AKT1 of the increasing number of cannabis use

 AKT1 genotype induces psychosis-like schizophrenia symptoms when smoking


Abstract| In an increasing
number of countries cannabis has become a legalized drug. The legalization has
caused a more global use of cannabis. Because of the increasing number of
cannabis use in the recent years, there has been made an association between
cannabis use and psychotic illness. There is in an indication that the
cannabinoids in the plant activate a certain pathway, AKT pathway, by acting on
cannabinoids receptors in dopaminergic brain areas. This process in the brain
might increase the risk for developing psychotic disorders, such as
schizophrenia. Since the cannabis use has increased, identifying people who are
vulnerable for developing psychosis is important. Here, we review the
association between the AKT pathway and schizophrenia, the activation of the
AKT pathway by cannabinoids and the risk of cannabis-induced psychosis caused
by genetic variation in the AKT gene.


to 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.,2016).  Still the main reason for cannabis use is
‘pleasure’ also known as being stoned (Curran et
al.,2016). Despite the positive effects of this plant there are some adverse
consequences like addiction and increased risk for psychotic disorders
(Curran et al.,2016).  Why some individuals develop psychosis while others, who smoke the same 

amount of
cannabis, remain well is unknown.   According to
Di Forti et al. (2012) there is some suggestion that there
might be genetic susceptibility for developing psychotic disorders, like schizophrenia.
Since, cannabis has been a legalized drug in many countries, the use of
cannabis increased with it (Curran et al.,2016). Thus, being able to identify
those who carry a genetic risk for developing cannabis-induced psychosis, is beneficial
for the public health (Curran et al.,2016).


 AKT1 and schizophrenia  

The schizophrenia phenotype has been defined by chronic psychosis and functional deterioration
(Thaker, 2000).  Weickert et
al. (2003) showed a decrease in activation of the prefrontal
cortex (PFC) in schizophrenia patients. The PFC has
been implicated with cognitive behavior and executive functions
(Weickert et al.,2003). There is found an association between schizophrenia and dysregulation of
AKT signaling (a.k.a. PI3K) pathway (Arguello & Gogos,
2008). First, some studies found an association between the AKT1 gene and
schizophrenia (Arguello & Gogos, 2008). Second, several studies
in schizophrenia brains found reduced AKT1 activity levels
(Arguello & Gogos, 2008). The AKT1 gene
been associated with schizophrenia in some but not all studies
(Di Forti et al.,2012). There are some suspicious genetic variations of the AKT1
gene, 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 rs2494732
gene (AKT1 rs2494732 C/C genotype). Furthermore, there are individuals that are homozygous
T/T rs2494732. There are also heterozygote carriers, C/T
rs2494732 namely. Di Forti et al. (2012) found that genetic variation
of the AKT1 genotype has an influence on cannabis induced
psychosis (Figure 1). According to
Figure  1, carriers with the C/C genotype
of the AKT1 rs2494732 SNP have an increased risk for
developing psychosis after cannabis use(Di Forti et al.,2012 p.814) . This suggest a molecular basis for a higher sensitivity to cannabis-induced



Figure 1. Odd ratio (OR) for developing
psychosis after cannabis use on subjects with various AKT1 rs2494732



AKT1 gene and dopamine 

Because the PFC gets dopaminergic excitation, abnormalities of the
mesocortical dopamine system have been suggested to has a role in the
pathophysiology of schizophrenia (Knabel & Weinberger, 1997).  The mesocotical dopamine system connects the
ventral tegmentum area (VTA) to the PFC. AKT (also known as PKB) is a mediator of signal transduction mechanisms mediated by protein phosphorylation 

and de-phosphorylation (Arguello & Gogos,2008). AKT is a
threonine/serine kinase and has three members: AKT1, AKT2 and AKT3.  AKT
has different kind of substrates, the most
important one is glycogen synthase kinase 3a
(GSK-3a) and GSK-3b both substrates are inhibited by AKT
(Arguello & Gogos,2008). The AKT pathway
becomes phosphorylated by two residues, Thr308 and Ser473, and both residues
are needed for full activation of AKT (Llorente, Sanchez &
Diaz-Laviada,2003). AKT1 gene is
a possible candidate because it is identified as
a mediator downstream of dopamine (DA) receptor 2 (DRD2) (Figure 2, Arguello & Gogos,2008, p. 2019). Studies
have showed that AKT function is essential for controlled dopaminergic transmission and expression of
dopamine associated actions (Di Forti et al.,2012). The two significant categories of
DA 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 that in a working memory task, depended
on a normal function of PFC, had a more insufficiency of the PFC in result to DRD2
agonists (Arguello & Gogos,2008).

Figure 2. The regulation of the rs1130233 A
allele through the AKT pathway in dopaminergic brain areas.  

A)The 5 single nucleotide polymorphisms (SNPs) that are
associated 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 of
AKT1 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 is mediated by AKT activity through
the PI3K substrate by glutamate (GLU), different growth factors
(GFs) and GABA. C) These effects on
DA regulation and synaptic connectivity could have an impact
on the function of cells in neuronal circuits
needed for cognitive function. The caudate has a part
in 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 PFC
are needed. 


See figure 2. A suggestion is that dopamine from the VTA results in an increase of
DRD2 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 how the AKT1 gene regulates in the
prefrontal cortex of schizophrenia patients through DA transmission.


Cannabis components  

According to Curran
et al. (2016) cannabis
has two big active components namely THC and CBD.
Furthermore, these two components have opposite effects
(Curran et al.,2016). For instance,
CBD can increase learning and has
anti-anxiety and antipsychotic characteristics. Whereas ?9-THC intensely weakens learning, increases anxiety and
is pro-psychosis. There is
a suggestion that 9-THC might activate the AKT pathway, which causes
cannabis-induced psychosis (Di Forti et al.,2012). A study showed that people with AKT1
gene variation have two times increased probability of
a psychotic disorder and seven times if using cannabis daily (Di
Forti et al.,2012).  

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
(Curran et al.,2016).
Therefore the chances of developing psychotic disorders by smoking
cannabis have probably increased over the years if the THC:
CBD ratio also has increased.  




 AKT1 pathway and the endocannabinoid system 

In dopaminergic
pathways essential for schizophrenia there are found cannabinoid receptors
(Fitzgerald, Shobin & Pickel,2012).

?9-THC inhibits through cannabinoid receptor
1 activation the release of glutamate neurons that project from the nucleus
to the VTA (Arguello & Gogos,2008) This causes increased dopamine
in the striatum, which is implicated in the pathogenesis of psychotic symptoms
(Arguello & Gogos, 2008). The endocannabinoid system
(eCBs) is a biological system composed of endocannabinoids that bind to the cannabinoid receptors
(Curran et al.,2016). There are two main cannabinoid receptors:
CB1(CB1R) and CB2 (CB2R) (Curran et al.,2016).  ?9-THC and other CB1 agonists change brain levels of eCBs
(Curran et al.,2016). The eCBs has a part in physiological processes such as motivation,
emotional homeostasis, reward, pain processing and synaptic plasticity for learning and memory
(Curran et al.,2016).  Chronic cannabis use causes decreases in CB1
density in reward, cognition and habit related circuits (Figure 3, Curran et al.,2016, p. 296).

Figure 3. Exposure to cannabis
on reward-and cognition related circuits 

A) Acute
cannabis: causes neurochemical processes in the mesolimbic system
such as increased DA release and a decrease of GABA and GLU release in the nucleus
accumbens (NAc). Disruptions in cognitive functions results from: reduced acetylcholine
(ACh) release in the PFC and hippocampus (HIPP) and decreased GABA
release and enhanced Glu release in the PFC, and enhanced noradrenaline
(NA) release in
HIPP and frontal cortical areas.  

B) Chronic ?9-THC:
results in reduced CB1R expression and function levels in cortical regions. 
Chronic ?9-THC disrupts rewardrelated signaling mechanisms in the mesolimbic system by decreased DA cell density in the VTA.  


Since the need to
identify the genes underlying the cannabis-induced psychosis has increased
(Di Forti et al.,2012). To be able to this, first of all the relevance of the
AKT1 gene in the biology of psychotic symptoms should be understood. The aim of this review is to

 understand that.
 To begin with the influences of
AKT1 genotype on schizophrenia. Second, the activation of
AKT pathway in the brain regulated by the eCBs system. Last
of all, cannabis-induced psychosis by AKT1 genetic variation. Thus, in the end the main question can be solved: Does
the AKT1
genotype induces psychosis-like schizophrenia symptoms when smoking


The AKT1
genotype could be a potential schizophrenia susceptibility gene.


Hall, Birnbaum, Karayiorgou and Gogos (2004) showed that the pathogenesis of
schizophrenia were provided by AKT1 signaling pathway. They used several
variations of kinases that were implicated in synaptic plasticity that are
expressed in various cell types such as peripheral blood lymphoctes. Their
first results showed that individuals with schizophrenia had 68% lower levels
of AKT1 kinases than controls, in contrast with the other protein kinases. They
found reduced AKT1 levels in the frontal cortex and lymphocytes in
schizophrenia patients. Second, they found 5 SNPs of the AKT1 locus in 268
families (a total of 335 schizophrenia patients) that were associated with
schizophrenia. These 5 SNPs markers were also associated with frontostriatal
dopaminergic system in healthy individuals by Tan et al. (2008). They found
that genetic variation of AKT1 may be linked to dopamine-associated prefrontal
cortical function and structure. They found the strongest association with
frontal lobe function with the A allele of the AKT1 SNP rs1130233. To measure
the cortical structural and functional changes in DA signaling, the subjects
had to perform a task (which is linked to cortical DA function) while undergoing
functional magnetic resonance imaging scanner (fMRI). They found that carriers of
the A allele had reduced information processing in the PFC. On top of that,
carriers had also reduced gray-matter volume in the right PFC and the caudate
nucleus.  Besides the AKT1 gene that has
been associated with schizophrenia there are more genes, like the
dystrobrevin-binding protein 1 (DTNBP1). Dysbindin is believed to play a role
in synaptic plasticity and signal transduction. Numakawa et al. (2004) showed
that the phosphorylation levels of AKT were suppressed by the downregulation of
dysbindin expression. They examined the neurotrophic effect through AKT
signaling pathway as a function of dysbindin. They showed that overexpression
of dysbindin resulted in activation of AKT. A PI3 kinase inhibitor, LY294002, inhibited
the activation of AKT by the overexpression of dysbindin. Their data implicates
that AKT signaling in schizophrenia patients might be due to reduced expression
of dysbindin.



psychosis modulated by genetic variation of AKT1

polymorphism of AKT1 are examined by different studies. The polymorphism may be
not the same but they are all from the AKT1 locus and showed that genetic
variation of AKT1 increases the cannabis-induced psychosis.


The same SNP
used by Di Forti et al. (2012) was used by Van Winkel et al. (2011). They found
that the rs2494732 polymorphism in AKT1 moderated the risk for psychotic
disorders following cannabis use. They found that the combined cannabis use and
the risk-increasing effects of AKT1 rs2494732 C/C genotype may be accompanied
by selective changes in sustained attention. They investigated this in
schizophrenia patients with past but not current cannabis use. The results showed
that among schizophrenia patients who used cannabis, participants with the AKT1
rs2494732 C/C genotype performed significantly worse on a test of sustained
attention compared with individuals with T/T genotype.


Freeman, Powell and Curran (2016) examined if this rs2494732 polymorphism also
is indicative of risk in individuals with no family history of schizophrenia,
assessed both at the time of smoking cannabis and not intoxicated. They showed
that the AKT1 rs2494732 C allele was associated with increased psychotic
symptoms after smoking cannabis, in healthy individuals. They examined the
acute psychotic symptoms induced by cannabis and one time including THC : CBD
ratio. These data indicate that acute psychotic response to cannabis are predicted
by variation at rs2494732 locus of the AKT1 genotype.


for the same SNP that Tan et al. (2008) investigated, Bhattacharyya et al.
(2012) found that healthy individuals carrying the AKT1 rs130233 genotype have
an increased sensitivity to the psychotic effects of 9-THC. They examined the
subjects while performing a verbal learning task inside a MRI, after acute
effects of 9-THC. They found an association of the AKT1 gene and the increase
of psychotic symptoms induced by 9-THC. Furthermore, they found a decrease in
the striatal and midbrain activation after acute administration of 9-THC.



activation of AKT pathway is regulated by cannabinoids (receptors) in the


Puighermanal and Maldonado (2007) showed activation of AKT in the brain after
acute administration of THC, which was mediated by CB1 receptors. They used
groups of mice, who received different doses of THC. The results showed that
AKT phosphorylation(inactivation) increased dose dependently (figure 4, Ozaita et al.,2007,1109 ). Furthermore,
administration of the cannabinoid antagonist stopped the enhanced
phosphorylation of AKT kinase induced by THC. These results show the
involvement of the CB1 receptor in the activation of AKT pathway.


Gomez del
Pulgar, Velasco and Guzman (2000) found that the activation of AKT may be
modulated by CB1 receptor. They used Chinese hamster ovary (CHO) cells, which
were transfected with CB1 cannabinoid receptor cDNA. These cells were for
different times treated with THC. The results showed that THC induced a
time-dependent stimulation of AKT. These data demonstrate the involvement of
the CB1 receptor in the THC-induced stimulation of AKT.  Not only the CB1 receptor has a role in the
AKT pathway. Sanchez, Ruiz-Llorente et al. (2003) showed that THC induced the
activation of the AKT pathway through CB1 and CB2 receptors. The results showed
that THC induced an enhanced phosphorylation of Thr308 –AKT and Ser473-AKT. To
examine the role of cannabinoid receptors in AKT pathway, they used CB1 and CB2
antagonists. They investigated that both antagonists were able to inhibit the
cannabinoid-induced phosphorylation of AKT. These data may indicate that the
AKT pathway is activated by the cannabinoid receptors, CB1 and CB2. In addition,
Molina-Holgado et al. (2004) found that the activity of the AKT pathway was
modulated by the CB1 and CB2 receptors. To examine the contribution of the
cannabinoid receptors they used CB1 and CB2 antagonist. Also, as a marker of
AKT activity they used phosphorylation of S473.The results showed that both the
antagonist prevented the phosphorylation of AKT S473.


Figure 4. AKT phosphorylation % increases
doses dependently after administration of acute THC.

From 1 THC
(mg/Kg) till 20 THC (mg/Kg), there is a significant increase in p-AKT % of




sub-questions have been answered. There could be suggested that the AKT1
genotype is a potential schizophrenia susceptibility gene. In addition, there
is evidence that the activation of AKT pathway is regulated by cannabinoids
(receptors) in the brain. Furthermore, there is a great chance that genetic
variation of AKT1 may increase cannabis-induced psychosis. Finally, the main
question can be answered: the AKT1 genotype induces psychosis-like
schizophrenia symptoms when smoking cannabis.


However, there are some things that should be
taken under consideration. It is likely, that the AKT1 gene works together with
other genetic variants. For example, the study of Morgan et al. (2016) also
examined the COMT gene. Unfortunately, they didn’t found an association between cannabis use and
the COMT gene. Although, Tan et al. (2008) found in their neuroimaging measures
with a main effect of the AKT1 genotype, also a significant epistasis of a
polymorphism in the COMT gene. This might be the reason why some studies didn’t
associated AKT1 with schizophrenia (Di Forti et al.,2012). Thus, there might be
a chance that the AKT1 gene together with the COMT gene contributes to the
psychosis effects of cannabis. Furthermore, the environmental risks factors
were not taken with them in several reviewed studies. For instance, the
frequency of smoking cannabis. Only, Van Winkel et al. (2011) looked at the
frequency of cannabis use. Because, according to Di Forti et al. (2012)
carriers of the AKT1 gene variation have seven times increased probability of
psychotic disorder if using cannabis daily. This could be a reason why not many
people have psychotic effects after using cannabis (Di Forti et
al.,2012). Moreover, there have been used different methods and different dosages of
cannabis, which means the THC: CBD ratio varied. Because of the adverse effects
of these components (Curran et al.,2016), more THC could increase the pro-psychosis
effects and together with CBD in cannabis the pro-psychosis effects could



THC Dosage



THC: 0.3 – 20 mg/Kg

Ozaita et al. (2007)


THC: 1 um

Gomez del Pulgar et al. (2000)


THC: 100 nM

Sanchez et al. (2003)


THC: different for each participant

Morgan et al. (2016)


Cannabis (no ratio)

Van Winkel et al. (2011)


THC ratio unknown

Bhutacharyya et al. (2012)

Tabel 1. Each method and THC dosages from papers. *PC-3
cells: human prostate epithelial cells.**PSI: Psychotimimetic States Inventory,
to measure acute cannabis-induced psychotomimetic effects ***CPT: Continiuous
Performance Test, to measure sustained attention. ****PANSS: Positive and
negative symptoms scale, to measure the psychotic symptoms.


Table 1 shows that there have been used
different measurements to assess the cannabis-induced psychosis and different
THC ratio’s but the studies showed the same results. Moreover, in vitro (Ozaita
et al.,2007) and in vivo (Sanchez et al.,2003) studies showed that THC can
activate the AKT1 pathway through cannabinoids receptors. Interestingly, in the
introduction was told that the AKT pathway was dependent of the dopaminergic
system (Arguello & Gogos, 2008). Now, Ozaita et al. (2007) suggested that
the AKT pathway may be independent of dopamine D1 and D2 receptor blockade.
They found that dopaminergic receptor antagonists did not block the activation
of AKT pathway. However, Tan et al. (2008) showed that carriers of the AKT
rs1130233 A allele (associated with schizophrenia) had the worse performance on
a task that dependent on proper levels of dopamine within the PFC. This
suggests that AKT1 has a part in regulating dopamine-related prefrontal
structure and functioning. One possibility might be that Ozaita et al. (2007)
examined the AKT pathway in vitro
mice brains and this pathway difference in comparison with human brains.


All these points should be taken in
consideration for future research and also suggests there cannot be taken any
conclusion yet. Although, all these studies do provide a strong direction in
future research for cannabis-induced treatment.


Cannabis-induced treatment is helpful to design educational and health
campaigns to identify those who should avoid the use of cannabis. Because, in
the pharmacology world more medicine are produced with cannabis (Curran et
al.,2016). Thus, for the public health importance. Moreover, the cannabis use
has increased all over the world (Curran et al.,2016). In addition, the
association between AKT pathway and schizophrenia could work as an important
pathway in psychotic disorders, such as schizophrenia as a marker for
anti-psychotics.  In conclusion, the AKT1
genotype induces psychosis like schizophrenia symptoms when smoking



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