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❡𝌅🍋🍐🌳🌲🌍☙▓ ☏ 👮FB👮 🆚☏
ꚑꙌ꙰꙰꙰꙰꙰⭆⭅🔚 ﹩ 🎱 ￠ ₪ ₶
⭆ ⺴ Ꚓ ₶ ⭅🀹🀺🀻🀼🀽🀾🀲 ♡ 🎲🎴🔑🔎🔌🔇⨴⨶⨵⨱⨱⨱ ⨾⨼⨽ + 📵🕣🕤🕥🕝🕝🕝🕝𝌄🛃✍✆✄⛾⛰⛼⛓⛓⛑⛐⛏⛍☤♼☒☠☟☞☛☙⛫🚾🚬🚁𝄲𝄳𝅀𝅙𝆖𝆛𝆜𝆞𝆡𝆢𝇜🎵 🎶🎷🎸🎹🎺🎻🎼𝆋𝆉ₘₜ ⱼₐ₎₍₀₁₂₃₄₉ₓª²³¹⁰⁴⁵⁶⁷⁽⁾⍨🚽✊☺☝👂👄👃👊👲💙💚💛💑🙏😷 💪 span 🙊💬␡␠␞␝␜␚␘␈␀❥🐕🚧🚫𝌄
Through serotonin (5-HT) binding, this receptor
mediates inhibitory neurotransmission. The serotonin
system has been shown to be important in the neural
processing of anxiety and the neurobiological control of
learning and memory. Similar to the glutamatergic pathway,
altered serotonergic neurotransmission is speculated to
contribute to schizophrenia susceptibility. Evidence
suggests that METH, which acts as a substrate for the 5-HT
transporter, elevates extracellular 5-HT levels by both
promoting the efflux via transporter-mediated exchange
and by increasing cytoplasmic levels by disrupting storage
of 5-HT in vesicles (Cadet and Krasnova 2009; Rothman
and Baumann 2003). Although studies have explored
whether there is an association between several of the
genes involved in 5-HT regulation and MAP, only the
rs878567 polymorphism in the 5-HT1A receptor was
significantly associated using an alpha level of 0.001 as
significant (Kishi et al. 2010). Polymorphisms in the
5HT1A receptor have been associated with schizophrenia in
several studies (Huang et al. 2004; Le Francois et al. 2008;
Lemonde et al. 2003, 2004), including the rs878567
polymorphism. Currently, 5-HT(1A) receptor agonists are
being considered for the treatment of schizophrenia
(McCreary and Jones 2010).
Prokineticin receptor 2 (PROKR2) PROKR2 encodes
prokineticin receptor 2 (PK-R2), an integral membrane
Gprotein coupled receptor for prokineticins. Prokineticins
and their receptors are involved in a wide range of
biological functions in multiple organ systems. In the
CNS, prokineticin 2 modulates neurogenesis, circadian
rhythms, and migration of the subventricular zone-derived
neuronal progenitors (Cheng et al. 2002; Ng et al. 2005).
The involvement of PK-R2 in circadian rhythm raises the
question of whether this gene may be associated with
mood disorders, a phenotype often observed in patients
with drug addiction. Several animal studies have shown
that METH increases expression of circadian genes in the
brain (Iijima et al. 2002). The PROKR2 gene is located
on chromosome 20p12.3, which was shown to be linked to
bipolar disorder in three studies (Detera-Wadleigh et al.
1997; Fanous et al. 2008; Ross et al. 2008). An association
between PROKR2 gene variants and major depressive
disorder and bipolar disorder was reported in a Japanese
population (Kishi et al. 2009b); however, this study was
small and confirmatory studies will be necessary to
validate this finding. Furthermore, these same
investigators have shown that 3 individual SNPs in the PROKR2
gene (rs6085086, rs4815787, rs3746682), as well their
haplotypes (p 0.00019), were associated with MAP
(Kishi et al. 2010).
Glycine transporter 1 (SLC6A9) SLC6A9, which encodes
the glycine transporter type 1 (GLYT1), is involved in
glutamatergic neurotransmission, particularly at
NMDAtype glutamate receptors. It is currently believed that
termination of the different synaptic actions of glycine is
produced by rapid re-uptake through two sodium- and
chloride-coupled transporters, GLYT1 (located in the
plasma membrane of glial cells) and GLYT2 (located in
pre-synaptic terminals). GLYT1 regulates both glycinergic
and glutamatergic neurotransmission by controlling the
reuptake of glycine at synapses. The NMDA receptors are
regulated in vivo by the amino acids glycine and D-serine.
Glycine levels, in turn, are regulated by GLYT1, which
serves to maintain low sub-saturating glycine levels in the
vicinity of the NMDA receptors. Competitive antagonists
of NMDA receptors produce a psychotic state in healthy
subjects and exacerbate symptoms in schizophrenics.
SLC6A9 has emerged as a key novel target for the
treatment of schizophrenia. Morita et al. examined SLC6A9
among Japanese subjects with METH-dependence and
psychosis (Morita et al. 2008). Two SNPs conferred an
increased risk for MAP (rs2486001 and rs2248829) in
addition to the haplotype T-G (p=0.000037). It is speculated
that variants of the SLC6A9 gene may affect susceptibility to
MAP by modulating NMDA receptor function.
In summary, there is reasonably strong evidence that
genetic variation in neurotransmitter systems and in neural
development or growth is associated with risk for MAP. Of
the seven genes with strong empirical support for
association with MAP, four are involved in glutamatergic
neurotransmission (DAOA, DTNBP1, GRM2 and
SLC6A9). Potential epistatic (i.e. gene x gene) interactions
among these glutamatergic genes should be investigated.
Polymorphism in a key gene in serotonin system regulation
and signaling (HTR1A) is also associated with risk for
MAP, which suggests that other 5-HT system genes may
also be good candidates. Finally, two genes with roles in
CNS development (FZD3) and neurogenesis (PROKR2)
may help to identify other genes as well as developmental
processes that mediate vulnerability to MAP.
Gaps in genetic research
These studies reviewed in relation to MAP have examined
candidate genes selected based on current concepts of
neurobiology. Priorities for future genetic research on MAP
include: replicate genetic associations within and across
ethnically diverse populations; adjust for multiple
comparisons to minimize false-positive associations; utilize linkage
disequilibrium and tagSNP information to capture the
polymorphic structure of candidate genes; increase
statistical power by using larger population cohorts to minimize
false-negative associations; improve phenotyping of MAP
by use of a continuum versus a categorical classification
and account for trajectory of cessation, treatment response
and relapse; identification of allele-specific in vivo activity
in humans and non-human animals.
METH neuropathobiology
Lines of evidence support the notion that METH abuse
leads to neurodegeneration and, as such, may be a
component part of MAP pathobiology (Krasnova and Cadet
2009). The neuropsychological events noted show deficits
in attention, working memory, and decision making in
METH addicts. Bioimaging and histopathologic
evaluations show that the clinical findings parallel composite
damage to dopamine and serotonin axons, loss of gray
matter with linked hypertrophy of the white matter and
microgliosis in different brain areas (Kuhn et al. 2008;
Thomas et al. 2004a, b, 2008a, b; Xu et al. 2005). The
molecular basis of such neurotoxicities, interestingly,
parallel neural damage seen in a range of neurodegenerative
disorders that include Alzheimers and Parkinsons disease,
HIV-associated neurocognitive disorders, and amyotrophic
lateral sclerosis. Such neurotoxicity and inevitable
neurodegeneration parallels the presence of oxidative stress,
excitotoxicity, neuroinflammation, mitochondrial
dysfunction, decreased antioxidants and stress patterns (Cadet and
Krasnova 2009). These effects a host of intracellular
organelle functions and suggests that a range of therapeutic
strategies can be developed that would slow or reverse
adverse neuronal events (Kosloski et al. 2010; Mosley and
Gendelman 2010; Stone et al. 2009).
Animal models
In this section, we review the published preclinical animal
research that aims to simulate or directly understand some
facet of METH-related psychosis. We will not attempt to
survey the vast literature on neurobiologic and neurotoxic
effects of METH exposure as it is beyond the scope and the
focus of the present paper. The interested reader is referred to
the following reviews on these topics (Cadet and Krasnova
2009; Fleckenstein et al. 2007; Volz et al. 2007). This section
of the review, however, will have an eye toward the validity
of the animal models that have been used to date, as well as
identifying key gaps in the methods and research that need to
be filled. Given the paucity of animal research directly
focused on questions related to MAP, an important goal of
this section is to make recommendations for future research
that involves the development of translationally-relevant
models that are reliable (i.e., reproducible) and predictive
(Geyer and Markou 1995).
Clearly, establishing animal models that are predictive of
the human phenomenon of interest (MAP in this case) will
not happen without experimental situations and associated
manipulations that are reproducible and consistent within
and across laboratories. We agree with writers that espouse
the best way to this broad form of predictive validity and to
strong translational animal models is to work toward
improving construct and etiological validity (Geyer and
Markou 1995; Markou et al. 2009). For construct validity,
attention to continually improving the match between what
is measured at the behavioral (psychological) and neural
levels in the animal models of MAP with what is believed
to be the behavioral and neural processes underlying this
psychosis in humans (Markou et al. 2009) is essential. As
an example, if the current state of knowledge suggests that
individuals with MAP have impaired sensorimotor gating
that leads to sensory flooding and cognitive fragmentation,
then some insight regarding the human condition may come
from a better understanding of a similar attentional process
in animal models. In this example, pre-pulse inhibition
(PPI) may be of particular import. Pre-pulse inhibition
refers to the decrease in startle response evoked by an
auditory stimulus that is preceded by a pre-pulse stimulus
(usually the startle stimulus at lower intensity and shorter
duration). Deficits in PPI inhibition have been reported in
patients diagnosed with schizophrenia, as well as in rats
pretreated with METH (Abekawa et al. 2008) or have a
history of self-administering METH (Hadamitzky et al.
2011; see later).
The strategy of searching for and establishing construct
validity likely means that no single animal model will be
sufficient to capture all processes relevant to the disorder of
interest in humans. Also, this strategy is inherently
translational. Working toward etiologic validity further
encourages the communication and sharing of ideas,
theories, and methods necessary for successful translational
research (Markou et al. 2009). Etiologic validity refers to
the matching of environmental and physiological precursors
presumably responsible for the onset of the disorder. There
is ongoing debate as to the extent that METH induces
psychotic symptoms versus exacerbating pre-existing
symptoms (see earlier). This is one of many unique
instances in which animal models could serve to inform
this important clinical issue. For instance, will rats
intravenously self-administer enough METH to alter those
behavioral and neural processes altered in humans
diagnosed with MAP? Are the predisposing factors, whether
environmental, neural, or genetic, thought to be relevant in
human MAP contributing to such effects in the animal
models? Prior research has demonstrated that under some
conditions rats self-administering METH will show deficits
in object recognition memory (Reichel et al. 2011) and PPI
(Hadamitzky et al. 2011). Unfortunately, this research is
quite limited within the context of greater understanding of
MAP in humans. Given that METH psychosis is associated
with severe behavioral and neuropsychiatric complications
(see earlier), there is a pressing need to definitively and
precisely identify the behavioral and neurobiological
mechanisms underlying the development of METH
psychosis. As a result of this identification, behavioral
interventions and psychopharmacological treatment
strategies can then be developed.
Despite the limited work, animal studies have
consistently shown that many psychological processes underlying
clinical features of METH psychosis can be reproduced in a
variety of animal species, including mice, rats, guinea pigs,
cats and non-human primates (e.g., Japanese monkeys).
Like METH addicts, animals that are chronically treated
with a low (non-toxic) dose of METH gradually develop
psychotic-like symptoms, such as a decrease in motor
activity, an increase in stereotypies, decreased interest to
external stimuli and surroundings, and decreased social
functioning (Kuczenski et al. 2009). Also, some of the
changed behavioral patterns (e.g., behavioral sensitization)
persist even long after the cessation of drug treatment, and
have a tendency to relapse or exacerbation upon re-exposure
to the drug. Furthermore, concurrent antipsychotic drug
treatment can prevent recurrence triggered by METH use
(Misra et al. 2000). These results strongly suggests that
animal models of METH psychosis have high face (e.g.,
similarities to clinical symptoms), construct (e.g., METH use
and associated brain changes), and predictive validity (e.g.,
antipsychotic effect), and are effective in reproducing
behavioral symptoms of human METH psychosis,
mimicking the time course of symptom development, and its
liability to exacerbation.
