the CB and GABA systems (Eggan et al, 2010). Indeed, converging lines of evidence, including post-mortem (Lewis et al, 2005), genetic (reviewed by Charych et al, 2009), and brain imaging studies (Busatto et al, 1997; Verhoeff et al, 1999) suggest that dysfunction of the GABA system contributes to the pathophysiology of schizophrenia. Although there is strong support for the existence of a GABA deficit in schizophrenia, the proportion of schizophrenia patients with this deficit is not known. The limited data available suggest that only 50% of schizophrenia patients have lower GABA levels compared with the lowest level found in healthy normal controls (Yoon et al, 2010). In several brain regions, particularly the cerebral cortex and hippocampus, CB1 receptors (CB1-Rs) are present on the axon terminals of cholecystokinin (CCK) containing GABA interneurons that target the perisomatic region of pyramidal cells (PCs) (Eggan et al, 2010). CB1-Rs are activated by endocannabinoids released postsynaptically by depolarized PCs (Wilson and Nicoll, 2002). The activation of CB1Rs inhibits the release of GABA by CCK-basket cells, leading to a disinhibition of postsynaptic PCs (Bartos and Elgueta, 2012; Klausberger et al, 2005). Thus, a CB1-R-mediated braking mechanism regulates the timing and release of GABA, and subsequently the overall inhibitory/excitatory balance in cortical networks (Farkas et al, 2010). This interplay between GABA and CB1-R systems provides a mechanism that could explain the higher vulnerability to CBs in schizophrenia. For instance, if CB1-R activation occurred in the presence of a pre-existing GABA deficit (as might be the case in schizophrenia), this could lead to further disinhibition and desynchronization of PC activity, leading to perturbations in gating, associative functions, and neurocognition, which could culminate in psychotic symptoms. This study tested the hypothesis that if, among other mechanisms, GABA deficits contribute to the increased vulnerability of schizophrenia patients to the psychosis-exacerbating effects of CBs, then inducing a GABA deficit in healthy subjects will increase the psychosis-inducing effects of THC. As described below, a GABA deficit was pharmacologically modeled by the administration of the GABAA inverse agonist, iomazenil.