AKT1 genotype induces psychosis-like schizophrenia symptoms when smoking cannabis. Introduction Cannabis Cannabis has been used for many reasons over the past years, medically and for religious purpose all over the world (Curran et al. (2016)). Even in the pharmacological world it plays a big part, for instance in the treatment of spasticity. Still the main reason for cannabis use is ‘pleasure’ also known as being stoned. Individuals who are stoned experience this event different but it mostly includes: the tendencies to eat, giggle a lot and a heightened awareness of music and/or colour. Despite all the positive effects (like calming the tremor by Huntington diseases or prevent/treat the eye disease glaucoma) of this plant there are a few adverse consequences, such as addiction, developing psychosis and cognitive impairment. Although cannabis is considered as a ‘soft drug’, addiction is still a big problem just like increased risk of psychotic illness. Not many people have psychotic effects after using cannabis or do not develop psychotic disorders such as schizophrenia. Why some individuals develop psychosis while others, who smoke the same amount of cannabis, remain well is unknown. There is some suggestion that young people who are vulnerable, by carrying a genetic susceptibility, to psychosis develop disorders too. Identifying the suspected genes would be of considerable public health importance, since the ingriedents of cannabis are becoming increasingly important in the pharmalogical world. AKT1 and schizophrenia The schizophrenia phenotype has been defined by chronic psychosis and functional deterioration. There are some finding that suggested a decrease in activation of the PFC. There is an association between schizophrenia and dysregulation of AKT signaling (a.k.a. PI3K) pathway. This is an interesthing gene because it has a role in risk of schizophrenia especially by cannabis use. AKT has multipele substrates, the most important one is glycogen synthase kinase 3a (GSK-3a) and GSK-3b. Both subtrates are inhibited by AKT in response to different external cellular stimuli. AKT1 and GSK-3 are known to be the framework of a signal transduction what is initiated by dopamine D2 signaling. Some pharmacological evidence indicates that several anti-psychotic can act as AKT signaling enhancers by activating AKT or by increasing the phosphorylation of its substrates GSK-3a/b. Second, several studies have found in individuals with schizophrenia reduced AKT1 mRNA and activity levels. There are some suspecious genetic variation of the AKT1 gene, one of them is the rs2494732 SNP. There are various phenotypes of this SNP. Individuals who carry two copies of the C allele of the rs2494732 gene (AKT1 rs2494732 C/C genotype). Furtermore there are individuals that are homozygoot T/T rs2494732. Besides them there are also individuals heterozygoot carriers C/T rs2494732 namely. Di Forti et al. Found that the differences at the rs2494732 locus of the AKT1 playes a role in the influence of the risk of cannabis use in causing psychosis. Their foundings found that the C/C genotype of the AKT1 rs2494732 locus moderates a role on the effect of cannabis use in increasing the risk of a psychotic disorder. This suggest a molecular basis for a higher sensitivity to cannabis for people with schizophrenia and those at risk. PLAATJE 1 The AKT1 gene and dopamine The AKT1 gene has been associated with schizophrenia in some but not all studies Over the past years it has been estabilised that schizophrenia patients have less function of the prefrontal cortex. The prefrontal cortex has been implicated with cognitve behavior and exectuve functions. Going on, AKT ( also known as PKB) is a mediator of signal tranduction mechanisms mediated by protein phosphorylation and dephosphorylation. The AKT gene has three members: AKT1,AKT2 and AKT3. AKT has multipele substrates, the most important one is glycogen synthase kinase 3a (GSK-3a) and GSK-3b. Both subtrates are inhibited by AKT in response to different external cellular stimuli. AKT1 gene is a possible candidate because in the striatum it codes for a protein kinase that forms an integral part of the dopamine receptor. AKT is identified as a mediator downstream of dopamine (DA) receptor 2 (DRD2). Studies have showed that AKT function is essential for controled dopaminergic transmission and expression of DA-associated actions in different ways from cAMP-dependent signaling. Furtermore the studies showed that DRD2 class receptors are important for the inhibition of AKT by DA. The two significant categories of DA receptors are, the DA receptor 1 (DRD1) and the DA receptor 2 (DRD2). Both these receptors are mediated by decreases and increases in cAMP levels. Moreover, mice laking the AKT1 gene showed a more explicited insufficiency in result to DRD2 but not DRD1 agonists in working memory exames that depend on normal function of prefrontal cortex (PFC). PLAATJE2 The functional impairments resulting from the SNP4-dependent attenuation of AKT1 expression and signaling. A) The 5 single nucleotide polymorphisms (SNPs) that are examined in the studie of Emamian et al. And Tan et al. The strongest association with schizophrenia, through frontal lobe function had the fourth SNP. The 4 SNP a.k.a the rs1130233 A allele reduces expression of AKT1. B) COMT inactivates DA in the cortex. DA activates DRD1 coupled cAMP signaling while DA also reduces DRD2 cAMP levels and inhibites AKT activity via b-arrestin2. Synaptic growth and transmission is mediated by AKT activity through PI3K by glutamate (GLU), different growth factors (GFs) and GABA. C) These united effects on DA regulation and snyaptic connectivity could have an impact on the function of cells in neuronal circuits crucial for the cognitive function. The basale ganglia and the caudate have a part in gating information, which dependants on the ventral tegmental area (VTA) and giving access to the working memory, therefore a good connection of the neurons in the PFC is neseccary. A suggestion is that dopamine from the VTA resulting in an increase of DRD1 which leads to psychosis and changes in neurnonal connection. Also, a decrease in DRD1 in the PFC can lead to cognitive dyfsunction. AKT1 pathway and the endocannabinoid system In dopaminergic areas there are cannabinoid receptors. ?9-THC inhibits through cannabinoid receptor 1 activation of the release of glutamate onto gamma neurons that project from the nucleus accumbent to the VTA (Arguello et al. (2008)) This causes increased dopamine release in the striatum, which is implicated in the pathogenesis of psychotic symptoms. The endocannabinoid system (eCBs) is a biological system composed of endocannabinoids that bind to the cannabinoid receptors. There are two main cannabinoid receptors: CB1 and CB2, which are G-protein coupled receptors. ?9-THC and other CB1R agonists change brain levels of eCBs. eCBs are endogenous lipids-based retrograte neurotransmitters that has a part in physiological processes such as motivation,emotional homeostatis, reward, pain processing and synaptic plasticity for learning and memory. ?9-THC has been found to disrupt long-term potentiation (LTP; a model for memory and learning) and long-term depression (LTD). In animal models the effects of cannabis were the high density of cannabinoid receptors in memory-associated regions such as PFC,hippocampus and amygdala. ?9-THC causes disruptions of LTP and LTD in the hippocampus. Furtermore, acute ?9-THC caused impairment of behavioural inhibition and enhances inpulsivity. Although the acute effects vary among individuals because of their tolerance. Tolerance is depending on an individual’s previous level of cannabis use. CB1R downregulation in chronic cannabis users has been found. The reward system function in the rodent brain, non-human primates, is increased by low doses of ?9-THC, while higher doses and more-potent CB1R agonists can reduce the reward-system function. PLAATJE 3 The dense CB1R expresssion in PFC,amygdala and hippocampus (HIPP) regions underlies the effects of cannabis and CB1R agonists on memory and cognitive function. PLAATJE 4 Acute exposure to cannabis on reward-and cognition related circuits Acute cannabis on CB1R agonist causes neurochemical processes in the mesolimbic system that are the same to those produced by other drugs of abuse, including enhanced DA release and a decrease of GABA and GLU release in the NAc. Disruptions in cognitive functions result from: reduced acetylcholine (ACh) release in the PFC and HIPP and decreased GABA release and enhanced Glu release in the PFC, and enhanced noradrenaline (NA) release in HIPP and frontal cortical areas. Chronic ?9-THC or CB1R agonist results in: reduced CB1R expression and function levels in cortical regions. Also rapid and profound reduces in the hippocampus and layer VI of the frontal cortex, which are consistent with cognitive impairments and memory associated with chronic cannabis use in humans. Chronic ?9-THC disrupts reward-related signaling mechanisms in the mesolimbic system by decreaed DA cell density in the VTA. Cannabis components Cannabis has two big active components namely THC and CBD. It is known that these two components have opposite effects. For instance, CBD can increase learning and has anti-anxiety and antipsychotic characteristics. Whereas ?9-THC intensely weaken learning, increases anxiety and produces psychosis-like effects. So, it is mostly the ?9-THC component in cannabis which increases the psychosis effects unlike the CBD component which reduces the psychosis effects (Di Forti et al). Over the past years, the ?9-THC percentage of the street cannabis has increased a lot, while the CBD percentage had decreased to insignificantly levels. For instance in Europa, cannabis contains ~ 15% ?9-THC and less than 0.1% CBD. Therefore the chances of developing psychotic disorders by smoking cannabis have probably increased over the years if the THC:CBD ratio now also has increased. In vivo studies found that ?9-THC can cause phosphorylation of the AKT1 with its activation in brain areas like the striatum. It is plausible that ?9-THC might enhance the responsebility to psychosis via the AKT1/GSK-3 cascade because it has an impact on D2 receptor signaling.There has been a founding that people with AKT1 gene variant have two times increased probability of a psychotic disorder and seven times if using cannabis daily (di Forti). Since the need to treat cannabis-induced psychosis has been growing. To be able to treat this, first of all the relevance of AKT1 gene in the biologly of psychotic symptoms should be understood. The aim of this review is to understand that. First of all, the influence of AKT1 genotype on schizophrenia. Second, the activation of AKT pathway in the brain induced by THC. Last of all, AKT1 gene variation may increase cannabis-induced psychosis. So in the end the main qeustion can be solved: Does AKT1 genotype induces psychosis-like schizophrenia symptoms when smoking cannabis?