Introduction

Cannabis has been used for many reasons over the past years, like medically and for religious purposes. The many cannabinoids in this plant are now becoming increasingly important in modern medicine, particularly in the treatment of chronic pain and spasticity. A much more widespread global use is for pleasure, called ‘stoned’. Despite its pleasurable effects, there are some adverse consequences of using  this drug, like cognitive impairment and a possible increased risk of psychotic illness. Several, population-based studies show an earlier first episode and a twofold increased in the risk of psychosis with regular cannabis use.  However, the majority of people who use cannabis do not develop psychotic disorders such as schizophrenia, and many people diagnosed with such disorders have never used cannabis. But why is it that certain individuals develop psychosis when others, who smoke similar amount of cannabis, remain well?

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It is well known that cannabis has two main components, 9-THC and CBD. THC is known for its psychosis-like effects and CBD for its antipsychotic effects. Taken together CBD may improve the harmful effects of 9-THC. 

Over the years from research it has been established that individuals with schizophrenia have less function of the prefrontal cortex. 

There is some suggestion that individuals may carry some genetic basis, with certain polymorphisms of the gene encoding AKT1, conferring risk of psychosis following smoking cannabis. Besides that AKT (also known as PKB) signaling pathway has been associated with the pathogenesis of schizophrenia. Studies provided evidence of a decrease in AKT1 mRNA, protein, and activity levels in brains of some individuals with schizophrenia. Pharmacological evidence indicates that antipsychotics can act as enhancers of AKT signaling in vivo and vitro by directly activating AKT. 

 

AKT1 genetic variation and its impact on multiple levels of neuronal function

5 SNPs that are indicated on the AKT1 locus. The fourth SNP that appears in red is the rs1130233 SNP which reduces expression of AKT1. The coding sequencing are in blue and the noncoding sequences are white indicated. AKT is a key for many signaling systems. Dopamine in the cortex is inactivated by COMT and activates DRD1-coupled cAMP signaling whereas DRD2 decrease cAMP levels and inhibits AKT activity via b-arrestin2. GABA, glutamate and various growth GFs also modulate AKT activity via PI3K, resulting in alterations in syntactic growth and transmission. The caudate of the basal ganglia plays a critical role in gating information and restricting access to working, which relies on proper connections among cortical neurons in the PFC. the gating information itself is heeabily dependent on dopamine transmission, which originates from the VTA. One scenario is that sensitization to dopamine via DRD2 may lead to psychotic symptoms and couples with altered neuronal connectivity and decreased DRD1 signaling, also contribute to cognitive dysfunction. 

There has been a founding that people with AKT1 gene variation have a two times increased probability of a psychotic disorder and seven times if using cannabis daily. 
So the main question is does AKT1 genotype induces psychoses like schizophrenia symptoms when smoking cannabis? 

Middendeel

Tan et al.
  Genetic variation of AKT1 may increase risk for psychiatric disorders, such as schizophrenia.

Tan et al. investigated whether genetic variation in the AKT1 gene influences structural and functional measures sensitive to changes in cortical dopamine signaling.
The authors also looked at the 5 AKT1 SNPs  which previously were associated with schizophrenia  like I said in the introduction. For them was the A allele of the AKT1 SNP rs1130233 also the strongest associated  with certain indices of frontal lobe function, such as IQ and executive function. In order to examine more closely how AKT may influence cognition,the authors administered an explicit task of working memory and executive function, the N-back task, which measures the ability to remember and manipulate information in short-term memory. Subjects completed the N-back task while undergoing MRI. Optimal execution of this task critically depends on proper levels of dopamine within the prefrontal cortex: either too much or too little dopamine can impair performance. They found that individuals who carried the AKT1 rs1130233 A allele had relatively inefficient information processing in the prefrontal cortex. To achieve the same level of performance required increased activation of their PFCs.  They found  a possible link between reduced AKT1 function and cognition in humans. This may result from the impact of AKT on dopamine function, its role in establishing cortical connections. They also found AKT1 rs1130233 A alley carries had reduced gray matter volumes of the caudate nucleus of the basale ganglia and the right PFC. These results may indicate how genetic variation of AKT1 may increase risk for psychiatric disorders, such as schizophrenia, which is linked to dopamine and PFC dysfunction. 

PLAATJE 1
Structural neuroimaging. A) Main effects of AKT1 SNP rs1130233 on gray-matter volumes showing reduced volume of the ventral prefrontal cortex and bilateral caudate. 

Ozaita et al. 
Activation of AKT after acute processing of THC in several brain areas. 
Ozaita et al. looked at he intraneuronal signaling pathways activated in vivo by THC. They analyzed the dose dependency of the effect of THC on the phosphorylation of AKT in the hippocampus. They used different group of mice. These mice received THC or its vehicle and the phosphorylation of AKT was examined after 30 min. They focused on four brain areas, hippocampus, cerebellum, striatum and frontal cortex. 

PLAATJE 2
The mice received different dosages: 0.3,1,10 and 20 mg/kg. They found that AKT phosphorylation increased dose dependently, but did not know a further increase at 20. They demonstrated that
acute THC administration in mice activated ATK phosphorylation in the hippocampus, cerebellum, striatum and the frontal cortex. This shows that THC, the main psychoactive component, in cannabis has an impact on the AKT signaling pathway in the brain. 

Morgan et al. 
 AKT1 genotype moderates the acute psychotomimetic effects by smoking cannabis

Morgan et al. examined the gene x cannabis use interaction in a group of health young cannabis users, with no family history of schizophrenia, assessed both at the time of smoking cannabis and when non-intoxicated. They assessed the impact of two loci that have been demonstrated to have an interaction between psychotic symptoms and cannabis, among which the AKT1 rs2494732 loci. There were two separate test days, non-intoxicated and intoxicated. The participants smoked on the intoxicated cannabis till they were ‘stoned’.  At this point, the testing began. They used the psychotomimetic states Inventory, to asses current schizotypal symptoms. Because it has been shown previously to be sensitive to acute cannabis-induced psychotomimetic effects. 

PLAATJE 3
They looked at three phenotypes, homozygoot T, homozygoot C and heterozygoot C. 
The acute psychotic symptoms, in total score when intoxicated with cannabis by AKT1 genotype. They found that the AKT1 genotype variation at the rs2494732 locus to be significant predictor of acute psychotic symptoms associated with cannabis, with increasing C allele to be associated with increasing acute psychotic symptoms induced by cannabis.These data  are important because acute psychotic response to cannabis is thought to be a marker of the risk of developing psychosis from smoking the drug.

Discussie

-In conclusion the main question can be solved: AKT1 genotype induces psychoses-like schizophrenia symptoms when smoking cannabis. 

There are a few things that should be taken in consideration. It is likely that  AKT1 contributes to the psychotogentic effects of cannabis together with other genetic variants, but these studies have not looked at this.  Furthermore the environmental risk factors has not been taken with them. Because there is probably a big difference between daily users of cannabis and less than a weekly use of cannabis. Besides that, in the introduction I said that there was a link between the AKT pathway and the dopaminergic pathway. But ozaita et al, the second studie, suggested that the AKT pathway is a independent pathway of the dopaminergic system. 

Despite all, the AKT1 genotype can be used as a clinically useful test of the risk of cannabis-induces psychosis because there is some evidence that proves that those at risk are more vulnerable. This is useful because in the pharmacological world more and more medicine are being produced with cannabis in them, so for the public health importance. There is more evidence now for the phamalogical research for schizophrenia in the AKT signaling pathway. Furthermore, is it useful to design health and educational campaigns to warn all the young pre-matured adolescent teenagers, who use cannabis. The findings of these studies contributes to a recent and growing body of evidence suggesting that variation at  the ATK1 locus confers detail of the risk of cannabis smoking for schizophrenia. However, the fat that AKT1 is relevant to the biological of psychotic symptoms suggests that this might be a promising direction for treating cannabis-induced psychosis. 

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