| risk for developing psychotic disorders, such as schizophrenia.

| In an increasingnumber of countries cannabis has become a legalized drug. The legalization hascaused a more global use of cannabis. Because of the increasing number ofcannabis use in the recent years, there has been made an association betweencannabis use and psychotic illness. There is in an indication that thecannabinoids in the plant activate a certain pathway, AKT pathway, by acting oncannabinoids receptors in dopaminergic brain areas. This process in the brainmight increase the risk for developing psychotic disorders, such asschizophrenia. Since the cannabis use has increased, identifying people who arevulnerable for developing psychosis is important. Here, we review theassociation between the AKT pathway and schizophrenia, the activation of theAKT pathway by cannabinoids and the risk of cannabis-induced psychosis causedby genetic variation in the AKT gene.

 Accordingto Curran et al. (2016) cannabis has been used for many reasons over the past years, medically and for religious purposes all over the world.Even in the pharmacological world it plays a big part, for instance in the treatment of spasticity(Curran et al.

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,2016).  Still the main reason for cannabis use is’pleasure’ also known as being stoned (Curran etal.,2016). Despite the positive effects of this plant there are some adverseconsequences like addiction and increased risk for psychotic disorders(Curran et al.,2016).  Why some individuals develop psychosis while others, who smoke the sameamount ofcannabis, remain well is unknown.   According toDi Forti et al.

(2012) there is some suggestion that theremight be a genetic susceptibility for developing psychotic disorders, like schizophrenia.Since, cannabis has been a legalized drug in many countries, the use ofcannabis increased with it (Curran et al.,2016). Thus, being able to identifythose who carry a genetic risk for developing cannabis-induced psychosis, is beneficialfor the public health (Curran et al.,2016). AKT1 and schizophreniaThe schizophrenia phenotype has been defined by chronic psychosis and functional deterioration(Thaker, 2000).  Weickert etal.

(2003) showed a decrease in activation of the prefrontalcortex (PFC) in schizophrenia patients. The PFC hasbeen implicated with cognitive behavior and executive functions(Weickert et al.,2003).

 There is found an association between schizophrenia and dysregulation ofAKT signaling (a.k.a. PI3K) pathway (Arguello & Gogos,2008). First, some studies found an association between the AKT1 gene andschizophrenia (Arguello & Gogos, 2008). Second, several studiesin schizophrenia brains found reduced AKT1 activity levels(Arguello & Gogos, 2008).

The AKT1 genehasbeen associated with schizophrenia in some but not all studies(Di Forti et al.,2012). There are some suspicious genetic variations of the AKT1gene, one of them is the rs2494732 single-nucleotide polymorphism(SNP) (Di Forti et al.,2012). There are various phenotypes of this SNP. Individuals who carry two copies of the C allele of the rs2494732gene (AKT1 rs2494732 C/C genotype).

 Furthermore, there are individuals that are homozygousT/T rs2494732. There are also heterozygote carriers, C/Trs2494732 namely. Di Forti et al. (2012) found that genetic variationof the AKT1 genotype has an influence on cannabis inducedpsychosis (Figure 1, Di Forti etal.

,2012 p.814). According to Figure  1,carriers with the C/C genotype of the AKT1 rs2494732 SNP havean increased risk for developing psychosis after cannabis use. This suggest a molecular basis for a higher sensitivity to cannabis-inducedpsychosis. Figure 1. Odd ratio (OR) for developingpsychosis after cannabis use on subjects with various AKT1 rs2494732phenotypes.  TheAKT1 gene and dopamineBecause the PFC gets dopaminergic excitation, abnormalities of themesocortical dopamine system have been suggested to has a role in thepathophysiology of schizophrenia (Knabel & Weinberger, 1997).

 The mesocotical dopamine system connects theventral tegmentum area (VTA) to the PFC. AKT (also known as PKB) is a mediator of signal transduction mechanisms mediated by protein phosphorylationand de-phosphorylation (Arguello & Gogos,2008). AKT is athreonine/serine kinase and has three members: AKT1, AKT2 and AKT3.  AKThas different kind of substrates, the mostimportant one is glycogen synthase kinase 3a(GSK-3a) and GSK-3b both substrates are inhibited by AKT(Arguello & Gogos,2008). The AKT pathwaybecomes phosphorylated by two residues, Thr308 and Ser473, and both residuesare needed for full activation of AKT (Llorente, Sanchez &Diaz-Laviada,2003). The AKT1 gene isa possible candidate because it is identified asa mediator downstream of dopamine (DA) receptor 2 (DRD2) (Figure 2, Arguello & Gogos,2008, p. 2019). Studieshave showed that AKT function is essential for controlled dopaminergic transmission and expression ofdopamine associated actions (Di Forti et al.

,2012). The two significant categories ofDA receptors are, the DA receptor 1 (DRD1) and the DA receptor 2(DRD2) (Arguello & Gogos,2008).Moreover, studies with mice lacking the AKT1 gene showed thatin a working memory task, depended on a normal function of PFC,had a more insufficiency of the PFC in result to DRD2agonists (Arguello & Gogos,2008).Figure 2. The regulation of the rs1130233 Aallele through the AKT pathway in dopaminergic brain areas.

A)The 5 single nucleotide polymorphisms (SNPs) that areassociated with schizophrenia The strongest association with schizophrenia, through frontal lobe function had the fourth SNP.The fourth SNP a.k.a. the rs1130233 A allele reduces expression ofAKT1 gene. B) catechol-O-methyltransferase (COMT) gene (Val158) inactivates DA in the cortex.DA activates DRD1 receptor while DA also reduces DRD2 activation.DRD2 inhibits the AKT activity.

 Synaptic growth and transmission are mediated by AKT activity throughthe PI3K substrate by glutamate (GLU), different growth factors(GFs) and GABA. C) These effects onDA regulation and synaptic connectivity could have an impacton the function of cells in neuronal circuitsneeded for cognitive function. The caudate has a partin gating information, which depends on the ventral tegmental area(VTA) and giving access to the working memory, therefore a good connection of the neurons in the PFCare needed. A suggestion is that dopamine from the VTA results in an increase ofDRD2 which leads to psychosis and changes in neuronal connections. Also,a decrease in DRD1 in the PFC can lead to cognitive dysfunctions(Arguello & Gogos,2008). This is an indication of how the AKT1 generegulates in the prefrontal cortex of schizophrenia patients through DAtransmission.