Basal Ganglia
Chapter 1
Does Striatum Play One of the Key Roles
in the Pathogenesis and Maintenance of
Emotional and Motivational Disturbances?
Nataliya A Krupina* and Nadezhda N Khlebnikova
Laboratory of the General Pathology of Nervous System,
Federal State Budgetary Scientific Institution “Institute of
General Pathology and Pathophysiology”, Russia
Corresponding Author: Nataliya A Krupina, Laboratory of the General Pathology of Nervous System,
Federal State Budgetary Scientific Institution “Institute
of General Pathology and Pathophysiology”, Russia, Tel:
+7-499-151-1756; Fax: +7-495-601-2366; Email: [email protected]
*
First Published June 19, 2017
Acknowledgement: These studies were partly supported
by the Russian Foundation for Basic Research (RFBR) (grant
number: 15-04-08784). The RFBR had no role in the design,
implementation, analysis, or interpretation of the data, in the
preparation of the manuscript, or in the decision to submit
the paper for publication.
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Copyright: © 2017 Nataliya A Krupina and Nadezhda N
Khlebnikova.
This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which
permits unrestricted use, distribution, and reproduction
in any medium, provided you give appropriate credit to
the original author(s) and the source.
Abstract
The functional role of the striatum as a component
of basal ganglia in the genesis of mental disorders is not
well understood. In this chapter, we make an attempt to
summarize the data obtained in our studies, on the role
of the dorsal and ventral striatum (DS and VS) in the
mechanisms of experimental emotional and motivational
disorders in rats. In the neurophysiological studies on the
model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP)-induced depressive syndrome, we observed the
most significant changes in the spectral characteristics of
electrical activities in the DS and the frontal cortex upon
the syndrome developing. After MPTP withdrawal, longterm rearrangement of the spectral characteristics was
maintained only in the DS when behavioral symptoms of
depression should already disappear. These changes could
serve as a basis for the persistence of the pathological processes in its inactive form and retain for some time the
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possibility of its transfer to an active state. In the neurochemical studies, using the rat model of MPTP-depressive
syndrome, the “behavioral despair” model of depression,
and the original model of anxiety- and depression-like disorders with increased aggression, induced by the neonatal
action of a synthetic dipeptidyl peptidase-IV (DPP-IV)
inhibitor methionyl-2(S)-cyano-pyrrolidine, we consistently observed the increase in the activity of proline-specific peptidases DPP-IV and prolyl endopeptidase (PREP)
exactly in the striatum (DS) and the frontal cortex. In the
latter case, the increase of PREP activity was also revealed
in the nucleus accumbens (VS). Only in the striatum as
a whole structure (without dividing into DS and VS) we
showed an increased expression of the gene encoding
PREP, in rats after the neonatal exposure to the DPP-IV
inhibitor diprotin A, as well as an increased expression of
the gene encoding DPP-IV, in rats after the neonatal exposure to another DPP-IV inhibitor, sitagliptin. We suggest that the striatum abnormalities may play one of the
key roles in the processes of emotional- and motivationalrelated disturbances thus contributing to the persistence
of the disorders.
Keywords
Striatum; Emotional And Motivational Disorders;
MPTP-Induced Depressive Syndrome; Rat Models; Brain
Electrical Activity; Proline Endopeptidase; Dipeptidyl
Peptidase IV; Monoamines; Gene Expression
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The functional role of the basal ganglia (BG) is not
yet fully understood. The findings assume that BG which
may interact with limbic, prefrontal and motor cortex take
part in the selection of action related to cognitive events
and emotional states as well as in the motor action [1]. BG
functionality based on the pre- and postsynaptic neuronal
plasticity [2] manifests in the restructuring of the neurotransmitter systems, which determine the BG interaction
with the cortex and subcortical brain structures [3].
The сomponents of the basal ganglia include corpus
striatum subdivided into the caudate and putamen known
collectively as the dorsal striatum (DS), the ventral striatum (VS, includes ventrolateral putamen, nucleus accumbens - NAcc), the substantia nigra (SN, includes the
pars compacta SNc and the pars reticulate SNr), the subthalamic nucleus (STN), and the globus pallidus (GP, includes the internal segment GPi and the external segment
GPe) [1,4]. It is generally accepted that BG are divided
into sensorimotor (DS, posterior part of the putamen), associative (dorsal part of the anterior striatum (caudate),
ventrolateral putamen), and limbic (the most ventral part
of the anterior striatum, including NAcc) territories thus
implicated in motor, cognitive, and motivational processing [4,5]. These territories partially overlap that provides
the basis for integrative activities. Given this, the involvement of the striatum in some neuropsychiatric disorders,
including emotional and motivational disorders is rather
natural.
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Indeed, numerous data confirm the involvement of
the striatum, especially VS, in the emotion processing
abnormalities in psychiatric populations including major
depressive disorder [6-8]. Although most studies focus on
the role of the VS in the pathophysiological mechanisms
of mental disorders, the involvement of the DS in these
processes cannot be ruled out. The main brain dopaminergic systems include nigrostriatal system, which originates from the dopaminergic neurons in the SNc with its
terminal field in the DS (associated with motor function),
mesolimbic and mesocortical dopamine systems, which
originate in the ventral tegmental area (VTA) with their
terminal fields in the limbic structures (NAcc and others)
and cortex (medial prefrontal, cingulate and perirhinal),
respectively (associated with motivation and emotion).
However, the DS is also essential for motivational activities, that is, the functional division of the brain dopaminergic systems is quite a matter of convention [9].
In the clinic, we usually see not the very beginning of
the pathological process but rather the peak of its development. How do we know what lies at the beginning? How
to understand what is happening in the brain structures
when emotional and motivational disorders develop?
Does the contribution of certain limbic structures change
in the dynamics of the pathological process? What happens when remission? What supports the dysregulation
in the neural circuits in the brain in patients with mental
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abnormalities? Answers to these questions suggest using
methods of translational medicine.
Based on the concept that the BG are involved in the
genesis of emotional and motivational disorders, in neurophysiological experiments, we tested the hypothesis
that DS and VS could play diverse roles at the different
stages of a pathological process. We used the model of a
depressive syndrome induced in Wistar rats by repeated
administration of the proneurotoxin 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP, at a dose of 20 mg/kg,
intraperitoneally, daily, for two weeks), which induces the
death of dopaminergic neurons in the SN [10,11]. MPTPtreated rats demonstrate lowered locomotion and exploration in the open field test, reduced daily liquid intake with
a decrease in the preference for the sucrose solution over
water, prolonged immobility and biorhythmic changes in
the forced swimming test that is the development of a state
of lowered motivation combined with anhedonia and “behavioral despair.” The changes in rat behavior maintain for
at least a week after drug withdrawal.
In neurophysiological experiments, we did not assess behavior but only estimate the dynamics of the body
weight as an indirect indicator of food motivation in rats.
We also measure the structure of a sleep-wakefulness cycle over four hour’s observation in the middle part of the
day because the increase the REM sleep density in the
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overall structure of the sleep was found as a biomarker or
an endophenotype of major depressive disorder [12].
A week before MPTP administration, electrodes for
recording electrical activity (EA) were implanted into the
DS, which is the terminal field of the nigrostriatal dopaminergic system (AP +1.0, L 2.5, H 5.0), the frontal cortex,
which is the terminal field of the mesocortical dopaminergic system (FC) (AP +4.0, L 1.5, H 1.0), the NAcc, which
is the terminal field of the mesolimbic dopaminergic system (AP +1.7, L 1.7, H 7.0), as well as into the amygdala
(basomedial amygdaloid nucleus, posterior part) (AP
–3.3, L 4.2, H 9.2), and the dorsal hippocampus (HIP)
(AP –4.3, L 3.5, H 3.5), using atlas coordinates [13]. We
estimated the changes in the relative spectral power (rSP)
of EA in the standard frequency bands, using fast Fourier transformation procedure. The differences in rSP, as
well as the changes in the proportion of REM sleep in the
sleep-wakefulness cycle, were evaluated using parametric
repeated measures ANOVA with a test week as a betweensubject factor followed by a comparison of means within
groups [14].
Experimental rats demonstrated the signs of the depressive state with a reduction in a body weight and an
increase in the percent of REM sleep in the sleep-wakefulness cycle by the end of two weeks MPTP administration.
The changes in the rSP in the brain structures are shown in
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Table 1. During the development of experimental depressive syndrome in rats, we observed the rearrangement of
the spectral characteristics of EA in the target structures
of the nigrostriatal, mesocortical, and mesolimbic dopaminergic systems of the brain, as well as in the amygdala
and HIP. As compared with the background, the most significant changes in rSP that are the decrease in the delta-1 and theta-1 bands and the increase in the beta-1 and
beta-2 bands were observed in the DS and FC. A similar
decrease in the rSP in the delta-1 and theta-1 ranges was
revealed in the NAcc. As for the HIP and amygdala, the
changes in the rSP were few and manifested only in the
decrease of theta-1 activity. Only in the DS, we saw the
increase in the rSP in the alpha-band on the development
of the depressive syndrome (during two weeks of MPTP
administration).
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Table 1: Dynamics of changes in the relative spectral power of electrical activity in the frontal cortex, dorsal striatum and nucleus accumbens in the rats with experimental 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-induced depressive syndrome.
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The «↑» (red arrow and background) and « ↓» (blue arrow and background) indicate statistically significant increase and decrease in the
relative spectral power compared with baseline (before MPTP administration), respectively. Delta-1 (1–2 Hz), delta-2 (3–4 Hz), theta-1
(5–6 Hz), theta-2 (7–8 Hz), alpha (9–13 Hz), beta-1 (14–20 Hz), beta2 (21–32 Hz) – standard frequency bands; t – trend.
On MPTP withdrawal, experimental animals showed
an increase in weight gain and the rapid disappearance of
alterations in the rSP in all the structures except the DS.
In this structure, the increase in the power in the alphaband was detected up to three weeks after MPTP withdrawal when there were no behavioral alterations in rats.
In the NAcc, we saw the increase in the rSP in the alphaband only a week after MPTP withdrawal that means the
significant difference between the VS and the DS in the
rearrangement of the spectral characteristics of EA in the
brain in animals with an experimental dopamine-deficit-
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dependent depressive syndrome. Moreover, only in the
DS, we observed the increase in the power of the delta-2
activity three and four weeks after MPTP withdrawal. It is
worth noting that in contrast to normalizing of the weight
and spectral changes in the EA of the brain, the increase
in REM sleep percent in the sleep-wakefulness cycle remained even a month after MPTP withdrawal.
As for the control animals, repeated saline administration was accompanied by the generalized decline in
rSP in the theta-2 but not in the theta-1-band which only
persisted in the HIP along with the emergence of increase
in the rSP in the delta-2-band after the saline withdrawal.
Similar to MPTP-treated rats, saline-treated animals demonstrated the increase in rSP in the beta-1 band in the FC
by the end of the saline administration which persisted for
a week after the treatment stopped. On the whole, the pattern of the EA changes in the saline-treated rats was different from that in the animals of the experimental group.
The high degree of communication between the FC
and the DS, which manifests in similar changes of EA in
rats with developing depressive syndrome, is noteworthy. It fits with the idea of the abnormal functioning of
the cortical-striatal neural circuits in affective disorders,
which is based on various data on functional organization
and anatomical connections of the cortex and striatum
and their changes in the decision-making, planning the
general strategy and reinforcement processes [3,15,16], in
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the neuroimaging, neuropathological, and lesion analysis
studies of emotional behavior in mood disorders [17-19].
The possibility of the obligate nature of neuronal abnormalities in the neural circuits in the pathogenesis of affective disorders is being discussed [18,20]. If the abnormalities in the brain structures reverse during symptom
remission, they likely reflect areas where changes respond
to the emotional and behavioral manifestations of the
disorder. If the abnormalities persist despite symptom
remission, in some cases they may be linked to anatomical differences between depressive and control subjects.
We cannot but agree with it. In the present not very long
study, we did not compare the anatomical features of the
brain structures in the experimental and control rats but
evaluate the character and the duration of the changes in
the EA of the brain. Long-term rearrangement of EA in
the DS when behavioral symptoms of depression should
already disappear testifies to neuroplastic changes in the
DS under the developments of the depressive-like state.
These changes could serve as a pathophysiological basis
for maintaining the pathological process in its inactive
form with subsequent transfer to the active state. To be
fair, we should remember that the changes in the EA in
the DS were accompanied by an increase in the percent
of the REM-sleep in experimental rats seen up to a month
after the withdrawal of exposure; therefore, some signs of
depressiveness persisted.
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Could the alterations in DS neuronal functioning
trigger the development of the experimental MPTP-induced state? An affirmative answer to this question is very
likely since chronic MPTP treatment produced a significant and irreversible DA depletion in the striatum as well
as a marked decrease in tyrosine hydroxylase mRNA level
in the SN [21]. In the model of the MPTP-induced depressive syndrome, using HPLC/ED, we have previously
shown that the content of the dopamine precursor L-3,4dihydroxyphenylalanine (DOPA) in the rat striatum was
decreased but restore when behavioral symptoms of depression disappear [22] (Table 2) that allowed characterizing this model as a dopamine-deficiency-dependent.
Alterations of midbrain DA neurons including SN are
known to be implicated in depression [23]. We believe
that primary abnormalities in the pathway SN – DS could
trigger the abnormal functioning in the cortical-striatal
nervous circuit, that is, trigger the functioning a pathological system (pathological integration) which includes
brain structures [24] involved in the realization of emotional and motivational behavior. In our studies, in addition to the DS, these are the FC, the HIP, the amygdala and
the NAcc since EA changes, to a greater or lesser extent
similar with the changes in the DS, were seen in each of
these structures. These views do not contradict Drevets’
notion [18] that dysfunction within and between structures in the neurocircuit that underlie depression may induce disturbances in emotional behavior.
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Table 2: Comparative analysis of changes in the monoaminergic systems and
activity/expression of PREP and DPP-IV in brain structures of adult male rats
with emotional and motivational disorders of different origin.
Experimental
models of
emotional and
motivational
disorders in
rats
Depressive syndrome induced
by repeated
MPTP administration
«Behavioral
despair»
induced in the
forced swim test
Mixed
anxiety-depression-like
disorder induced
by neonatal
action of methionyl-2(S)-cyano-pyrrolidine
Mixed anxiety-depression-like disorder induced by
neonatal action
of diprotin A
Mixed anxiety-depression-like disorder induced by
neonatal action
of sitagliptin
Monoamines
Frontal
cortex
Nucleus
Striatum
accumbens
(includes
(included in
DS)
VS)
↓DOPA
Not assessed
Not assessed
Not
assessed
Not assessed
↑5HIAA/
5-HT
↓HVA
N/S
N/S
↓HVA/
DA
Peptidases
Hypothalamus
Not assessed
Not assessed
↓(DOPAC
+ HVA)/
DA
Frontal
cortex
↑PREP
Nucleus
Striatum accumbens Hypo(includes
(included
thalamus
DS)
in VS)
↑PREP
N/S
↑PREP
N/S
N/S
↑DPPIV
↑PREP
↑PREP
↑PREP
↑DPP-IV
↑PREP
↑DPP-IV
↑PREP
↓HVA
↑PREP
↑DPP-IV
↑DOPAC/DA
N/S
↓5-HT
N/S
N/S
↑PREP
N/S
N/S
N/S
↑DPP-IV
N/S
↓5-HIAA
↓5-HT
N/S
↓5-HIAA
↓5-HIAA/5-HT
DOPA – dihydroxyphenylalanine; DA – dopamine; DOPAC – dihydroxyphenylacetic acid; HVA –
homovanillic acid; 5-HT – 5-hydroxytryptamine; 5-HIAA – 5-hydroxyindoleacetic acid. N/S - no
significant difference vs. the control. On models of mixed anxiety-depressive state induced by the
neonatal action of diprotin A and sitagliptin, expression of the prep and dpp4 genes was evaluated
(gray background); on the other models, the activity of the enzymes was assessed. The italic font
indicates unstable detection of the increase in the enzyme activity (for two series) or trend. The «↑»
and « » indicate statistically significant increase and decrease compared to the controls, respectively.
↓
Measurements of the activity of peptidases (fluorometrically by hydrolysis of synthetic fluorogenic
substrates carbobenzoxy-alanyl-proline 4-methylcoumarin-7-amide for PREP and glycyl-proline
4-methylcoumarin-7-amide for DPP-IV) or gene expression (quantitative Real-Time-PCR; Data
were normalized to GAPDH mRNA expression and calculated as relative fold changes compared to
control rats using method 2-ΔΔCt) encoding the peptidases as well as the content of monoamines
and their metabolites (high-performance liquid chromatography with electrochemical detection
HPLC/ED) were performed in adult rats aged from three to four months. In neurochemical studies,
we did not denote the striatum as DS (dorsal striatum), and we implied the structures of VS (ventral
striatum) under the notation of NAcc since the isolation of the structures was performed under
visual control. On the models of mixed anxiety-depression-like disorders we used the samples for
neurochemical and genetic analysis from the same animals; on the models induced by the neonatal
action of diprotin A and sitagliptin, we isolated the striatum, without dividing it into DS and VS.
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In approximately 93% of the experimental animals, we
observed rare bursts of synchronous epileptiform activity
represented by single spikes, ictal discharges, and spindles
in the brain structures. Presumably, under the systemic
administration of MPTP, the neurons of the studied structures are disinhibited, that creates the basis for combining
them into a hyperactive neural ensemble, the functioning
of which underlies the development of the depressive syndrome. This is in agreement with the views of Palazidou
[25] that a decrease in the inhibitory control of the limbic
structures by the pre-FC is associated with emotional processing abnormalities, cognitive performance, behavioral
and other signs of depression as well as abnormalities in
neurotransmitter activity. The author considers functional
abnormalities within the cortico-thalamic-striatal-limbic
neurocircuit as one of the causes of disrupting the whole
system balance. Given this, the degree of participation and
the order of involvement of the structures in the pathological integration, which manifest as affective disorders
may be determined by many factors [24]. For example,
Matheus et al. [26] showed that various manifestations of
depression-like behavior in rats submitted to 6-hydroxydopamine (6-OHDA) into the dorsolateral striatum are
accompanied by different temporal fluctuations of the
dopaminergic receptor density in the striatum and preFC leading to altered dopaminergic system sensitivity in
these two brain structures.
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How could we explain the increase in the rSP of EA
in the alpha-band in the DS? The alpha-like oscillations
in rats do not carry the same functional load as in human, and the generation of these oscillations is not clear
enough. After unilateral lesion of the nucleus reticularis
thalami, Marini et al. [27] observed stereotyped discharges developed progressively from multiple spikes within
the alpha frequency range through the lengthening of the
wave component recorded from the frontoparietal cortex.
The data confirm the hypothesis for similar corticothalamic networks of the generation of alpha oscillations in
rats and human. The evidence is obtained for the idea that
alpha rhythm plays a major role in the timing of neural
processes in both human and rats when encoding information [28]. Despite the fact that we did not record EA
from the structures of the thalamus, an increase in the
rSP in the alpha-band in the DS indicates abnormalities
in the functioning of cortical–BG–thalamic circuits [15]
in rats with depression-like behavior. In depressed patients, greater theta and alpha current density was accompanied by reduced ability to recognize positive emotions
[29]. Perhaps, the persistent and prolonged increase in the
power of alpha oscillations in the DS of animals with the
symptoms of the MPTP-induced depressive syndrome is
also associated with maintaining of emotional processing
biases. This assumption is confirmed by the observation
that depressive animals, in addition to the increase in the
rSP in the alpha range, demonstrated changes in the rSP
in the theta-band which were different from the control,
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namely, a long-term decrease in the theta-1, but not in
the theta-2 frequency range. The striatal theta rhythm is
known to be coherent with the HIP which has an association with emotions [30], indicating that the striatum
along with medial FC [31] share a common theta modulation. The data evidenced to the rearrangement of EA in
the HIP in depressive rats, which fits with the results obtained by Castro-Hernández et al. [32] who demonstrated
a time-dependent effect of the MPTP-induced dopaminergic lesion in the HIP. At the moment it’s hard to answer
the question why there were no significant changes in the
power of alpha oscillations in the FC, unlike the DS. Further research is needed.
EEG in depressive patients is characterized by the increased spectral power in the alpha (9–13 Hz) and beta
(15–23 Hz) frequency bands (occipital and parietal areas)
and decreased power in the delta (2– 3 Hz), theta (4–7
Hz), and alpha (8–11 Hz) frequency bands (frontal areas) [33]. These data, with few exceptions, is similar to the
pattern of changes in rSP in the DS and FC in the rats
with the MPTP-induced depressive syndrome. Lubar et
al. [34] related the decrease in the current density power in the delta range which was detected using LORETA
analysis, with the hypermetabolic desynchronized activity
in the right hemisphere of depressed patients that agrees
with the increase in the power of beta oscillations. These
findings coincide with our notions of disinhibition of the
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brain structures within the pathological system, which determines the clinical course of the depressive syndrome.
The increase in the rSP and coherence of beta-2 oscillations (22 – 32 Hz) in the FC and STN was associated with
6-OHDA lesions in awaked rats [35]. Thus, the increase
of the relative power in the beta-2-band in the FC and
DS in MPTP-treated rats could be the result of the dopamine deficit. However, the increase in the rSP in the beta-1-band, which was observed in FC in both depressive
and control rats predominantly during the period of drug
administration, may have another explanation. In both
groups, the rats were subjected to a stress-induced procedure of two-week injections and showed the increase
in norepinephrine (NE) content in the FC as compared
to the intact rats [22]. Stress is often accompanied by increased beta-1 activity over the cortex [36,37]. Perhaps,
the increased power of beta-1 oscillations is the consequences of a stressful injection procedure.
Our assumption that the striatum, in particular, the
DS, can play a specific role in the maintenance of the
pathophysiological basis of affective disorders, even during the remission, has been tested in biochemical studies.
Clinical data show that proline-specific peptidases, e.g.
dipeptidyl peptidase-IV (DPP-IV; EC 3.4.14.5) and prolyl endopeptidase (PREP; EC 3.4.14.5) are involved in the
pathophysiological mechanisms of depressions and anxiety [38-40]; new facts continue to appear identifying altered DPP-IV activities in plasma as potential biomarkers
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for unipolar depression [41]. However, the contribution
of these enzymes to the development of emotional and
motivational disorders remains unclear. We measured the
activities of PREP and DPP-IV in the brain structures of
rats with the experimental MPTP-induced depressive syndrome [42,43] and found an increase in PREP and DPPIV activities in the FC and PREP activity in the striatum
from series to series (see Table 2). (It should be mentioned
that in neurochemical experiments, we isolated brain
structures under visual control, so we did not use the DS
designation, but called the corresponding brain region as
striatum). In one of the series, an increase in PREP activity in the hypothalamus was observed. According to the
data, PREP activity increased in target structures of two
central dopaminergic systems – mesocortical and nigrostriatal, while DPP-IV activity increased in the target structure of the only mesocortical system. It is noteworthy that
we did not find any changes in the activity of peptidases
in the NAcc. The results confirmed the neurochemical rearrangement in the FC and striatum and agreed with the
notion that primary abnormalities in the pathway SN –
striatum could trigger the abnormal functioning in the
cortical-striatal nervous circuit. We suggested that the increase in the activities of these peptidases in the FC and
striatum could be a biochemical marker of affective disorders and, moreover, play a role in the pathogenesis of the
depression-like behavior. This assumption was tested on
other models of emotional and motivational disturbances.
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In the model of «behavioral despair» manifested as a
refusal to continue the efforts to escape from the aversive
situation in the forced swimming test, we also observed
the increase in the PREP in the FC while increased activities of the both peptidases were shown in the striatum
(see Table 2) [44]. These data support the assumption
mentioned above and raise the question of the different
contribution of increasing the activity of each of these
peptidases in the brain structures to the pathogenesis of
depressive-like behavior of various etiology.
Another approach to validating the assumption of
an increase in the activity of peptidases in the striatum
and FC as one of the mechanisms of pathogenesis of
emotional and motivational disorders consisted in an attempt of modeling such disorders by modulating the activity of DPP-IV in rats in the early neonatal period. We
used a synthetic non-competitive irreversible inhibitor
of DPP-IV methionyl-2(S)-cyano-pyrrolidine as a tool
to affect DPP-IV activity in the immature rat brain. Neonatal exposure to the inhibitor caused long-term anxiety- and depression-related behaviors in adolescent and
adult rats – from the first to the seventh month [45]. In
the social contact test, adult animals demonstrated aggression provoked by two-days-isolation stress (so-called
latent or hidden aggression) [46]. In the dynamics of the
emotional and motivational abnormalities, we observed
the alternation of the predominance of increased anxiety
and depressive-like behavior, which resembled the course
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of a mixed anxiety-depressive disorder in humans. The
changes in peptidases activity in the FC and striatum in
the three-month-old rats was similar to that in the model of «Behavioral despair,» however, in addition, we observed the increase in proteases activities in the NAcc and
hypothalamus (see Table 2) [47,48]. In one of the series,
the rats aged three months did not demonstrate the signs
of increased anxiety and depression, but we did detect the
increase in PREP activity in the NAcc and hypothalamus.
We emphasize that anxiety and depression were detected
in these animals at the age of one and two months while
the only aggression was observed in the three-month-old
rats. Is there a particular association between the aggression and the increase in PREP activity in the NAcc and hypothalamus? Does the increase of PREP activities in these
brain structures support the existence of a pathological
system during periods of its incomplete clinical manifestation? These questions are not settled yet.
An age-related dynamics of increasing peptidases
activity in brain structures of rats with a mixed anxietydepressive state induced by the action of a synthetic DPPIV inhibitor is of interest. In the one-month-old animals,
we observed an increase in the activity of both peptidases
only in the FC and the hypothalamus; Statistically significant changes in the PREP in the hypothalamus persisted in
the three-month-old rats, and an increase in PREP activity in the NAcc manifested; Finally, in the seven-monthold rats, an increase in the activity of DPP-IV was detected
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in all brain structures, and the activity of PREP increased
in the FC and striatum. At different stages of observation,
as mentioned above, these or other symptoms of emotional and motivational abnormalities prevailed. Thus, there
was no apparent reason to suppose worsening in the state
of animals, but from the analysis of peptidases activity,
we saw an increase in the number of brain structures, in
which the activities of the enzymes were increased. In the
dynamics of the pathological process, a gradual involvement of the striatum structures in the pathological process occurred, and the increase in peptidases activities in
the NAcc preceded that in the striatum. In our opinion,
these data may indicate the expansion and strengthening
of interrelations in pathological neuronal integration as
the neuroplastic changes develop, which contributes to its
stabilization and creates difficulties in the search for appropriate therapy.
Of particular interest, that the neonatal action of the
DPP-IV inhibitor ultimately leads not to the expected decrease, but, on the contrary, to an increase in the activity
of not only DPP-IV but also PREP in the brain structures.
Increased activity of DPP-IV can be an adaptive response
to prolonged enzyme suppression by the DPP-IV inhibitor
in the period of neurodevelopment when the activity of
the protease increases. We believe that it is the increase in
the activities of DPP-IV and PREP that is associated with
the appearance of emotional and motivational abnormalities. This assumption is in good agreement with the data
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Basal Ganglia
that targeted inactivation of the gene encoding DPP-IV
leads to an antidepressant-like and hyperactive phenotype
in mice [49], and DPP-IV deficiency in rats manifests as
decreased anxiety and reduced stress-like behavioral responses [50,51]. However, we want to emphasize that for
the development of emotional and motivational disorders,
an increase in the activity of peptidases exactly in the striatum (DS + VS) and FC may be of the most importance.
The changes in the activity of proteases are most likely the
result of epigenetic regulation when a long-acting DPPIV inhibitor is administered in the early postnatal period.
When asked why the increase in DPP-IV activity is accompanied by an increase in PREP activity, there is no answer yet. It is the subject of a particular analysis.
Recently we have shown that systemic administration
of two well-known reversible competitive DPP-IV inhibitors diprotin A (H-Ile-Pro-Ile-OH, 2 mg/kg per day) and
sitagliptin (4 mg/kg per day) in the early postnatal period
alters the emotional and motivational behaviors of adolescent and adult rats [52]. In the one-month-old animals,
we observed increased anxiety and depressive-like behavior in both the diprotin A- and sitagliptin-treated animals;
while only the diprotin A-treated rats exhibited significant
signs of depression at the age of two and three months.
Increased aggression was observed in the one to threemonth-old diprotin A-treated rats; and in the two-monthold sitagliptin-treated rats. Thus, diprotin A exhibits a
more significant impact on the animals’ behaviors com24
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Basal Ganglia
pared to sitagliptin. We proposed considering the behavioral disturbances induced by the DPP-IV inhibitors as
models of mixed anxiety-depression-like disorders with
disinhibited aggression upon mild stress provocation. On
both models, the increase in dpp4 or prep gene expression
has been found only in the striatum and for only one of the
peptidases in each model [53]. Dpp4 gene expression was
increased after neonatal exposure to sitagliptin, and prep
gene expression was increased in rats after the neonatal
exposure to diprotin A (see Table 2). The changes in gene
expression encoding DPP-IV and PREP in the brain of
the adult rats treated with DPP-IV inhibitors in the early
postnatal period may be responsible for the development
of behavioral alterations. We should remember that at the
moment when the brain samples were taken, the diprotin
A-treated rats still demonstrated increased aggression and
the signs of depression while the sitagliptin-treated rats
did not show behavioral abnormalities. Is it possible to
consider increased expression of DPP-IV in the striatum
as a mechanism to support the functioning of pathological integration in the CNS during remission? Is it feasible
to relate the more severe behavioral abnormalities in rats
after the action of diprotin A with the expression of PREP,
rather than DPP-IV in striatum? And does this difference
in the expression of DPP-IV and PREP in the striatum of
rats after the action of sitagliptin and diprotin A relate to
a redistribution of peptidases contribution to the pathological process for enhancement of the expression/activwww.avidscience.com
25
Basal Ganglia
ity of PREP compared with DPP-IV? This scientific puzzle
should yet to be solved.
It was mentioned above that a decrease in the DOPA
content was observed in the striatum in rats with the experimental MPTP-induced depressive syndrome, which
is quite expected since a depressive action was produced
by low doses of proneurotoxin which is specific for dopaminergic SN neurons. Really, in the models of mixed anxiety-depression state induced by the neonatal exposure
to DPP-IV inhibitors, we did not see the changes in the
DOPA content in the striatum. But in the case of methionyl-2(S)-cyano-pyrrolidine we did observe the changes in
the functional activity of the striatal dopamine system related to a decrease in DA turnover according to the HVA/
DA ratio and the decrease in the HVA content (see Table
2) [54]. We also found a decrease in DA metabolism in
the hypothalamus, which was seen as a decrease in levels of the HVA and (DOPAC + HVA)/DA ratio [55]. In
this model, in one of the series, we noted an increase in
5-HT turnover in the FC. In all the structures, changes
in the functional state of monoamine systems were usually accompanied by an increase in the activity of prolinespecific peptidases, except NAcc, in which no deviations
in the level of monoamines and their metabolites were detected, but an increase in the PREP activity was revealed.
Given that, it could be assumed that the changes in the
level and turnover of the monoamines go in parallel with
the changes in the DPP-IV and PREP activities and may
26
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Basal Ganglia
be interrelated, although the mechanism of such an interrelation has not yet been studied.
A convincing confirmation of this assumption was
obtained in our studies on the models of mixed anxietydepressive states induced by the neonatal action of diprotin A and sitagliptin [56]. Indeed, a decrease in the level
of the 5-HT, 5-HIAA and the 5-HT turnover according to
the 5-HIAA/5-HT ratio in both models and an increase in
the DA metabolism according to the DOPAC/DA ratio in
the diprotin A-treated animals were accompanied by the
increase in the expression of proline-specific peptidases in
the striatum, that is of interest.
In rats with the MPTP-induced depressive syndrome,
there is some disparity with the above assumption, in
particular, the absence of disturbances in the content of
monoamines and their metabolites in the frontal cortex,
whereas changes in both peptidases have been detected.
Perhaps, we should modify the assumption of concomitant disturbances in monoamine and proline-specific
peptidases in the brain structures in rats with emotional
and motivational disorders, through a limitation of the
structures to a single striatum. All that we say emphasizes
the necessity for further study of the contribution of the
functional rearrangement in the striatum to the genesis
and the maintenance of emotional and motivational disorders of different origins.
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Conclusion
Based on the data of neurophysiological, neurochemical and genetic studies, we assume that emotional
and motivational disorders are based on the formation
of a complex pathological system in CNS which manifest
in various symptoms at different stages of the process,
including latent periods and remission, when the process continue developing or maintaining without specific
outer features. The disorder can be supported by the neuroplastic and, perhaps, epigenetic changes that occur in
the brain structures playing a key role in the particular
manifestations of behavioral abnormalities. We consider
the striatum as such a structure, without dividing it into
functional components.
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