Neurochem Res (2014) 39:2040–2046 DOI 10.1007/s11064-014-1381-4
ORIGINAL PAPER
Age-Related Differences in NMDA Receptor Subunits of Prenatally Methamphetamine-Exposed Male Rats Monika Vrajova´ • Barbora Schutova´ • ˇ ´ıpova´ Jan Klaschka • Hana Sˇteˇpa´nkova´ • Daniela R Romana Sˇlamberova´
•
Received: 10 April 2014 / Revised: 27 June 2014 / Accepted: 2 July 2014 / Published online: 31 July 2014 Ó Springer Science+Business Media New York 2014
Abstract There is accumulating evidence that methamphetamine (MA) is a widely abused drug popular among pregnant women. MA exposure is associated with changes in the function of neurotransmitter systems, namely the dopaminergic, serotonergic and glutamatergic systems. Since N-methyl-D-aspartate receptors (NMDA) are affected by MA-induced glutamate release, we assessed the expression of NMDAR subunits (NR1, NR2A, and NR2B) and postsynaptic density protein 95 (PSD-95), which is connected with NMDAR. We measured the expression of these proteins in adolescent (30 days old) and adult (60 days old) rat males exposed to MA during the entire prenatal period and compared them with the same parameters in age matched saline-exposed rats. There was a significant increase in the NR1 and NR2B subunits in the hippocampus of adult males, but not in adolescent males. We identified a significant change in adult MA-induced rats when compared to adult controls for NR2A and NR2B, while in adolescent MA rats this change was close to the boundary of significance. In summary, our study suggests that prenatal MA exposure is connected with changes in NMDAR subunit expression in adult rats but not in adolescent rats. M. Vrajova´ (&) H. Sˇteˇpa´nkova´ D. Rˇ´ıpova´ Prague Psychiatric Center, Ustavni 91, 181 03 Prague 8, Czech Republic e-mail:
[email protected] B. Schutova´ R. Sˇlamberova´ Department of Normal, Pathological and Clinical Physiology, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic J. Klaschka Institute of Computer Science, Academy of Sciences, Prague, Czech Republic
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Keywords Methamphetamine In-utero NMDA receptor subunits Hippocampus
Introduction Methamphetamine (MA) is a powerful psychostimulant with great potential for abuse. It has a major impact on the cortical and striatolimbic brain regions, such as the striatum, frontal cortex, and hippocampus. Moreover, due to its anorectic effects, it is one of the most common drugs abused by pregnant women addicted to drugs [1]. Since MA can cross both the placental and hematoencephalic barriers easily [2, 3], prenatal exposure to MA can result in developmental anomalies of the central nervous system of exposed fetuses. MA administration has been shown to produce dopaminergic and serotonergic dysfunction [4, 5]. In addition, MA also evokes a delayed overflow of glutamate in the brain. Neurotransmitters such as dopamine, serotonin, and glutamate can modulate multiple ontogenetic processes both directly and indirectly, including neurogenesis, neuronal migration, axon and dendritic growth, and the stabilization/elimination of immature connections [6]. MA-induced glutamate release may overactivate N-methylD-aspartate receptors (NMDAR), thus causing excitotoxicity [7]. Evidence has shown that NMDA receptor subunit expression is developmentally regulated during brain maturation [8–10]. One of the pivotal changes that occurs in NMDA receptor subunit composition during development is a reduction in NR2B levels, with an associated increase in NR2A levels [8, 11]. The ratio of NR2B/NR2A mRNA expression declines with age in rat hippocampi [12]. Furthermore, there is evidence for the role of the
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NR2B subunit of NMDA in alcohol, cocaine, and opioid abuse [13]. NMDA receptors are associated with multiprotein postsynaptic density (PSD) [14]. PSD-95 belongs to this group of proteins and is bound to the C-terminal end of the NR2A and NR2B subunits. PSD-95 is associated with NMDA stabilization at the cell surface and may be differentially associated with NR2A and NR2B subunits [15, 16]. The role of PSD-95 in psychostimulant action has been described previously [17]. In prenatally MA-exposed children, magnetic resonance imaging identified volumetric reductions in the hippocampus [18]. In rats, neonatal MA exposure alters dendritic morphology in the hippocampus, a structure that is integral to spatial function [19]. Further, MA exposure during hippocampal development (postnatal day (PND) 11-20) impairs spatial learning and memory in adult rodents [20, 21]. Our previous studies demonstrated that prenatal MA exposure impairs spatial learning of adult male rats [22] and impairs sensorimotor learning during adolescence [23, 24]. In addition, studies of others have shown impaired cognitive functions in adolescent as well as adult rats after prenatal MA exposure [25, 26]. However, it has been documented that protein expression of NMDA receptor subunits already occurs during embryonic development of rat hippocampus [27], but the effect of MA on this process is not known. Therefore, the objective of the present study was to determine whether expression of the NR1, NR2A, NR2B, and PSD-95 proteins in the hippocampus of adolescent and young adult male rats is influenced by chronic prenatal MA exposure.
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rats were housed with sexually mature males overnight. There were always one female and one male in a cage. The next morning females were smeared for the presence of sperm and returned to their previous home cages. This was counted as gestational day (GD) 1. Females were randomly assigned to a MA-treated and a saline-treated (SAL) groups. On GD 1 the daily injections started and continued to the day of delivery, which usually occurred on GD 22 (for details see [29]). The females in the MA group were administered 5 mg/kg D-MA HCl (Sigma, Prague, The Czech Republic) subcutaneously (s.c.). This MA dose was chosen because it results in drug concentrations in the fetal brain similar to those found in human infants of MA addicted women [30]. This is also a standard dose used in our experiments [31]. The females from the SAL group were administered 0.9 % NaCl solution s.c. at the same time and in the same volume (1 ml/kg) as the MA group. The day of delivery was counted as PND 0. On PND 1, the offspring were marked according to their prenatal exposure by intradermal application of black India ink: offspring of MA mothers were marked on the left foot pad, and offspring of SAL mothers on the right footpad. A total of 16 litters (eight MA-treated and eight saline-treated) were used in the experiment. The number of pups in each litter was adjusted to 12. Whenever possible, the same number of male and female pups was kept in each litter. On PND 21, the animals were weaned and housed in groups according to sex. Males prenatally exposed to MA or SAL were used for Western blotting on PND 30 (adolescent) or PND 60 (young adults). That gave rise to four groups to be further compared: adolescent MA or SAL, and young adult MA or SAL. The rest of the animals from each litter were used in other studies.
Methods Western Blotting The animal experiment procedures used in this report were reviewed and approved by the Institutional Animal Care and Use Committee and were in agreement with Czech Government Requirements under the Policy of Humane Care of Laboratory Animals (No. 246/1992) and with the regulations of the Ministry of Agriculture of the Czech Republic (No. 311/1997). Animals and Drug Administration Adult male (300–400 g) and female (250–300 g) Albino Wistar rats from Charles River Laboratories International, Inc. were delivered by Anlab (Prague, the Czech Republic). Females were smeared by vaginal lavage to determine the phase of the estrous cycle. The smear was examined by light microscopy. To ensure successful insemination, at the onset of the estrous phase of the estrous cycle [28] female
The rats were decapitated on PND 30 (MA group, n = 8; SAL group, n = 8) or on PND 60 (MA group, n = 8; SAL group, n = 8), the brains were rapidly removed, and the hippocampi were dissected and stored at -70 °C until Western blot analysis [32]. The blots were incubated overnight with anti-NMDAR1 (1:1,000; Merck Millipore, USA); or anti-PSD-95 (1:500, SantaCruz, USA); or for 2 h in anti-NR2A or anti-NR2B (1:500; Merck Millipore, USA) as primary antibodies. Anti-a-tubulin antibody was used as the loading control (1 h incubation; 1:1,000; Exbio, CZ). Then the blots were washed in TBS-T buffer and incubated for 1 h with a horseradish peroxidase-conjugated secondary antibody (1:3,000; Dako, Denmark). The bands were detected using a chemiluminescent substrate (Pierce, USA) and evaluated using the Gel Doc Analysis system (Bio-Rad, USA).
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Statistical Analysis
* 2.5
Ratio NR1/ α-tubulin
Statistical analyses were performed using BMDP software. The data are given as mean ± standard error of the mean (SEM), and P \ 0.05 was considered statistically significant. Protein expression data from the four groups (see Animals and drug administration) were compared by twoway ANOVA with factors of age and exposure. Taking into account unequal group variances (as indicated by the Levene test), the Brown–Forsythe test [33] was chosen instead of the classical ANOVA F-test. In cases of significant ANOVA results, Bonferroni-adjusted separate-variance t tests were used for the post hoc analyses. The Pearson correlation coefficients between the parameters in individual groups were calculated and their significance tested with t-statistics using the BMDP6D program. The correlations in the experimental and control groups of the same age were compared using the z-test based on the Fisher z-transformation.
2.0
1.5
1.0
0.5
Semi-quantification of the NR1 protein, expressed as a ratio of the NR1 and a-tubulin (loading control) proteins, showed a statistically significant interaction of age and exposure (F [1, 17] = 10.90, P = 0.0042). In other words, the difference between the MA exposed and control groups was not the same in adolescent and adult rats. Moreover, both exposure and age were statistically significant (F [1, 17] = 10.42, P = 0.0049; F [1, 17] = 276.53, P \ 0.0001). In post hoc analyses (t tests), we found a significant increase in the group of adult rats (MA versus SAL: T [12] = 3.48, P = 0.0041), while in the group of adolescent rats the analogous difference (MA versus SAL) was not significant (Fig. 1). Significant differences in NR1 expression between the adolescent and adult animals were observed in both control and exposed groups (adolescent versus adult SAL: T [8] = 10.25, P \ 0.0001; adolescent versus adult MA-exposed rats: T [9] = 13.10, P \ 0.0001). ANOVA of the NR2A data (calculated as a ratio of NR2A/a-tubulin) only revealed a significant effect for age (F [1, 18] = 6.40, P = 0.0209), while the effect of MA and the age-exposure interaction were not significant (Fig. 2). NR2B protein expression (calculated as a ratio of NR2B/a-tubulin) showed a statistically significant interaction between age and exposure (F [1, 21] = 26.76, P \ 0.0001). Additionally, there was a significant effect of MA exposure (F [1, 21] = 32.52, P \ 0.0001). Post-hoc analyses revealed a significant increase in NR2B protein levels in the adult group (MA versus SAL: T [11] = 6.90, P \ 0.0001), whereas in the group of adolescent rats the
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Adolescent
A
L
M
SA
M
SA
L
A
0.0
Results
Adult
Fig. 1 Representative western blot and bar chart show the quantification of the NR1 subunit levels in adolescent (PND 30) and young adult (PND 60) rats prenatally exposed to MA or saline. Notation: control adolescent, control adult, SAL; methamphetamine adolescent, methamphetamine adult, MA. For all groups, n = 8. Values are given as mean ± SEM. Significance: *P \ 0.05
analogous difference (MA versus SAL) was not significant (Fig. 3). Significant differences in NR2B expression between the adolescent and adult animals were found in both the control and applied groups (adolescent versus adult SAL: T [13] = 3.44, P = 0.0043; adolescent versus adult MA exposed rats: T [13] = 4.26, P = 0.0009). ANOVA analysis of the PSD-95 data (calculated as the ratio of PSD-95/a-tubulin) revealed that the only significant effect was that of age (F [1, 15] = 34.98, P \ 0.0001), while an effect of MA exposure, or an interaction between age and exposure, was not demonstrated (Fig. 4). Correlations between the expressions of NR1, NR2A, NR2B and PSD-95 in the four groups of rats are shown in Table 1 (adolescent) and Table 2 (adult). Table 1 shows significant correlations between the pairs of NR1 9 NR2A, NR1 9 NR2B, NR2A 9 NR2B and NR2B 9 PSD-95 in the adolescent SAL group. In the MA adolescent group, these correlations were not significant. In contrast, there was a significant NR2A 9 PSD-95 correlation. In adulthood (Table 2), two correlations were significant: (1) a positive correlation of NR2B and PSD-95 in the adult SAL group, and (2) a negative correlation of NR1 and NR2B in
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1.5
Ratio NR2B/ α -tubulin
0.8
0.6
0.4
0.2
* 1.0
0.5
S
M
A
L
A M
A S
A
0.0
L
Ratio NR2A/ α -tubulin
1.0
Adolescent
A
L
M
SA
A M
SA
L
0.0
Adult
Fig. 2 Representative western blot and bar chart show the quantification of the NR2A subunit levels in adolescent (PND 30) and young adult (PND 60) rats prenatally exposed to MA or saline. Notation: control adolescent, control adult, SAL; methamphetamine adolescent, methamphetamine adult, MA. For all groups, n = 8. Values are given as mean ± SEM
the adult MA-exposed rats. When testing the equality of the corresponding correlations in the SAL and MAexposed groups of the same age (last columns of Tables 1 and 2), we identified only one significant difference: a high positive correlation (0.7056) between NR2A and NR2B in the adult SAL became negative (-0.4393) in the adult MA-exposed group (P = 0.0328). Interestingly, a similar decrease in the NR2A 9 NR2B correlation from r = 0.9070 in the SAL group to r = 0.3337 in the MAexposed group was observed in the adolescent rats. However, this difference was only close to the limit of significance (P = 0.0658) and not significant. All of the remaining correlation equality tests yielded P [ 0.15.
Discussion In this study we demonstrated that prenatal MA exposure influences protein expression of NMDA receptor subunits. Unique to the study is that we compare the effect of prenatal MA exposure on rat hippocampus during two periods of development: adolescence (PND 30) and young adults (PND 60).
Adolescent
Adult
Fig. 3 Representative western blot and bar chart show the quantification of the NR2B subunit levels in adolescent (PND 30) and young adult (PND 60) rats prenatally exposed to MA or saline. Notation: control adolescent, control adult, SAL; methamphetamine adolescent, methamphetamine adult, MA. For all groups, n = 8. Values are given as mean ± SEM. Significance: *P \ 0.05
In this study, we found differences in NR1 expression between MA-exposed and control groups in adult rats, but not in adolescence. There was an increase in NR1 expression in the group of MA-exposed young adults. An increase in NR1 expression has also been previously reported in the nucleus accumbens of young adult male rats (Sprague–Dawley) after postnatal cocaine treatment (10 mg/kg, for 8 days) followed by a 10 day washout [34]. By contrast, postnatal MA exposure (4 mg/kg, for 14 days) in young adult Sprague–Dawley males did not change its expression level in the hippocampus [35]. Moreover, no significant difference in NR1 expression was observed in the hippocampus of any group of male mice after postnatal MA exposure (2 mg/kg, decapitation 0.5, 1, 2 and 4 h after MA injection) [36]. Our data also showed that the expression of NR2A was not changed by prenatal MA exposure. These results are partly similar to, but partly different from, the findings of study [37], where Sprague–Dawley males were exposed to MA postnatally. Acute MA treatment (30 mg/kg) in adult males did not change NR1 expression, but did increase the levels of NR2A in the hippocampus [37]. Additionally, in the same study, an escalating dose (over 7 days, from 10 to 30 mg/kg) resulted in a decrease in NR1 levels, but no change in NR2A levels.
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1.1
Ratio PSD-95/ α-tubulin
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
A
L
Adolescent
M
SA
A M
SA
L
0.0
Adult
Fig. 4 Representative western blot and bar chart show the quantification of the PSD-95 subunit levels in adolescent (PND 30) and young adult (PND 60) rats prenatally exposed to MA or saline. Notation: control adolescent, control adult, SAL; methamphetamine adolescent, methamphetamine adult, MA. For all groups, n = 8. Values are given as mean ± SEM
Table 1 The result of Pearson correlation analysis performed on adolescent rats
* P \ 0.05 Table 2 The result of Pearson correlation analysis performed on adult rats
* P \ 0.05
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Parameters
We also observed a significant effect of MA treatment on NR2B subunit expression. There was an increase in NR2B in the adult MA-exposed group when compared to adult controls. A previous study [38] also revealed increased expression of NR2B (mRNA and protein) in the hippocampus following postnatal amphetamine treatment (2 mg/kg, for 4 days) in young adult male Wistar rats. A subsequent study showed increases in NR1, NR2A, and NR2B subunit expression in the lower midbrain of male mice postnatally exposed to MA (1 mg/kg, for 3 days) [39]. Furthermore, our results support the previously described idea that NMDA-mediated toxicity is connected with the activation of NR2B-containing, but not NR2Acontaining, NMDA receptors [40]. The higher expression of NR1 and NR2B in the MA-exposed adult rats evident in the present study might suggest that there are synapses containing predominantly NR1/NR2B heteromers, which have been described in vitro as immature sites [41]. Our results indicated that immature (adolescent) hippocampus is able to conserve protein expression of NMDA subunits at normal levels, so it seems the hippocampus is insensitive to a prenatal stressor at this stage of development (e.g. MA injections). Our results are in accordance with a study in which the effect of prenatal ethanol was tested [42]. There it was shown that prenatal (in utero) ethanol exposure did not affect neurogenesis in the adolescent rat (PND 33 ± 2) hippocampus, but did lead to a significant reduction in hippocampal neurogenesis in aged animals [42]. The prenatal ethanol-induced deficits in the neurogenic capacity of the hippocampus were also seen in adult rats (4–5 month) [43, 44]. However, we have seen
Adolescent control
Adolescent MA
r
p
r
p
NR1 9 NR2A
0.7580
0.0483*
0.6689
0.1004
0.7959
NR1 9 NR2B
0.8176
0.0247*
0.3108
0.4975
0.2415
NR1 9 PSD95
0.1070
0.8195
0.5164
0.2354
0.5116
NR2A 9 NR2B
0.9070
0.0019*
0.3337
0.4192
0.0658
NR2A 9 PSD95
0.6666
0.0710
0.7170
0.0453*
0.8784
NR2B 9 PSD95
0.7345
0.0380*
0.6685
0.0699
0.8367
Parameters
Adult control r
Adult MA p
r
p
Correlation equality test
Correlation equality test
NR1 9 NR2A
0.0046
0.9921
0.6359
0.0901
0.2657
NR1 9 NR2B
-0.3942
0.3816
-0.7926
0.0190*
0.3239
NR1 9 PSD95
-0.2398
0.6045
-0.1818
0.6666
0.9279
NR2A 9 NR2B
0.7056
0.0505
-0.4393
0.2762
0.0328*
NR2A 9 PSD95
0.5121
0.1945
0.3845
0.3470
0.8000
NR2B 9 PSD95
0.7753
0.0238*
0.1494
0.7239
0.1627
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changes in NMDA subunits in young adults (PND 60) exposed prenatally to MA, while prenatal ethanol did not affect neurogenesis in the same aged rats [45]. Thus, we can speculate that the effect of prenatal ethanol is developmentally delayed compared to prenatal MA exposure in rat hippocampus. We did not detect an effect of prenatal MA exposure on PSD-95 expression in the hippocampus in any group. Similarly, in the study of Yao et al., PSD-95 protein levels were not altered in the hippocampus of adult mice treated with cocaine (20 mg/kg, for 5 days), while postnatal cocaine exposure selectively decreased PSD-95 only in striatum [17]. Nevertheless, elucidation of the role of PSD95 in mechanisms underlying the effect of MA will need further studies. In our study, the expression of the NMDA receptor subunits was significantly changed in the adolescent controls when compared to the adult control group. While expression of the NR1 subunit was higher in the adult groups, NR2B was lower in the adult controls relative to the adolescent animals. Only a few studies have compared subunit expression between adolescent and adult developmental periods, and their results do not fully match. In one study investigating the hippocampus of male Wistar rats, NR2A and NR2B protein levels were significantly higher in adults (PND 74-88) as compared to adolescents (PND 37-52) [46]. A post-mortem study in human hippocampal formation did not reveal significant differences in the mRNA expression of NR1, NR2A, and NR2B between adolescent and young adult males [47]. Moreover, differences in NR1 and NR2B protein expression between the hippocampi of 3-, 10- and 30-month-old male mice have been reported [11]. There was higher expression of NR2B in the 10-month-old mice as compared to both other groups, and the NR1 subunit was lower in 30 month-old mice as compared to both younger groups [11]. In addition, there might be regional differences in how NMDA receptors are affected by aging; more pronounced changes were seen in the intermediate than in the dorsal hippocampus [48]. Furthermore, we observed a marked difference (close to the limit of significance) in the NR2A 9 NR2B correlation between the MA and SAL adolescent groups. The analogous difference became significant in adulthood. Interrelationships between NR2A and NR2B expression are important because of the distinct characteristics of the two subunits. There may be a compensatory mechanism in the prenatally MA-exposed hippocampus, as a result of which a higher expression of one of the NR2 subunits is balanced by a lower expression of the other subunit. In conclusion, chronic prenatal MA exposure is associated with changes in protein expression of the NMDA receptor subunits in hippocampus. These changes are seen
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in young adult (PND 60) rats, but not in adolescent (PND 30) rats. Further studies of this phenomenon will be necessary to elucidate the MA-induced influence on NMDA receptor development in the rat hippocampus. An explanation of this latent effect of prenatal MA will be necessary in order to assess the expression of these subunits in other brain structures such as prefrontal cortex and striatum. Acknowledgments This research was supported by project GA P303/10/0580 from the Grant Agency of the Czech Republic, project CSM 7/CRP/2014 from the Ministry of Education, Youth and Sports and research programs PRVOUK P34 and 260045/SVV/2014 from Charles University in Prague, as well as by the following institutional supports: MH CZ–DRO: 00023752 (Prague Psychiatric Center) and RVO: 67985807 (Institute of Computer Science).
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