Current Pharmaceutical Design, 2012, 18, 5113-5130 5113 1873-4286/12 $58.00+.00 © 2012 Bentham Science Publishers The Yin and Yang of Cannabis-induced Psychosis: the Actions of  9 -Tetrahyd- rocannabinol and Cannabidiol in Rodent Models of Schizophrenia J.C. Arnold 1,2,3, *, A.A. Boucher 2 and T. Karl 3,4,5 1 Discipline of Pharmacology, University of Sydney NSW 2006, Australia; 2 Brain and Mind Research Institute, Sydney, NSW 2050, Australia; 3 Schizophrenia Research Institute, Darlinghurst NSW 2010, Australia; 4 Neuroscience Research Australia, Randwick, NSW 2031, Australia; 5 University of New South Wales, Sydney, NSW 2052, Australia Abstract: The link between cannabis and psychosis has often been debated with polarized views on the topic. There is substantial epi- demiological evidence showing that cannabis increases the risk of psychosis, whereas other research suggests that schizophrenia patients self-medicate with the substance. These conflicting accounts may at least be partially explained by the two phytocannabinoids can- nabidiol (CBD) and  9 -tetrahydrocannabinol (THC) and their opposing actions on schizophrenia-related symptoms. In the present review we will first focus on how traditional rodent models of schizophrenia have been used to improve our understanding of the propsychotic actions of THC and the antipsychotic actions of CBD. We will also review novel rodent models used to address genetic vulnerability to cannabis-induced schizophrenia and show that specific genes are being uncovered that modulate cannabinoid action (e.g. the schizophre- nia susceptibility gene neuregulin 1). We will also review rodent studies that have addressed interactions between THC and CBD. These animal studies underscore great complexity with some studies showing that CBD antagonises the neurobehavioural effects of THC, while others show the opposite, that CBD potentiates the actions of THC. Various mechanisms are put forth to explain these divergent effects such as CBD antagonism at central CB1 receptors or that CBD inhibits proteins that regulate THC disposition and metabolism (e.g. the ABC transporter, P-glycoprotein). Keywords:  9 -tetrahydrocannabinol, cannabidiol, schizophrenia, rodent model, CB1, CB2, neuregulin. INTRODUCTION It has been estimated that psychotic disorders affect 3% of the world’s population [1]. Those diagnosed specifically with schizo- phrenia approaches 1%, although there exist a range of related di- agnoses such as schizophreniform disorder, schizoaffective disor- der, delusional disorder and drug-induced psychosis that can also be added to estimates of lifetime prevalence of psychosis. The onset of schizophrenia occurs normally in late adolescence/early adulthood and is characterized by negative symptoms (e.g. social withdrawal), cognitive dysfunction and positive symptoms (e.g. hallucinations and delusions). The chronic nature of schizophrenia makes it one of the leading forms of permanent disability. Since the discovery of typical antipsychotic drugs, the subsequent development of atypical compounds has provided marginal improvement in the treatment of schizophrenia. These agents are variably effective in dampening positive symptoms and 30% of patients remain treatment-resistant [2]. Importantly, antipsychotic drugs are poorly effective in treating cognitive dysfunction and negative symptoms in schizophrenia [3]. Although the exact causes of schizophrenia are still unknown, the role played by cannabis as a major risk factor has been widely debated with polarized views on the topic. For example, there is substantial epidemiological evidence showing that cannabis in- creases the risk of psychosis by at least 2-fold, whereas other re- search suggests that schizophrenia patients self-medicate with the substance to reduce schizophrenia symptoms or to alleviate the side effects of antipsychotic medication. These conflicting accounts may be partially explained by two phytocannabinoids cannabidiol (CBD) and  9 -tetrahydrocannabinol (THC) and their opposing ac- tions on schizophrenia-related symptoms. Indeed much human and animal research is now focussing on these two constituents (see also other papers published in this issue). A growing body of evi- dence indicates that THC increases the risk of anxiety, psychotic symptoms and memory impairment in healthy individuals *Address correspondence to this author at the Discipline of Pharmacology, University of Sydney NSW 2006, Australia; Tel: +61 2 9351 6954; Fax: +61 2 9351 2658; E-mail: jonathon.arnold@sydney.edu.au [4, 5] and those with an established psychotic disorder such as schizophrenia [6, 7]. In contrast, CBD, another major constituent of cannabis that lacks detectable intrinsic psychoactivity, has anx- iolytic [8-10] and possibly antipsychotic properties [11, 12] and does not appear to impair memory or other cognitive functions. Furthermore, when co-administered, CBD can reduce the anxio- genic, memory-impairing and psychotomimetic effects induced by THC [13]. Other papers in the present issue will specifically address the neurobiological effects of cannabinoids on the brain. Functional neuroimaging studies directly comparing THC and CBD found distinct modulatory effects on regional neural responses to fearful faces [14]. Specifically, the authors observed a CBD-induced at- tenuation of neural responses to intensely fearful faces in the amygdala and cingulate cortex, which was correlated with an elec- trophysiological response and behavioural evidence for an anx- iolytic effect. There was also a distinct effect for CBD on the brain connectivity linking these two regions [15]. In a subsequent fMRI study in the same cohort, THC and CBD had opposing effects on striatal activation during verbal recall, on hippocampal activation during response inhibition, on amygdalar activation in response to fearful faces, on temporal activation during an auditory task, and on occipital activation during visual processing [13]. A third experi- ment in the same study showed that pretreatment with CBD pre- vented acute induction of THC-induced psychotic symptoms com- pared to pretreatment with placebo, and suggested that THC and CBD can have opposing effects on regionally-specific brain activa- tion, which may underlie their different symptomatic and behav- ioural effects. Thus, there is converging in vivo evidence supporting a differential neurobiological effect for different cannabinoids in the brain. The present critical review aims at integrating the above evi- dence with findings from animal models. We will specifically focus on rodent studies that have been used to improve our understanding of the propsychotic actions of THC and the antipsychotic actions of CBD. Furthermore, we will carefully overview research that ad- dresses interactions between these major cannabinoid constituents. Send Reprints Orders on reprints@benthamscience.org Send Orders of Reprints at reprints@benthamscience.org