The meth brain: methamphetamines alter brain functions via NMDA receptors

Abstract

Commentary to: Functional changes in pyramidal neurons in the chronic methamphetamine-treated rat. (Gen. Physiol. Biophys. 2015, pp.5-12).

Full text

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E d ito ri al C o m m e n t a r y
Gen. Physiol. Biophys. (2015), 34, 1–3
doi: 10.4149/gpb_2014044
Correspondence to: Juliane Pro, Institute of Organic Chemistry
and Biochemistry, Academy of Sciences of the Czech Republic,
v.v.i., Flemingovo nám. 2, 166 10 Prague 6 – Dejvice, Czech Re-
p
ublic
E-mail: pro@uochb.cas.cz
N
orbert Weiss, Institute of Organic Chemistry
and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i.,
Flemingovo nám. 2, 166 10 Prague 6, Dejvice, Czech Republic
E-mail: weiss@uochb.cas.cz
Methamphetamines (MAP) like crystal meth (MDA 3.4
methylendioxyamphetamine) and ecstasy (MDMA, 3.4
methylendioxymethamphetamine) are a group of neuro-
t
oxic drugs oen used as a recreational drug and poten-
t
ially to treat some neurological disorders. For instance,
MDMA has been used as a therapeutic drug for posttrau-
m
atic stress disorder (PTSD) (Parrott 2014) as well as for
attention deficit hyperactivity disorder (ADHD), although
it has been declared as non-safe treatment due to its neu-
r
otoxicity and its addictive effect in human (Rusyniak
2013; Parrott 2014). Furthermore, addictive use of MAP
derivatives has been shown to cause impaired learning
and memory as well as other mental disorders (Schroder
et al. 2003). In addition, an increased risk of Parkinson’s
disease (Bognar et al. 2013) has been documented in MPA
users (Callaghan et al. 2012). Neurotoxicity of MPAs was
explained by alteration of NMDA receptors and dopamine
signaling pathways (Simoes et al. 2007; Ares-Santos et al.
2013). In addition, ecstasy binds to serotonin transporters
and causes depletion of serotonin from its storage as well
as release of dopamine and other neurotransmitters (White
et al. 1996; Kish et al. 2010). Considerable efforts were
made to characterize the influence of MAP derivatives
on hippocampal structures in the brain, but little is known
about the alterations in the sensory system, especially the
piriform cortex, the area that is mostly known to sense
odors (White et al. 1996).
In this issue of General Physiology and Biophysics,
Hori et al. (pp. 5–12) treated rats chronically with MPA
and investigated via electrophysiological recordings the
influence of MPA on piriform cortex neurons, especially
focusing on NMDA and AMPA receptors activity. e
group observed the typical sniffing behavior and increase
of movement in chronically-treated rats, the same behavior
that is oen observed in humans using MPA over a long
period of time. ese changes in behavior come with
alterations of the morphology of dentrites of pyramidal
cells. MPA-treated rats showed blebbing of the dentrites
visible aer staining with Lucifer yellow, to better identify
the soma and dentrites of neurons. Blebbing of the cell
typically occurs during apoptosis where the cytoskeleton
breaks up causing an outward bulge of the cell membrane
(Vermeulen et al. 2005). Blebbing can also play a role in
other cellular processes like necrosis (Wyllie et al. 1980),
chemical or physical stress, cell locomotion or division
(Norman et al. 2010).
In addition, the authors observed a significant altera-
t
ion of the electrical properties of the pyramidale neurons
characterized by decrease of the membrane potential and
input resistance of the cells. In order to further investigate
the influence of MPA on neuronal network excitability and
plasticity, transient post tetanic potentiation (PTP) and
long-term potentiation (LTP) were analyzed (Gasparova
et al. 2014). While PTP remains unaltered, LTP was sig-
n
ificantly decreased in MPA-treated animals. In addition,
ionotrophic application of AMPA and NMDA indicates an
e meth brain: methamphetamines alter brain functions via NMDA
receptors
Juliane Pro and Norbert Weiss
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic
Commentary to: Functional changes in pyramidal neurons in the chronic methamphetamine-treated
rat. (Gen. Physiol. Biophys. 2015, pp. 5–12)
Key words: Ion channel — Met
hamphetamine — Piriform cortex — NMDA receptor — AMPA
receptor

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altered AMPA/NMDA receptors activity in MPA-treated
rats. Considering that NMDA and AMPA receptors repre-
s
ent the molecular substrate of LTP, it is likely that alteration
of NMDA/AMPA response contributes to the alteration
of LTP induced by MPA treatment.
Glutamatergic NMDA and AMPA receptors represent
essential component of synaptic plasticity and long-term
potentiation and depression (Luscher and Malenka 2012;
Mokrushin and Pavlinova 2013). eobservationthatchronic
treatment with MPA alters NMDA/AMPA response certainly
represents an interesting molecular substrate for MPA-de-
p
endent alteration of cognitive functions. In addition, it is
well accepted that alteration of NMDA and AMPA receptors
significantly contribute to neurodegenerative disorders like
Parkinson’s and Alzheimer’s diseases (You et al. 2012; Proand
Weiss 2014). Interestingly, a MPA-induced animal model for
Parkinson’s disease (Pro et al. 2011; Curtin et al. 2014; Tai et
al. 2014) has been described. Moreover, a binding of MPA to
α-synuclein has been reported and causes missfolding of α-
synuclein, a key protein in Parkinson’s disease (Tavassoly and
Lee 2012). It is possible that missfolded α-synuclein could alter
gluramatergic NMDA-dependent signaling pathway like it has
been shown for missfolded amyloid (Pro and Weiss 2012;
Stys et al. 2012; You et al. 2012).
Overall the results described in the paper by Hori et al.
represent an interesting molecular substrate of how drug
abuse might cause neurodegenerative disorders and a better
understanding of the interaction of those drugs with key
neuronal proteins will certainly highlight not only the
molecular mechanism of drug-induced cognitive disorders
but also potentially translate to a better basic understanding
of those diseases.
Acknowledgment. e workin N.W.’s laboratory was supported by
the Czech Science Foundation [Grant 15-13556S] and the Institute
of Organic Chemistry and Biochemistry (IOCB). J.P. is supported
by a postdoctoral fellowship from IOCB.
References
Ares-Santos S., Granado N., Moratalla R. (2013): e role of
dopamine receptors in the neurotoxicity of methamphetamine.
J. Intern. Med. 273, 437–453
http://dx.doi.org/10.1111/joim.12049
Bognar C., Baldovic M., Benetin J., Kadasi L., Zatkova A. (2013):
A
nalysis of Leucine-rich repeat kinase 2 (LRRK2) and Par-
k
inson protein 2 (parkin, PARK2) genes mutations in Slovak
Parkinson disease patients. Gen. Physiol. Biophys. 32, 55–66
http://dx.doi.org/10.4149/gpb_2013006
Callaghan R. C., Cunningham J. K., Sykes J., Kish S. J. (2012):
I
ncreased risk of Parkinson’s disease in individuals hospital-
i
zed with conditions related to the use of methamphetamine
or other amphetamine-type drugs. Drug Alcohol Depend.
1
20, 35–40
http://dx.doi.org/10.1016/j.drugalcdep.2011.06.013
Curtin K., Fleckenstein A. E., Robison R. J., Crookston M. J.,
S
mith K. R., Hanson G. R. (2015): Methamphetamine/am-
p
hetamine abuse and risk of Parkinson’s disease in Utah:
A population-based assessment. Drug Alcohol Depend.
1
46, 30–38
http://dx.doi.org/10.1016/j.drugalcdep.2014.10.027
Gasparova Z., Stara V., Stolc S. (2014): Effect of antioxidants
o
n functional recovery after in vitro-induced ischemia and
long-term potentiation recorded in the pyramidal layer of
the CA1 area of rat hippocampus. Gen. Physiol. Biophys.
3
3, 43–52
http://dx.doi.org/10.4149/gpb_2013062
Hori N., Kadota T., Akaike N. (2014): Functional changes in piri-
f
orm cortex pyramidal neurons in the chronic methampheta-
m
ine-treated rat. Gen. Physiol. Biophys.
Kish S. J., Lerch J., Furukawa Y., Tong J., McCluskey T., Wilkins
D., Houle S., Meyer J., Mundo E., Wilson A. A. et al. (2010):
Decreased cerebral cortical serotonin transporter binding in
ecstasy users: a positron emission tomography/[(11)C]DASB
and structural brain imaging study. Brain 133, 1779–1797
http://dx.doi.org/10.1093/brain/awq103
Luscher C., Malenka R. C. (2012): NMDA receptor-dependent
l
ong-term potentiation and long-term depression (LTP/LTD).
Cold Spring Harb. Perspect. Biol. 4
Mokrushin A. A., Pavlinova L. I. (2013): Effects of the blood
components on the AMPA and NMDA synaptic responses in
brain slices in the onset of hemorrhagic stroke. Gen. Physiol.
Biophys. 32, 489–504
http://dx.doi.org/10.4149/gpb_2013038
Norman L. L., Brugues J., Sengupta K., Sens P., Aranda-Espinoza
H
. (2010): Cell blebbing and membrane area homeostasis in
spreading and retracting cells. Biophys. J. 99, 1726–1733
http://dx.doi.org/10.1016/j.bpj.2010.07.031
Parrott A. C. (2014): e potential dangers of using MDMA for
p
sychotherapy. J. Psychoactive Drugs 46, 37–43
http://dx.doi.org/10.1080/02791072.2014.873690
Pro J., Faraji J., Robbins J. C., Zucchi F. C., Zhao X., Metz G. A.,
B
raun J. E. (2011): Identification of bilateral changes in TID1
expression in the 6-OHDA rat model of Parkinson’s disease.
PLoS One 6, e26045
http://dx.doi.org/10.1371/journal.pone.0026045
Pro J., Weiss N. (2012): Jekyll and Hide: e two faces of amyloid
b
eta. Commun. Integr. Biol. 5, 405–407
http://dx.doi.org/10.4161/cib.22571
Pro J.,Weiss N. (2014):Rectifying rectifier channelsin Huntington
di
sease. Commun. Integr. Biol. 7, e29410
http://dx.doi.org/10.4161/cib.29410
Rusyniak D. E. (2013): Neurologic manifestations of chronic
m
ethamphetamine abuse. Psychiatr. Clin. North Am. 36,
2
61–275
http://dx.doi.org/10.1016/j.psc.2013.02.005
Schröder N., O’Dell S. J., Marshall J. F. (2003): Neurotoxic meth-
a
mphetamine regimen severely impairs recognition memory
in rats. Synapse 49, 89–96
http://dx.doi.org/10.1002/syn.10210
Simoes P. F., Silva A. P., Pereira F. C., Marques E., Grade S., Milhazes
N
., Borges F., Ribeiro C. F., Macedo T. R. (2007): Methampheta-

3
mine induces alterations on hippocampal NMDA and AMPA
receptor subunit levels and impairs spatial working memory.
Neuroscience 150, 433–441
http://dx.doi.org/10.1016/j.neuroscience.2007.09.044
Stys P. K., You H., Zamponi G. W. (2012): Copper-dependent
r
egulation of NMDA receptors by cellular prion protein:
implications for neurodegenerative disorders. J. Physiol. 590,
1357–1368
http://dx.doi.org/10.1113/jphysiol.2011.225276
Tai Y., Chen L., Huang E., Liu C., Yang X., Qiu P., Wang H. (2014):
P
rotective effect of alpha-synuclein knockdown on metham-
p
hetamine-induced neurotoxicity in dopaminergic neurons.
Neural. Regen. Res. 9, 951–958
http://dx.doi.org/10.4103/1673-5374.133146
Tavassoly O., Lee J. S. (2012): Methamphetamine binds to alpha-
s
ynuclein and causes a conformational change wich can be
detected by nanopore analysis. FEBS Lett. 586, 3222–3228
http://dx.doi.org/10.1016/j.febslet.2012.06.040
Vermeulen K., Van Bockstaele D. R., Berneman Z. N. (2005): Ap-
o
ptosis: mechanisms and relevance in cancer. Ann. Hematol.
84, 627–639
http://dx.doi.org/10.1007/s00277-005-1065-x
White S. R., Obradovic T., Imel K. M., Wheaton M. J. (1996): e
e
ffects of methylenedioxymethamphetamine (MDMA, “Ec-
s
tasy”) on monoaminergic neurotransmission in the central
nervous system. Prog. Neurobiol. 49, 455–479
http://dx.doi.org/10.1016/0301-0082(96)00027-5
Wyllie A. H., Kerr J. F., Currie A. R. (1980): Cell death: the signifi-
c
ance of apoptosis. Int. Rev. Cytol. 68, 251–306
http://dx.doi.org/10.1016/S0074-7696(08)62312-8
You H., Tsutsui S., Hameed S., Kannanayakal T. J., Chen L., Xia P.,
E
ngbers J. D., Lipton S. A., Stys P. K., Zamponi G. W. (2012):
Abeta neurotoxicity depends on interactions between copper
ions, prion protein, and N-methyl-D-aspartate receptors. Proc.
Natl. Acad. Sci. U.S.A. 109, 1737–174
http://dx.doi.org/10.1073/pnas.1110789109