Classic serotonergic psychedelics for mood and depressive ...
The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing...
-
Upload
evan-ra-mantri -
Category
Documents
-
view
216 -
download
0
Transcript of The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing...
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
1/25
The Doors of Reception:
Functionally selective receptor mosaics
and the plasticity-inducing psychedelics that bind them.
Evan Martin
Spring 2011
1
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
2/25
ABSTRACT
The past decade has seen many exciting new developments in neurobiology. Three particularly
paradigm-rattling revelations reviewed in this report include; first, the elucidations of 'functional
receptivity,' which expand multi-fold the elegant complexity of receptor function by showing that, not
one, but rather, myriad unique cascades of intracellular signals leading to discrete profiles of gene
activation can result from multiple receptor conformations, as opposed to merely an active or inactive
state. Second: epigenetic and state-dependent neuroplasticity which suggests monumental therapeutic
potential and challenges the status quos of biological reductionism and pharmaceutical industry. And
last: receptor heteromerization wherein metabotropic receptors belonging to separate families form
complexes engaging in functional, allosteric co-modulation and neurotransmitter signal integration,
humbling the current level of neurological comprehension while presenting the potential for vastly
improved pharmacological interventions. The author makes use of psychedelics as a vector connecting
these exciting areas noting how they have played, and will continue to play, an indispensable role in
their exploration.
2
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
3/25
INTRODUCTION
Psychedelics*
are commonly described as 'mind expanding' drugs. Perhaps it wouldn't be untrue
either to identify them as science expanding drugs: work with them in the 1950's and 60's helped reveal
the significance of the serotonin system, develop novel concepts in cognitive neuroscience, illuminate
new realms of psychology, and facilitate the development of many pivotal psychopharmacological
medicines. Now, after three decades of scientists being politically barred access to these remarkable
substances, the psychedelics have re-entered the labs and are again helping us discover and delineate
new and extraordinarily profound insights into the functions and dysfunctions of the nervous system.
Just as psychedelics might allow reality appear to users of them as though viewed through a fractal
lens, wherein a universe can be seen in a grain of sand, so has the depth and detail of the dynamic
complexity of neural architecture expanded by several orders of magnitude over the past decade
through the application of psychedelics as biochemical research probes. When fifty years ago
psychedelics were helping us identify discrete neurotransmitters and correlate them with aspects of
cognition and the major psychiatric disorders, we are now, with the help of psychedelics, learning that
single receptors can initiate myriad discreet intracellular signal cascades directed by conformational
adjustments to various ligands, each inducing a unique set of protein activations and gene translation
outcomes relating to neural metabolism and synaptic organization. Psychedelics are also helping
elucidate the fascinating revelation that metabotropic G protein-coupled receptors (GPCRs) can form
mosaic-like complexes with other categorically distinct GPCRs, essentially forming super-receptors
that are capable of receiving and integrating input from 2, 3 and possibly more distinct ligands,
allosterically modulating each other and further complexifying the conformation directed intracellular
*It is common to refer these materials in the scientific literature as hallucinogens, psychotomimetics or simply 'drugs of abuse' and while all these terms are
valid in various circumstances, the designation psychedelic is the most socially accepted and descriptively accurate term in most contexts. However, I
often find hallucinogen to be a more sonorous, easier word, so I will use it in most circumstances, but have taken the liberty to alternate terms dependingon context.
3
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
4/25
signaling pathways. These discoveries allow for the development of medicinal therapies far more
specific and with far less side effects than previously possible.
In this review I will briefly describe some of these ground-shattering breakthroughs,
spearheaded by work with psychedelic probes and models, and discuss their far-reaching implications.
FUNCTIONAL SELECTIVITY
G protein-coupled receptors (GPCRs) are characterized by their seven transmembrane -helices
and are a highly conserved family of membrane receptors, found in nearly everything from plants to
protozoa (Gonzalez-Maeso & Sealfon 2009a). They are among the largest family of vertebrate
receptors comprising 1 to 3% of the mammalian genome and 1 to 5% of the total cell proteins
(Gonzalez-Maeso & Sealfon 2009a). The GPCRs are involved in countless different physiological
responses from vision to olfaction. Their malfunctions can lead to pathologies ranging from diabetes
and asthma to immunological and neurological disorders and their importance in medicine is attested to
by the estimates that 30 to 40% of currently available pharmaceutical drugs target the GPCR's (Albizu
2010).
Traditionally, metabotropic events initiated by a specific type of GPCR were thought to be the
same for all varieties of agonists that bound to it, merely varying in different degrees of efficiency.
Over the past two decades, however, it became increasingly clear that different agonists bearing similar
binding affinities for the same sites, could trigger distinctly separate signaling cascades within the cell,
based upon subtle differences in the conformation taken on by the receptor in response to the different
ligands. This phenomenon has been referred to as agonist-trafficking of receptor signaling, biased
agonism, conformational selection, functional selectivity, among other terms (Simmons 2005).
One of the most illustrative cases of functional selectivity has been the example of the 5-HT2A
receptor agonist hallucinogens such as lysergic acid diethylamide (LSD), mescaline and psilocin.
4
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
5/25
When these compounds bind to 5-HT2A receptors (Vollenweider 1998) they elicit profound changes in
cognition, perception, mood and behavior, however, when molecules with similar pharmacological
activity, such as lisuride, ergotamine or serotonin itself, bind to the same site, no such changes in
behavior or consciousness arise (Gonzalez-Maeso & Sealfon 2009a). This intimated that
hallucinogenic 5-HT2A receptor agonists induce intracellular responses different from those of the non-
hallucinogenic agonists. The behaviorally distinct effects of the hallucinogenic and non-hallucinogenic
agonists also serves a unique utility in experimental systems exploring this phenomenon of diverging
cellular events in vivo.
In response to extracellular cues, signal transduction cascades eventually regulate gene
expression, so in 2003, Gonzalez-Maeso et al. assayed mouse somatosensory cortex cells for
differential levels of mRNA transcripts in response to receptor activation by various hallucinogenic and
non-hallucinogenic 5-HT2A receptor agonists in vitro and in vivo. Although gene expression assays had
been conducted before on GPCRs to monitor response, this was the first reported time it had been done
to differentiate various agonist-driven responses of the same receptor (Gonzalez-Maeso et al. 2003).
They were able to identify 23 transcripts specifically dependent on 5-HT2A receptor activation, and
each agonist tested showed its own unique and reproducible profile of varying levels of these
transcribed genes; its own transcriptome fingerprint. Even more notably, they found that there were
certain gene expressions that were induced by the hallucinogenic agonists but not by the non-
hallucinogenic ones (Gonzalez-Maeso et al. 2003). These particular genes mainly belong to the family
of early growth response (EGR) elements which are primarily known to be involved with neural
growth and plasticity (Leah & Wilce 2002). Two gene transcriptions, egr-1 and egr-2, were induced by
all six hallucinogens tested (DOI, DOM, DOB, mescaline, LSD and psilocin, representing 4
structurally diverse classes of 5-HT2A receptor agonists) with no induction at all by the various non-
5
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
6/25
hallucinogen 5-HT2A receptor agonists (Gonzalez-Maeso et al. 2007). The hallucinogen-specific
transcript for the protein Egr-2 showed particularly robust expression.
Further investigations by Gonzalez-Maeso et at. elucidated details concerning the signaling
cascades that lead to the gene transcriptions. They found that the psychotropic effects of the
hallucinogens depended on the same Gq/11 protein activated pathway that the non-hallucinogenic 5-HT2A
receptor agonists did, however, the hallucinogens also co-activated a G i/0protein-initiated cascade
simultaneously, which was responsible for the unique hallucinogen-specific pattern of gene induction
(Gonzalez-Maeso et al. 2007). This data contributed mightily to the interpretation that GPCRs can
adopt multiple, functional conformations directed by the binding of different ligands and commencing
distinct cellular responses.
The fact that receptors can exhibit such a variety of precise and functional pathways in response
to varying agonists, producing a specific set of gene transcriptions for every different agonist tested, is
interesting to contemplate. Might this imply that single receptor types may have evolved to bind to
numerous endogenous or exogenous ligands? Some, perhaps, existing in trace amounts, sequestered
into sparse vesicles or unassuming astrocytes, hidden from our blunt instruments or only synthesized in
rare circumstances? We rightly assumed that the tightest binding endogenous ligand was the receptor's
main key to it's lock, but perhaps we should take a closer look at the cellular events and gene
transcriptions that take place when less obvious endogenous molecules bind a receptor.
PLASTICITY
It is unlikely the expression of the psychedelic-specific genes are directly responsible for the
immediate physiological and behavioral effects of the psychedelic drugs, which can begin before the
genes are even induced (Gonzalez-Maeso et al. 2007). The mechanisms underlying those more salient
aspects of psychedelic experience remain a mystery. However, the gene expressions are directly
6
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
7/25
involved in neuroplastic effects that might correlate with the extremely long term efficacy of
psychedelic experiences in therapeutic contexts for relieving psychiatric symptoms such as depression,
anxiety, OCD, PTSD, chronic pain, addiction and other maladaptive behaviors (Multidisciplinary
Association for Psychedelic Studies 2011) and likewise for the lingering emotional, behavioral and
perceptual side effects that can be elicited by taking hallucinogens in a threatening or non-conducive
setting. Hallucinogens have been shown to stimulate long-term potentiation (LTP) and long-term
depression (LTD) of various receptors (Vollenweider 2010) and induce transient increases in dendritic
spine size of cortical neurons (Jones et al. 2009) as well as rapid synapse formation (Li et al. 2010). 5-
HT2A agonists, particularly the Hallucinogens have also been shown to preferentially activate proteins
involved in the regulation of microtubule structure and function such as kalirin-7, PAK (Jones et al.
2009) and -arrestin-2 (Schmid et al. 2008) and others (Woerkom 1990). Indeed, tryptamines such as
serotonin and melatonin interact robustly with cytoskeletal elements such as actin, tubulin and
micotubule-associated proteins (MAPs) and play apical roles in differentiation and cell morphology;
measures of which are correlated with neuropathologies such as schizophrenia and depression
(Woerkom 1990; Azmitia 2001; Massimiliano, et al. 2003; Bianchi 2005; Bellon et al. 2007; Gardiner
2011).
Synaptic plasticity and neural mitosis are burgeoning areas of research and medicine. Neural
degeneration and matter-loss in specific brain areas have been correlated with many psychiatric
diseases. The monoamine deficiency hypothesis has been the basis of the pharmacological treatment of
depression for over five decades, yet the reuptake inhibitor class of antidepressants are not effective in
all patients, and when clinical efficacy does occur, it requires 2 to 5 weeks to begin, even though
monoamine concentrations in the synaptic cleft increase within hours of administration (Vidal et al.
2011). Drugs that increase monoamine levels through other mechanisms have shown to be ineffective
in the treatment of depression (Vidal et al. 2011), further suggesting that a simple deficiency in the
7
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
8/25
monoaminergic neurotransmitters, while being a symptom, is likely not the primary cause of depressive
disorders.
Untreated depressed subjects show decreased hippocampal volume (Martinowich et al. 2007)
and it has been established that the antidepressants enhance neural proliferation, particularly in the
hippocampus (Martinowich et al. 2007; Vidal et al. 2011). The time required for the differentiation and
maturation of new nerve cells correlates with the lag time seen in clinical response to antidepressants
(Vidal et al. 2011). Brain-derived neurotrophic factor (BDNF) exerts a potent trophic effect on
serotonin and norepinephrine neurons and displays increased expression by the chronic use of
antidepressant medications and decreased BDNF levels are found in subjects with untreated major
depression (Baudry et al. 2005; Vidal 2011). The increased levels of BDNF are also correlated with
the onset of the therapeutic effects of antidepressants (Baudry et al. 2005) and direct infusions of
BDNF into the midbrain has shown to have antidepressant effects in animal models (Martinowich et al.
2007). Data such as this and that which is to follow in this report has led to what has been called the
neuroplastic or neurotrophin hypothesis of depression (Baudry et al. 2005; Martinowich et al. 2007).
Different antidepressants enhanceBdnfexpression using different combinations of promoters,
of whichBdnfhas at least seven (Martinowich et al. 2007), which indicates possibilities for more
guided and specific pharmacological regulations of the gene. Also leading to increased complexity and
confusion while simultaneously presenting better therapeutic possibilities, BDNF is known to exist in
two forms: a precursor, proBDNF, and its cleaved form, mature BDNF (mBDNF). mBDNF is what is
responsible for long-term potentiation (LTP) while proBDNF actually facilitates long-term depression
(LTD) (Martinowich et al. 2007). Each form has it's own receptors and while the balance of the two
seems to help regulate synaptic plasticity, it is not clear whether an overabundance of proBDNF, a
deficiency mBDNF, or both are involved with the etiology of depression, however increasing evidence
points toward toward the conversion process being very significant. For example, knocking out the
8
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
9/25
genes involved in the BDNF conversion pathway or the pro & mBDNF receptors does not directly
cause symptoms of depression, but it does render antidepressants ineffective, indicating that they elicit
their effects by activating the BDNF conversion pathway (Martinowich et al. 2007) .
Another intriguing result from the investigations of the catalytic process involved in this
conversion involves the protein p11. Like BDNF, decreased expression levels of p11 have been
correlated with depression and the efficacy of antidepressants. Svenningsson et al. attribute this effect
to p11's ability to upregulate and localize 5-HT1B receptors (Svenningsson et al. 2006), however,
Martinowich et al. pointed out that p11 is a dramatic enhancer of tPA, the enzyme that converts
proBDNF to mBDNF (Martinowich et al. 2007), which would also offer an explanation for its
antidepressant properties.
A number of other neurotrophins are also being investigated for their apparent roles in cortical
and midbrain plasticity such as fibroblast growth factor (FGF), insulin-like growth factor (IGF-1),
nerve growth factor (NGF) and vasoendothelial growth factor (VEGF) (Krystal et al. 2009).
As mentioned previously, the transcriptome fingerprints of cellular responses to 5-HT2A receptor
agonists revealed transcriptions unique to compounds with hallucinogenic activity. The products of
these transcriptions mainly belong to the class of early growth response proteins (EGRs), which are
transcription factors critically involved in glial proliferation (Mayeret al2009) and neural plasticity
(Knapska & Kaczmarek 2004), and are being investigated for their roles in the circadian regulation of
the pineal gland (Man & Carter 2008), long-term memory formation (Davis et al. 2003) and various
other cognitive processes (DeSteno et al. 2008). Their genes are a subclass of the immediate early
genes (IEGs) which are the first gene targets activated by intracellular signal pathways. Because they
are inducible transcription factors they continue the signaling cascade to further downstream genes,
acting perhaps as both messengers and gateways to later gene responses (Beckmann & Wilce 1996).
9
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
10/25
There are four principle EGR proteins; Egr-1, Egr-2, Egr-3 and Egr-4. Out of the four,
transcripts for Egr-1 and Egr-2 were found to be induced only by hallucinogenic 5-HT2A receptor
agonists and not by non-hallucinogenic 5-HT2A receptoragonists, with Egr-2 showing the strongest
response (a four-fold increase) from every hallucinogen (Gonzalez-Maeso & Sealfon 2009b). For this
reason I will review some of the data on Egr-2, although most research thus far has been conducted on
Egr-1 and Egr-3.
Egr-2 controls genes that are required for the onset and completion of Schwann cell myelination
in the peripheral nervous system and appears to be involved in a process that regulates myelination and
demyelination programs as well as the maintenance of the myelinated state (Decker, et al. 2006).
Mutations affecting Egr-2 result in various human hereditary peripheral neuropathies, including
congenital hypomyelinating neuropathy and Charcot-Marie-Tooth disease (Warneret al. 1998) which is
one of the most common inherited neurological disorders (Pareyson et al. 2000).
The Egr-2 transcription factor is the only Egr protein necessary for life. Deletion of the gene is
lethal in mice, due to peripheral nerve myelination failure (Beckmann and Wilce 1997). Egr-2 is also
required for the segmentation of the hindbrain, which arises from Hox genes under Egr-2's control.
EGRs are also necessary for astrocyte proliferation (Mayeret al. 2009). Astrocytes, which
outnumber neurons five-fold, are now widely acknowledged for their potentially complex
computational roles in the brain's circuitry. They can share nearly all the same channels and receptors
as neurons, including such pharmacological darlings as the 5-HT2A, mGlu2/3 and dopamine D2 receptors
(Xu & Pandey 2000; Aronica et al. 2000; Khan et al. 2001, respectively). The involvement of
astrocytes and other glia in the neuropatholgy of schizophrenia (Moises et al. 2002) and mood
disorders has been attracting increasing investigation. Reductions in glial number and density have
been found in the fronto-limbic brain regions of subjects with depression and bipolar disorder
(Rajkowska & Miguel-Hidalgo 2007), so gliogenesis could prove to be an important therapeutic target.
10
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
11/25
Genes encoding at least half a dozen growth factors have been identified as targets of the EGR
transcription factors in astrocytes (Mayeret al. 2009).
Less is known about Egr-2 than Egr-1 and Egr-3 (DeSteno & Schmauss 2008), yet it is apparent
that Egr-2 bears some unique qualities distinct from the rest of the family. For example, it is the only
EGR that exists in the cytoplasm as well as the nucleus, and in the nucleus it remains for substantially
longer the others (Perez-Cadaha et al. 2011). Egr-2 can be induced by BDNF like the other EGRs but
also uniquely by NGF, and it has specific involvement in mossy fiber sprouting (Ludwig et al. 2011).
If activated in a tumor cell such as a glioma, however, Egr-2 reverses it's role as a growth facilitator and
instead induces apoptosis (Unoki 2003), linking this psychedelically-induced gene to tumor
suppression.
Another unique property of Egr-2 is that is has a different pattern of expression in and across the
cerebral cortex than the others. For instance, there is a strong basal expression of Egr-1, -3 and -4 in
layers II and VII of the cortex, whereas Egr-2 occurs mostly in layers II and III (Leah & Wilce 2002).
Interestingly, hallucinogens induced Egr-2 in layer V, but not in layers II and III (Gonzalez-Maeso et al.
2007). Layer III is also the cortical layer where schizophrenic patients show significant diminished
dendritic spine density compared to other layers and compared to controls (Glantz & Lewis 2000),
possibly mirroring a neuroplastic neglect of that layer by hallucinogens, which could potentially be
another correlation between hallucinogen pharmacology and schizophrenia.
An association between mutations of the EGR genes and schizophrenia was reported in Japan as
well as postmortem studies that revealed EGR transcripts were down-regulated in the prefrontal cortex
of schizophrenics, but not bipolar, patients. (Yamada et al. 2007) A similar link between EGR
mutations and schizophrenia was later reported in Korea (Kim et al. 2010) whereas no such correlation
was found in a study of the Chinese population (Liu et al. 2010).
11
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
12/25
Differential expressions of individual members of the EGR family were induced during
different cognitive processes in mice and it was reported that Egr-2, but not Egr-1 nor Egr-3, was
induced by cognitive tasks associated with attention and attentional shifts. The level of Egr-2
expression was proportional to the magnitude of attentional demand. In tasks involving spatial
working memory, the reverse was true; Erg-1 and Egr-3 were expressed but not Egr-2 (DeSteno &
Schmauss 2008). In other tests, Egr-1 was shown to be essential for the formation of long-term
memories (Davis et al. 2003) and Egr-3 was shown to have a pivotal role in adaptation to novelty and
stress (Gallitano-Mendel et al. 2007). Correlating these neuroplastic elements with various cognitive
domains may reveal some interesting and useful things about our brains. Being able to selectively
strengthen the circuits involved with attention may turn out be a more effective treatment for childhood
ADD than amphetamines, and transcription factors associated with long term memory are enticing for
many reasons.
Plasticity is highly activity-dependent phenomenon. In mouse models, environments enriched
with toys, colors, wheels and ramps lead to marked increases in plasticity and production of BDNF and
NGF. Even in aged mice, a five-fold increase in neurogenesis was observed, actually reversing deficits
imparted by impoverished youth conditions (Baudry 2005). The hypothesis that depressive disorders
involve impaired activity-dependent plasticity and that antidepressants work by ameliorating this
deficit is supported by the interesting findings that depressed individuals exhibit impaired visual system
plasticity in response to visual stimuli and also that healthy, non-depressed individuals chronically
administered sertraline (Zoloft) developed increased visual stimulus-dependent plasticity (Krystal et al.
2009). It was also shown that ocular dominance plasticity was was enhanced in rats administered
fluoxetine (Prozac) (Krystal et al. 2009). These non-mood-related plasticity effects correlated with
depression and antideprssants may point towards a more causal mechanism than a mere transmitter
imbalance.
12
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
13/25
Considering the activity-dependence of plastic outcomes, it follows that patients taking
antidepressants would experience different results based upon which behaviors and outlooks were
reinforced by the environment. Indeed, the case was demonstrated that cognitive-behavioral therapy in
combination with antidepressant medication was significantly more effective than either treatment
alone (Kelleret al. 2000).
D-cycloserine (DCS) is a partial agonist at the glycine coagonist site of NMDA receptors,
having the effect of stabilizing NMDA receptor activity against fluxing glycine levels. DCA has been
observed to increase neuroplasticity, yet it has negligible psychoactive effects when compared to
antidepressants and related psychiatric medications. Because of the known role of NMDA-dependent
amygdalar functions in Pavlovian fear conditioning, consolidation, and extinction, DCA was tested and
found to effectively promote the extinction of fear conditioning in animals, a neuroplastic process
involving associational learning and adaptation to novelty (Krystal et al. 2009). The first studies of
DCS in humans was for acrophobia and patients who used DCS in combination with virtual reality
exposure therapy benefited more than those who received placebo (Davis et al. 2005). The results were
replicated and trials using DCS and exposure therapy have also begun for patients with social anxiety,
panic disorder, obsessive compulsive disorder (Krystal et al. 2009), cocaine addiction (Paolone &
Stewart 2009) and schizophrenia (Goffet al. 2008).
The results so far from DCS studies are mostly positive, but with a wide range of efficacy from
insignificant to highly significant. DCS may also have potentially moderate CNS side effects.
However, a key facet of these trials was that the patients who benefited from the DCS / exposure
therapy combination were found during follow up to have retained their cognitive-behavioral
improvements after discontinuation of the treatment. Many current psychopharmacological therapies
require continual and often indefinite administration because of the high risk of relapse There is also
the concern that such long-term pharmacological symptom maintenance simply aggravates the
13
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
14/25
underlying psychiatric condition into an increasingly chronic state. In either case, a more curative,
permanent treatment is immeasurably more desirable by a patient yet, sadly, would be neglected by the
profit-driven pharmaceutical industry.
As neuroplasticity-based therapies emerge and begin their refinement, the two novel and central
attributes they entail, that of qualitative activity-dependence and potentially permanent curative
capability, parallel precisely the two key aspects of psychedelic therapy that have, over the past six
decades, been a conceptual and ideological challenge for conventional medical science to address and
antithetical to its economic landscape.
The long-standing dominant model of biological medicine has been based on the premise that
medications acting on biochemical features produce their efficacy on psychiatric conditions in a
bottom-up (body to mind) manner, and that this trend would continue indefinitely, simply becoming
ever more specific and efficacious as science advances forward. Psychedelics have long existed as a
thorn in the side of this kind of biological reductionism and behavioral materialism because the effects
of identical doses of the same drug can produce extremely varied psychological and somatic responses
between subjects or even in the same subject during different administrations.
It was learned early on that that the variable effects of psychedelics were not random but were
shaped entirely by two factors (three if one includes the obvious factor of dose): the external
environment in which the experience takes place as well as the internal bio-psychological milieu such
as personality, anxiety, fears, intentions and state of physical health. The influential Harvard
psychologist Dr. Timothy Leary coined the terminology 'set and setting' to describe these internal and
external factors that shape a psychedelic experience. While set and setting can influence the
experience of many psychoactive drugs ranging from alcohol to amphetamines, in the case of
psychedelic drugs it seems to dictate nearly the entirety of the effects, wherein stripped away of the
environmental stimuli and subjective mental dynamics, such as in an anesthetized subject, there would
14
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
15/25
be no externally observable effects such as excitation, sedation nor alterations of heart rate or
metabolism. This type of action has led many to concur with the psychiatrist Dr. Stanislav Grof's
description of psychedelics as non-specific amplifiers of consciousness.
This priority of consciousness as a factor in the action of psychedelics did not quite fit into the
materialistic paradigm of Western medicine where drugs have a specific given effect. Psychedelics are
simply not something one's doctor would recommend to take two and call me in the morning. Their
ability to heal, or aggravate, deep psychological wounds is utterly activity-dependent, just as
neuroplastic adaptations are. Indeed, it is increasingly apparent that neuroplastic brain rewiring are
exactly what the psychedelics provoke.
Those currently working on developing neuroplastic therapies have been confronted with the
challenge of how to develop and obtain FDA approval for therapeutic strategies that entail
pharmacological medications conjoined with cognitive-behavioral elements (Krystal et al. 2009).
Luckily for them, this very same problem has been worked on diligently for the past 10 years by those
pursuing clinical approval for the therapeutic applications of psychedelic medicines in conjunction with
psychotherapy by developing and carrying out dozens of protocols and clinical trials, some of which
are nearly ready for phase III (Multidisciplinary Association of Psychedelic Studies 2011).
The other critical attribute of psychedelic therapy and, likely, other neuroplastic therapies yet to
be developed, is that the desired effects are very long-lasting (Griffiths, et al. 2008; Doblin 1998),
potentially even permanent. While the benefits of not having to indefinitely take side-effect-laden
medications are obviously desirably in every way for patients, they pose a challenge for the medical
establishment's current economic structure. Pharmaceutical companies can not make money from pills
that only need to be taken once or a dozen times so they have no incentive to fund the multi-million-
dollar clinical trials required to bring them to market. At this time, psychedelics are still somewhat
controversial so large-scale corporate funding and philanthropy has not yet lent support to the venture
15
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
16/25
and most governments wouldn't let public funds anywhere near such an endeavor, which is why the
expensive clinical trials for psychedelic medicines thus far have been paid for entirely by the private
sector through the fund-raising and outreach efforts of non-profits such as The Multidisciplinary
Association for Psychedelic Studies (MAPS). However, it is feasible that other kinds of non-
psychedelic neuroplastic treatments could gather funds for development from more conventional
sources of capital since they would not bear the unfortunate stigma that psychedelics drugs do.
Deciphering the biological mechanisms of hallucinogenic drugs holds very high potential for
the discovery of non-psychoactive neuroplastic agents targeted at a wide range of psychiatric illnesses.
LSD has been found to downregulate 5-HT2Areceptors in the frontal cortex (Gresch et al. 2005) which
may help to explain the antidepressant effects of hallucinogens considering that frontal cortex 5-HT2A
receptor density was found to be increased in untreated depressed patients and that antidepressants also
reduce prefrontal 5-HT2A receptor density (Vollenweider 2010). Fronto-limbic 5-HT2Areceptor density
upregulation has also been correlated with anxiety, the ability to cope with stress and responses to tonic
pain (Vollenweider 2010); all conditions that have been successfully treated with hallucinogens (Grob
2010).
Dissociative anesthetics such as ketamine also share some of the same subjective effects as the
classical psychedelics. Ketamine has been getting much recent attention for it's unique antidepressant
properties. While being too psychoactive for efficient regular use in treating depression, a single
administration of ketamine has immediate and pronounced antidepressants effects that last a relatively
long period of approximately two to three weeks, which is likely due to a very quickly initiating
neuroplastic effect (Li et al. 2010) [2012 Update: Confirmed (Kavalali 2012 & Schmidt 2012).], albeit
a more transient one than the classical psychedelics can induce. Unlike the 5-HT2A agonists, ketamine
is an antagonist of the NMDA receptor, however, both 5-HT2A agonism by hallucinogens and NMDA
16
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
17/25
antagonism by ketamine result in activation of prefrontal-limbic glutamatergic circuits, which have
been demonstrated to be required for the hallucinogenic effects (Vollenweider 2010). Neuroimaging
studies also reveal that psilocybin and ketamine activate very similar prefrontal cortical areas
(Vollenweider 2010), further indicating common modes of action. Patients with depression have been
observed to have reduced prefrontal glutamatergic activity (Vollenweider 2010) and not only do 5-HT2A
agonist hallucinogens and ketamine increase glutamate levels in the prefrontal-limbic areas, they also
increase BDNF levels in the same areas, which might play a role in the antidepressant effects of these
drugs that persist long after the psychotropic effects have ceased (Vollenweider 2010).
While hallucinogens have shown efficacy in treating a vastly wide range of psychopathologies,
one illness they seem to be contraindicated for, at least in modern medical contexts, is schizophrenia.
Although most hallucinogens tend to predominantly induce visual phenomena while auditory
hallucinations are more common in schizophrenia, the similarities between hallucinogenic drug effects
and psychosis has been long appreciated. (It has been reported that some novel synthetic 5-HT2A
agonist hallucinogens do tend to produce more to auditory distortions than visual ones. Indeed, the
spectra of qualitative variations in perceptual effects among the hallucinogens may prove very useful in
future neurocognitive and neuropathological investigations.) Based upon the stimulant-model of
psychosis, the first wave of antipsychotics were the D2 receptor blockers. Later, atypical antipsychotics
came into favor which also blocked D2 receptors but blocked 5-HT2A with a much greater affinity,
indicating 5-HT2A receptor function abnormality in the etiology of schizophrenia. This hypothesis was
later supported when it was found that the hallucinogens also acted on 5-HT 2A receptors and by the fact
that the atypical antipsychotics partially block the effects of hallucinogens (Gonzales-Maeso & Sealfon
2009b).
Later, the NMDA antagonist phencyclidine (PCP) was shown to mimic the effects of
17
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
18/25
schizophrenia even more accurately than D2 stimulants or LSD-like drugs, implicating glutamate
hypofunction in schizophrenia, however, glutamate receptor agonists were scant and no such
medications were developed until recently, where successful trials with an mGlu2/3 receptor agonist in
treating schizophrenia have caused quite a stir in the field (Patil et al. 2007). Congruent with these
pharmacological findings, levels of 5-HT2A receptors in the cortices of untreated schizophrenic subjects
were found to be significantly higher and mGlu2 receptors significantly lower than controls (Gonzales-
Maeso et al. 2008).
It has been discovered that not only do the atypical antipsychotics block the effects of 5-HT2A
receptor agonist hallucinogens, they also block the effects of NMDA antagonist dissociative
anesthetics. Further, the new class of mGlu2 receptor agonists currently being looked at for
antipsychosis applications were also found to abolish the effects of 5-HT2A receptor agonist
hallucinogens as well as the NMDA antagonist dissociative anesthetics (Gonzales-Maeso & Sealfon
2009b). The evidence that 5-HT2A receptors and mGlu2 receptors exhibit multiple forms of cross-talk
has been observed and investigated for some time and now the reason has become quite clear: these
two different types GPCRs form a functional dimer on the postsynaptic side of cortical pyramidal
neurons (Gonzales-Maeso et al. 2008).
RECEPTOR COMPLEXES
The 5-HT2A-mGlu2 heterodimer has unique properties beyond either receptor individually. It
exhibits both positive and negative ligand-dependent cooperative binding through allosteric
interactions, with mGlu2 receptor activation increasing the affinity of the 5-HT2A receptor agonists
while, in contrast, 5-HT2A receptor activation decreases the affinity of mGlu2 receptor agonists
(Gonzales-Maeso et al. 2008), in what appears to be regulatory integration of serotonin and glutamate
18
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
19/25
neurotransmission into specific patterns of cellular response.
There exist unique G protein pathways associated with the dimer that are not activated by either
receptor alone. For example, the 5-HT2A receptor hallucinogen-specific pathway involving the Gi/0
signaling cascade leading to the induction ofegr-2 requires the dimerization with the mGlu2 receptor
and the psychotropic effects of hallucinogens are abolished by the elimination of the mGlu2 receptor
(Moreno et al. 2011). This and a wealth of other data support the finding that it is the 5-HT2A-mGlu2
heterodimer that is the prime target of hallucinogens, atypical antipsychotics andthe new class of
metabotropic glutamatereceptor agonist antipsychotics (Gonzales-Maeso & Sealfon 2009b).
There still remains the challenge of how to tie in the dopamine hypothesis of schizophrenia with
the emerging serotonin-glutamate hypothesis. The activation of the 5-HT2A-mGlu2 heterodimer with
hallucinogens or via NMDA receptor antagonism does have downstream effects on dopaminergic
activity in the nucleus accumbens where D2 receptor antagonists appear to have their antipsychotic
effect. The nucleus accumbens is involved in emotions and motivation which might explain why the
D2 receptor antagonist typical antipsychotics are effective against negative symptoms such as social
withdrawal and less so with the positive ones such as delusions. The prefrontal cortex circuits
activated by hallucinogens also innervate dopaminergic pathways of the ventral tegmental area and lead
to increased concentration of dopamine in the striatum, which has been correlated with feelings of
euphoria induced by hallucinogens, but blocking D2 receptors with haloperidol only decreases
psilocybin-induced euphoria by about 30% (Vollenweider 2010), implying another more salient
mechanism involving dopamine in schizophrenia.
The existence of GPCR receptor dimers such as the T1R1/T1R3 taste receptor have been
recognized for over a decade now, but in the past few years the number of homodimers, heterodimers,
heterotrimers, heterotetramers and even mosaics of recepter oligomer complexes involving dozens of
19
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
20/25
discreet receptor types has been pushed up to scores of identified or hypothesized combinations and the
number is increasing rapidly (Kniazeffet al. 2011). Current speculations are that, given the large
number of GPCR genes and their ability to form combinations, there may be tens or even hundreds of
thousands of unique receptor heteromers in the brain and nervous system. (Albizu et al. 2010)
Dopamine D2 receptors, for example, appear to exist in dimeric and trimeric combinations with
with D1, D3, CB1, mGluR5 and A2a receptors, giving rise to complexity previously unimagined. It has
even been found that D2 partial agonists surprisingly behave as D2 antagonists at the D2-D3 heterodimer
(Fuxe et al. 2009)! Investigating the the D2 containing heteromers and receptor mosaics along the
circuits implicated in schizophrenia could reveal important aspects of receptor dysfunction and new
targets for pharmacological intervention. Indeed, countless diseases can be approached anew with this
understanding. One example of a novel pharmacological approach to be taken is to develop bivalent
ligands: two ligands attached by amino acid or perhaps alkyl links, that bind both individual
components of the heterodimer (Albizu et al. 2010).
CONCLUSION
While the scope of complexity revealed by such leaps in neuroscientific comprehension as the
existence of ligand-directed signal trafficking, epigenetic neural plasticity and receptor
heteromerization may appear daunting, the implications for medicinal and therapeutic opportunities are
staggering. Given that psychedelics play such a crucial role in exploring and expanding the
neuroscientific landscape, one may take pause and wonder if the field of neuro-cognitive science would
not be several years more advanced than it is now if these compounds were never wrenched from hands
of scientists and kept out of the labs for nearly 3 decades. Perhaps our society, groggily waking from
the slumber of a dark age of authoritarian fundamentalism, was not yet ready nor capable of fathoming
the magnitude of mysteries such keys to the doors of perception would reveal, but now, faced with the
20
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
21/25
critical choice between planetary stewardship or peril, we are prepared to take on the maturity and
responsibility these ancient sacraments and synthetic mind manifesting molecules ask of us.
Albizu, Laura, et al. (2010). Heteromerization of G protein-coupled receptors: relevance to
neurological disorders and neurotherapeutics. CNS Neurol Disord Drug Targets. 9(5):636-50.
Aronica E, et al. (2000). Upregulation of metabotropic glutamate receptor subtype mGluR3 and
mGluR5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy. Eur J
Neurosci. (7):2333-44.
Azmitia, Efrain C. (2001). Modern views on an ancient chemical: serotonin effects on cell
proliferation, maturation, and apoptosis. Brain Research Bulletin 56(5):413-424
Bianchi, Massimiliano, et al. (2003). Cytoskeletal Changes in the Hippocampus Following Restraint
Stress: Role of Serotonin and Microtubules. Synapse 49:188 194
Baudry, Michel, et al. (2005). Synaptic Plasticity: Basic Mechanisms to Clinical Applications. Boca
Raton, FL: Taylor & Francis Group.
Beckmann, A.M., Wilce, P.A., (1997). Egr transcription factors in the nervous system. Neurochem. Int.
31, 47751
Bellon, Alfredo (2007). Melatonin induces neuritogenesis at early stages in N1E-115 cells through actin
rearrangements via activation of protein kinase C and Rho-associated kinase. Journal of Pineal
Research 42(3)214-221
Brennand, K.J. et al. (2011). Modelling schizophrenia using human induced pluripotent stem cells.
Nature; Published online 13 April 2011.
Davis, Michael, Karyn M. Myers, Kerry J. Ressler and Barbara O. Rothbaum (2005). Facilitation of
Extinction of Conditioned Fear by D-Cycloserine. American Psychological Society 14 (4): 214219.
Davis, Sabrina, et al. (2003). How necessary is the activation of the immediate early gene zif268 in
synaptic plasticity and learning? Behavioural Brain Research 142; 1-2, 17-30
21
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
22/25
Doblin, Rick (1998). Dr. Leary's Concord Prison Experiment: A 34-year follow-up study. Journal of
Psychoactive Drugs 30(4):419
Decker, Lawrence, et al. (2006). Peripheral Myelin Maintenance Is a Dynamic Process RequiringConstant Krox20 Expression. The Journal of Neuroscience, 26(38): 9771-9779.
DeSteno DA, Schmauss C. (2008) Induction of early growth response gene 2 expression in theforebrain of mice performing an attention-set-shifting task. Neuroscience. 152(2):417428.
Fuxe, Kjell, et al. (2009). Integrated signaling in heterodimers and receptor mosaics of different typesof GPCRs of the forebrain: relevance for schizophrenia, J Neural Transm 116: 923939.
Gardiner, John, et al. (2011). The microtubule cytoskeleton acts as a key downstream effector ofneurotransmitter signaling. Synapse 65(3)249256.
Kim SH, et at. (2010). EGR3 as a potential susceptibility gene for schizophrenia in Korea.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics ;153B(7):1355-60.
Keller MB, et al. A comparison of nefazodone, the cognitive behavioral-analysis system of
psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med.342 (20):14621470.
Kniazeff J, Przeau L, Rondard P, Pin JP, Goudet C. (2011). Dimers and beyond: The functionalpuzzles of class C GPCRs. Pharmacol Ther. 130(1):9-25.
Krystal, John H., et al. (2009). Neuroplasticity as a target for the pharmacotherapy ofanxiety disorders,
mood disorders, and schizophrenia. Drug Discov Today. 14(13-14): 690697.
Gallitano-Mendel, Amelia, et al. (2007).The immediate early gene Egr3 mediates adaptation to
stress and novelty. Neuroscience. 2007 September 7; 148(3): 633643.
Glantz, Leisa A., David A. Lewis (2000). Decreased Dendritic Spine Density on Prefrontal Cortical
Pyramidal Neurons in Schizophrenia. Arch Gen Psychiatry. 57:65-7
GoffDC, et al. (2008) Once-weekly D-cycloserine effects on negative symptoms and cognition in
schizophrenia: an exploratory study. Schizophr Res106:320327
Gonzalez-Maeso, J. et al. (2003) Transcriptome fingerprints distinguish hallucinogenic and
nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J.
Neurosci., 23, 8836-43.
Gonzalez-Maeso, J. et al. (2007). Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated
signaling pathways to affect behavior. Neuron 53, 439452.
Gonzalez-Maeso et al., (2008) Identification of a serotonin/glutamate receptor complex implicated in
psychosis, Nature 452 , pp. 9397.
22
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
23/25
Gonzalez-Maeso, J. & Sealfon, S. C. (2009a). Agonist-trafficking and hallucinogens. Curr. Med.
Chem. 16, 10171027
Gonzalez-Maeso J., Sealfon S. (2009b). Psychedelics and schizophrenia. Trends Neurosci. 32, 225232.
Gresch PJ, Smith RL, Barrett RJ, Sanders-Bush E (2005). Behavioral tolerance to lysergic aciddiethylamide is associated with reduced serotonin-2A receptor signaling in rat
cortex. Neuropsychopharmacology 30: 16931702.
Griffiths, Roland, et al. (2008). Mystical-type experiences occasioned by psilocybin mediate the
attribution of personal meaning and spiritual significance 14 months later. J Psychopharmacol vol.
22 no. 6 621-632.
Grob CS, Danforth AL, Chopra GS, Hagerty MC, Halberstadt AL and McKay CR (2010) Pilot study of
psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry,
doi:10.1001/archgenpsychiatry.2010.116.
Jones, K. A. et al. (2009). Rapid modulation of spine morphology by the 5-HT2A serotonin receptor
through kalirin-7 signaling. Proc. Natl Acad. Sci. USA 106, 1957519580.
Kavalali ET, Monteggia LM. (2012). Synaptic Mechanisms Underlying Rapid Antidepressant Action of
Ketamine. Am J Psychiatry. 2012 Oct 3. (pre-print Epub)
Khan, ZU, et al. (2001). An astroglia-linked dopamine D2-receptor action in prefrontal cortex. Proc
Natl Acad Sci 98(4):1964-9.
Knapska E, Kaczmarek L. (2004). A gene for neuronal plasticity in the mammalian brain: Zif268/Egr-
1/NGFI-A/Krox-24/TIS8/ZENK? Prog Neurobiol 74: 183211.
Krystal, J. H. et al. (2009). Neuroplasticity as a target for the pharmacotherapy of anxiety disorders,
mood disorders, and schizophrenia. Drug Discov. Today 14, 690697.
Leah, John, Peter A. Wilce (2002). The Egr transcription factors and their utility in mapping brain
functioning. Handbook of Chemical Neuroanatomy 19, 309-328.
Li, Naxin, et al. (2010). mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant
Effects of NMDA Antagonists. Science Vol. 329 no. 5994 pp. 959-964.
Liu B.C. Et al. (2010). No association between EGR gene family polymorphisms and schizophrenia inthe Chinese population. Prog Neuropsychopharmacol Biological Psychiatry. 34(3):506-9.
Ludwig, Anastasia et al. (2011). Early Growth Response 4 Mediates BDNF Induction of PotassiumChloride Cotransporter 2 Transcription. The Journal of Neuroscience 31(2), 644-649.
23
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
24/25
Man, Pui-Sui, David A. Carter (2008). Pineal gland expression of the transcription factor Egr-1 is
restricted to a population of glia that are distinct from nestin-immunoreactive cells. J Mol
Histol. 39:6975.
Multidisciplinary Association of Psychedelic Studies (2011). R&D Medicines > Other Psychedelic
Research Around the World. Retrieved 4/19/11 from http://www.maps.org/research/
Martinowich K, Manji H, Lu B. (2007). New insights into BDNF function in depression and
anxiety. Nature Neurosci. 10:10891093.
Mayer, Sabine I. Et al. (2009) Epidermal growth factor-induced proliferation of astrocytes
requires Egr transcription factors, J. Cell Sci. 122, pp. 33403350.
Moises, Hans W, Tomas Zoega, Irving I Gottesman (2002). The glial growth factors deficiency and
synaptic destabilization hypothesis of schizophrenia. BMC Psychiatry 2: 8.
Moreno JL, Holloway T, Albizu L, Sealfon SC, Gonzlez-Maeso J. (2011). Metabotropic glutamatemGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic
5-HT2A receptor agonists. Neurosci Lett. 493(3):76-9.
Paolone G, Botreau F, Stewart J. (2009). The facilitative effects of D-cycloserine on extinction of a
cocaine-induced conditioned place preference can be long lasting and resistant to reinstatement.
Psychopharmacology (Berl) 202(13):4039
Pareyson D, Taroni F, Botti S, et al. (2000). Cranial nerve involvement in CMT disease type 1 due to
early growth response 2 gene mutation.. Neurology 54 (8): 16968.
Patil, S. T. et al. (2007). Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a
randomized Phase 2 clinical trial. Nature Med. 13, 11021107.
Perez-Cadaha, Beatriz, Bojan Drobic, James R. Davie (2011). Activation and function of immediate-
early genes in the nervous system. Biochem. Cell Biol. 89: 6173.
Schmid CL, Raehal KM, Bohn LM. (2008). Agonist-directed signaling of the serotonin 2A receptor
depends on beta-arrestin-2 interactions in vivo. Proc. Natl. Acad. Sci. USA 105:107984.
Schmidt A, et. al. (2012). Modeling Ketamine Effects on Synaptic Plasticity During the Mismatch
Negativity. Cereb Cortex. (pre-print Epub)
Rajkowska G, Miguel-Hidalgo JJ. Gliogenesis and glial pathology in depression. CNS Neurol DisordDrug Targets. 2007;6:219233.
Simmons MA. (2005). Functional selectivity, ligand-directed trafficking, conformation-specificagonism: What's in a name? Mol Interv. 5:154157.
Svenningsson, Per, et al. (2006) Alterations in 5-HT1B Receptor Function by p11 in Depression-LikeStates. Science 311: 77-80.
24
-
7/30/2019 The Doors of Reception: Functionally selective receptor mosaics and the plasticity-inducing psychedelics that bind
25/25
Unoki M, Nakamura Y (2003). EGR2 induces apoptosis in various cancer cell lines by direct
transactivation of BNIP3L and BAK.Oncogene 22 (14): 217285.
Vidal, Rebecca, et al. (2011). New strategies in the development of antidepressants: towards the
modulation of neuroplasticity pathways. Curr Pharm Des 17(5): 521-33.
Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bbler, A., Vogel, H. & Hell, D. (1998).
Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist
action. Neuroreport 9, 38973902
Vollenweider, Franz X. & Michael Kometer (2010). The neurobiology of psychedelic drugs:
implications for the treatment of mood disorders. Nature Reviews Neuroscience 11, 642-651
Warner LE, Mancias P, Butler IJ, et al.(1998). "Mutations in the early growth response 2 (EGR2) gene
are associated with hereditary myelinopathies.". Nature. Genetics 18(4): 3824.
Van Woerkom, A.E. (1990). The major hallucinogens and the central cytoskeleton: An association
beyond coincidence? Towards subcellular mechanisms in schizophrenia.Med. Hypothes. 31 , p. 7.
Xu T, Pandey SC. (2000). Cellular localization of serotonin(2A) (5HT(2A)) receptors in the rat brain.
Brain Res Bull. 51(6):499-505.
Yamada, K., et al. (2007). Genetic analysis of the calcineurin pathway identifies members of the EGR
gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia. Proc Natl Acad
Sci U S A.104(8):2815-20.
25