Background: The continuing epidemic of methamphetamine addiction has prompted research aimed at understanding striatal dysfunctions potentially associated with long-term methamphetamine use. Methods: Here, we investigated transcriptional and translational alterations in the expression of neurotrophic factors in the rat striatum at 30 days following methamphetamine self-administration and footshock punishment. Male Sprague– Dawley rats were trained to self-administer methamphetamine (0.1 mg/kg/injection, i.v.) or saline during twenty-two 9-hour sessions. Subsequently, rats were subjected to incremental footshocks for 13 additional methamphetamine self- administration sessions. This paradigm led to the identification of rats with shock-resistant and shock-sensitive phenotypes. Thirty days following the last footshock session, the dorsal striatum was dissected and processed for gene expression and protein analyses. Results: PCR arrays revealed significant differences in neurotrophins and their receptors between the 2 phenotypes. Brain- derived neurotrophic factor and nerve growth factor protein levels were increased in the dorsal striatum of both shock- resistant and shock-sensitive rats. However, neurotrophic receptor tyrosine kinase 1 phosphorylation and nerve growth factor receptor protein expression were increased only in the shock-sensitive phenotype. Moreover, shock-sensitive rats showed increased abundance of several phosphorylated proteins known to participate in Ras/Raf/MEK/ERK signaling cascade including cRaf, ERK1/2, MSK1, and CREB. Conclusions: These findings support the notion that animals with distinct phenotypes for methamphetamine intake in the presence of adverse consequences also display differential changes in an intracellular signaling cascade activated by nerve growth factor-TrkA/p75NTR interactions. Thus, the development of pharmacological agents that can activate nerve growth factor-dependent pathways may be a promising therapeutic approach to combat methamphetamine addiction. Keywords: addiction, footshocks, neurotrophins, signal transduction Received: September 20, 2017; Revised: November 2, 2017; Accepted: November 16, 2017 © The Author(s) 2017. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 281 provided the original work is properly cited. For commercial re-use, please contact email@example.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/3/281/4642156 by Ed 'DeepDyve' Gillespie user on 16 March 2018 282 | International Journal of Neuropsychopharmacology, 2018 Significance Statement Methamphetamine addiction is characterized by continued drug use despite adverse life events associated with its use. To mimic the human conditions, we used a self-administration model of methamphetamine (METH) intake performed in conjunction with footshocks as adverse consequences. This paradigm helped to discriminate shock-sensitive (SS) from shock-resistant (SR) rats, with SR rats being considered an addicted phenotype. Our main findings indicated that there were specific differences in the stri- atal expression of genes coding for neurotrophic factors between the 2 METH self-administration (SA) phenotypes. Importantly, nerve growth factor (NGF) and its downstream signaling pathway (NGF-TrkA and p75NTR/MAPK signaling) were found to be selectively increased in the SS rats. These observations suggest that METH abstinence may be associated with an upregulated NGF-signaling cascade. Our data may have important therapeutic implications in the treatment of patients at different stages of METH addiction. that alterations in their striatal expression might occur follow- Introduction ing prolonged abstinence from our METH SA procedures. Here, Addiction to methamphetamine (METH) is considered a chronic we provide evidence that the striatal NGF-TrkA/p75NTR/MAPK neuropsychiatric disorder characterized by striatal dysfunc- signaling pathway is selectively activated in SS rats at 30 days tions, cognitive deficits, and loss of control over drug consump- following METH SA and footshocks. Our results support the tion despite adverse consequences associated with its use (Scott view that distinct signaling cascades may play important roles et al., 2007; Rusyniak, 2013). METH addiction is also associated in mediating the long-lasting effects of METH taking depending with a high prevalence of relapse to drug-taking behaviors even on the level of control over drug consumption. after years of sobriety (Brecht and Herbeck, 2014Go ; win et al., 2015). These clinical observations have implicated long-lasting Methods neuroplastic changes in brain regions involved with both reward mechanisms and compulsive diatheses (Belin et al., 2013). In Animals and SA Procedures fact, several groups of investigators have reported significant changes in gene expression within mesolimbic reward circuitry Male Sprague-Dawley rats (Charles River) weighing 350 to 400 g following noncontingent injections of METH in rodents [for a were used in these experiments. Rats were anesthetized with a review see (Cadet and Krasnova, 2009)]. Using the self-admin- ketamine/xylazine mixture (50 and 5 mg/kg, i.p., respectively) istration (SA) model of METH intake in rats, we and others have and were inserted with catheters into the jugular vein. After also documented substantial transcriptional and translational recovery, rats were placed in Med Associates SA chambers and changes within the rodent dorsal striatum (Krasnova et al., 2013; trained to self-administer METH (0.1 mg/kg/injection, i.v.) on an Cadet et al., 2015; Li et al., 2015; Caprioli et al., 2017). The dorsal FR-1 schedule during three 3-hour sessions/d (9 h/d). Each 3-hour striatum is indeed a key structure involved with the habitual session was separated by a 30-minute time interval. Following manifestations of addiction (Koob and Volkow, 2010Belin et ; al., SA training, rats were subjected to punishment where 50% of 2013). Together, these findings support the notion that the path active lever-presses resulted in a mild foot-shock. Animals were from casual drug use to habitual drug taking may depend on classified as SS if they reduced their intake by 70%. Subgroups long-lasting neuroadaptations that include a shift in control were divided into SR (n = 7), SS (n = 9), and saline controls (n from ventral reward circuits to more dorsal striatal habit circuits = 5) as previously reported by Torres et al. (2017). Cue-induced (Feil et al., 2010; Everitt and Robbins, 2013). drug-seeking behavior was assessed at 2 and 21 days post-shock We recently developed a rat model in which we use foot- essentially as described in Krasnova et al. (2014). Briefly, each shocks as adverse consequences during METH SA. This model test consisted of a 1-hour session without METH availability, has helped to dichotomize rats into 2 distinct addiction-related during which time drug-associated lever presses resulted only phenotypes (Cadet et al., 2017). Specifically, these proce- in tone and light cues previously paired with METH infusions. dures were able to segregate rats that continued to take METH All animal procedures were conducted following the NIH Guide despite footshock punishment (shock-resistant [SR]) from rats for the Care and Use of Laboratory Animals and were approved that reduce their METH intake with increasing shock inten- by the Animal Care and Use Committee of the NIDA Intramural sity (shock-sensitive [SS]). Interestingly, SR rats were found to Research Program. exhibit higher incubation of METH-seeking behavior compared with SS rats (Krasnova et al., 2017 T; orres et al., 2017). Tissue Collection and RNA Extraction In the present study, we examined tissue from animals used in a previous behavioral study (Torres et al., 2017) to test To measure potential differences in gene expression between whether neurobiological alterations in the striatum might the SR and SS phenotypes after a long period of abstinence, rats reflect molecular adaptations that may distinguish SR from SS were killed 9 days following the second extinction test (30 days even after a prolonged period of drug abstinence. We focused total after the last METH SA session). This time frame was based on the dorsal striatum, because neuroadaptations within this on our previous studies showing METH-induced changes in stri- structure might underlie the transition from casual to compul-atal expression of neurotrophins and genes involved in the CREB sive drug-seeking behavior (Everitt and Robbins, 20132016 , ). The (cAMP responsive element binding protein) signaling pathway importance of striatum is also highlighted by substantial tran-1 month after METH SA (Krasnova et al., 2013 2016 , ). Following scriptional and translational changes following models of METH rapid decapitation, dorsal striatal tissue was dissected, imme- SA (Krasnova et al., 2013; Cadet et al., 2015; Li et al., 2015; D’Arcy diately placed on dry ice, and stored at -80°C. Total RNA was et al., 2016). Because neurotrophins are known to participate in then isolated using Qiagen RNeasy Mini kits and treated against the generation of long-lasting plastic changes in the brain (Alder genomic DNA contamination by using Qiagen RNase-free DNase et al., 2003; Bekinschtein et al., 2008), we tested the possibility kits (Qiagen) following the manufacturer’s protocol. RNA levels Downloaded from https://academic.oup.com/ijnp/article-abstract/21/3/281/4642156 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Torres et al. | 283 were then assessed using a NanoDrop 2000 spectrophotometer tissue was homogenized in ice-cold lysis buffer A (10 mM HEPES, (Thermo Fisher Scientific). RNA integrity numbers were also 1.5 mM MgCl , 10 mM KCl, and 1% igepal) containing protease examined, as described by Schroeder et al. (2006), using an Agilent and phosphatase inhibitor cocktail tablets (Roche Diagnostics). 2100 Bioanalyzer System in conjunction with the RNA LabChip After homogenization, samples were centrifuged at 14 000 g for assay (Agilent) with no sample showing signs of degradation. 5 minutes at 4°C. Supernatant was collected and used as cyto- solic protein fraction. Nuclear fractions were then suspended in buffer B (20 mM HEPES, 840 mM NaCl, 1.5 mM MgCl, 4 mM 2 2 RT Profiler PCR Array EDTA, and 10% glycerol) containing protease and phosphatase inhibitor cocktail tablets (Roche Diagnostics). Individual protein The RT Profiler PCR Array (PARN-031Z, Qiagen) discovery plat- concentrations were determined by utilizing the BCA assay kit form was used to examine differences in striatal gene expression (Thermo Fisher Scientific). Samples were then transferred on to between SR and SS rats. Each array contained 84 gene-specific PVDF membranes and incubated overnight at 4°C with a specific primers related to neurotrophic signaling, neuropeptides, and antibody raised against: Pro-BDNF (Millipore, #AB5613P), BDNF transcription factors. Total RNA (0.5 g) μwas treated with 5x buffer (Santa Cruz Biotechnology, #SC546), Pro-NGF and mature NGF GE, incubated at 42°C for 5 minutes, and placed on ice. Purified (Santa Cruz, #SC365944), TrkB (Millipore, #07-225), pTrkB (Sigma- RNA was then reverse-transcribed to cDNA by using the R F Tirst Aldrich, #SAB 4301317), TrkA (Cell Signaling, #2508), pTrkA (Cell Strand Kit (Qiagen) and RNase-free water following the manu- Signaling, #9141), P75NTR (nerve growth factor receptor) (Cell facturer’s instructions. Each 96-well R Pr T ofiler PCR Array was Signaling, #2693), Sortilin (Thermo Fisher Scientific, #PA5-19481), applied on a LightCycler 480 II PCR system (Roche Diagnostics) for p-cRaf (Cell Signaling, #9421), pMEK1/2 (mitogen activated pro- each striatal sample. Each array plate contained a genomic DNA tein kinase 1) (Cell Signaling, #9154), pErk1/2 (mitogen activated contamination control, 3 reverse transcription controls, 3 positive protein kinase 3) (Cell Signaling, #4370), pMSK1 (mitogen and PCR controls, and 5 wells with different housekeeping genes (Beta- stress activated protein kinase 1) (Cell Signaling, #9595), pCREB actin, Beta-2 microglobulin, Hypoxanthine phosphoribosyltrans- (Cell Signaling, #9198), H3ac (acetylated histone H3) (Active Motif, ferase 1, Lactate dehydrogenase A, and Ribosomal Protein, Large, #39139), p-MeCP2 (methyl-CpG binding protein 2) (ActiveMotif, p1). Data analyses for threshold amplification cycle numbers (Tc) #39733), and p-mTOR (mammalian target of rapamycin) (Cell were performed using the complimentary web-based Qiagen soft- Signaling, #2971). To confirm equal protein loading, blots were ware tools following the manufacturer’s protocol and normalized reprobed with an antibody against α-Tubulin (Sigma) for 2 hours to the 4 housekeeping genes. To confirm primer specificity of each at room temperature. Optical densities were measured using the gene product, amplicon melting curves were recorded and ana- ChemiDoc MP Imaging system (Bio-Rad) and normalized using lyzed after every array experiment. the signal intensity of α-tubulin. The results are reported as per - centage of control changes calculated as the ratios of protein expression for each METH group compared with the saline SA Independent qRT- PCR Analysis control group. RT Profiler PCR Array data were verified by individual qRT-PCR comparisons. Briefly, unpooled total RNA (0.5μg) was reverse- Statistical Analysis transcribed to cDNA using oligo dT primer from the Advantage RT for PCR kit (Clontech). Sequences for rat gene-specific prim- Profiler PCR Array data were analyzed using the Qiagen web- based software. qRT-PCR data were analyzed using 1-way ers corresponding to PCR targets were then designed using the LightCycler Probe Design software version 1 (Roche Diagnostics) ANOVAs followed by posthoc tests (Bonferroni) or planned comparisons (2-tailed Student tests) (SPSS 20). Western-blot and synthesized by the Synthesis and Sequencing Facility of Johns Hopkins University. qRT-PCR reactions were carried out in data were also analyzed by 1-way ANOVAs followed by posthoc tests (Fisher’s LSD) or planned comparisons (StatView, SAS). a final volume of 12.5 μ L consisting of reverse transcribed cDNA, gene-specific primers, nucleic-acid free water, and iQ SYBR Green Individual planned comparisons were used in specific cases where the difference between SR and SS rats was based on an Supermix (Bio-Rad). All qRT-PCR experiments were conducted using a LightCycler 480 II instrument (Roche). qRT-PCR primers empirical framework. Correlations between R Pr T ofiler PCR Arrays and qRT-PCR data were assessed using linear regression were designed for the specific amplification of rat Bdnf (brain- derived neurotrophic factor), Ngf (nerve growth factor), Tr kA (SPSS 20). All data are presented as means ± SEM and considered statistically significant when P ≤ .05. (neurotrophic receptor tyrosine kinase 1), Tr kB (neurotrophic receptor tyrosine kinase 2), Gfra2 (GDNF family receptor alpha 2), Crh (corticotrophin-releasing hormone), Crhr1 (Crh receptor 1), Results Crhr2 (Crh receptor 2), Crhbp (Crh binding protein), Ucn2 (urocortin 2), c-fos, fosb, Egr1 (early growth response 1), Egr2 (early growth Transcriptional Alterations in the Dorsal Striatum 30 response 2), and Egr3 (early growth response 3) (sequences are Days after METH SA and Footshock Punishment listed on supplementary Table 1). The purity of each amplicon was subsequently verified by melting curve analysis. Expression To identify differentially expressed neuroplasticity-related of mRNA levels for each gene was normalized to the reference genes that might distinguish SR from SS rats, we used the gene beta-2-microglobulin. Results are reported as fold changes unbiased discovery platform Neurotrophins and Receptors R T calculated by the ratios of normalized target gene products com- Profiler PCR Array system. This approach allowed us to poten- pared with the gene expression data of saline SA control group. tially target a specific subset of genes that were found to be affected after cessation of METH SA experiments (Krasnova et al., 2013, 2016). Figure 1a illustrates METH-induced changes in Western-Blot Analysis the expression of neurotrophic and neuropeptide associated Western-blot analyses were carried out essentially as previously genes in the dorsal striatum. Specifically, mRNA expression for described by our laboratory (Jayanthi et al., 2009). Briefly, striatal Bdnf, Ngf, Vgf, Trkb, Ntf3 (neurotrophin 3), Gfra1, and Gfra2 were Downloaded from https://academic.oup.com/ijnp/article-abstract/21/3/281/4642156 by Ed 'DeepDyve' Gillespie user on 16 March 2018 284 | International Journal of Neuropsychopharmacology, 2018 Figure 1. Transcriptional alterations 30 days after the punishment phase of methamphetamine (METH) self-administration (SA) in the dorsal striatum of shock-resistant (SR) and shock-sensitive (SS) rats. (a) The graph shows neuro- trophic- and neuropeptide-associated genes that were differentially expressed between SR and SS rats as determined by RT Profiler PCR Arrays. (b) The figure shows transcriptional responses obtained by Profiler Arrays (“x” axis) and indi- vidual qRT-PCRs (“y” axis) for upregulated genes in the dorsal striatum of SR rats (in grey circles) and SS rats (in black circles). Data are presented as fold-changes relative to saline control rats. A significant correlation was observed between the # ## 2 analyses (P = .001). Key to statistics: P < .05, P < .01 compared with SR rats. Figure 2. Distinct neurotrophin, neuropeptide, and immediate early genes (IEGs) expression in the dorsal striatum of shock-resistant (SR) and shock-sensitive (SS) rats. (a) Independent qRT-PCR analyses for neurotrophin mRNA levels in the dor - sal striatum with increased expression of Bdnf in both SR and SS rats, decrease upregulated in SS rats compared with SR rats at 30 days after TrkA levels in SS rats, and increased Gfra2 levels also in SS rats. (b) Differential METH SA and punishment. These findings may be related to the expression neuropeptide-related genes and receptors in the dorsal striatum, with demonstration that METH exposure can increase synaptic spine SS rats having increased mRNA levels for crhr1 crhbp , , and unc2 compared with density and structural plasticity in the dorsal striatum (Jedynak saline controls and SR rats. (c) Altered mRNA levels of IEGs in the dorsal striatum et al., 2007). We also found that Crh Crhr1 , , and Crhbp mRNA lev- of SR and SS rats. Both SR and SS rats had increased expression of c-fos mRNA lev- els were increased in SS rats relative to SR rats (P < .05). Array els compared with saline controls, while only SR rats had increased egr1 and egr2 mRNA levels compared with saline and SS rats. Key to statistics: * < .05, P **P < .01, data were subsequently validated by running qRT-PCRs using # ## ***P < .001 compared with saline controls; P < .05, P < .01 compared with SR rats. the same RNA samples isolated from the dorsal striatum of these rats. We found a significant correlation (r = 0.90, P < .01) between the array and PCR data (Figure 1b). significant increases compared with saline control and SR rats (P < .05) (Figure 2b). To test if other genes known to be regulated by trophic fac- Differential Expression of Neurotrophins, tors were also altered between the SR and SS phenotypes, we Neuropeptides, and Immediate Early Genes measured mRNA levels of some IEGs (Figure 2c). We found sig- (IEGs) in SR and SS Phenotypes nificant increases in c-fos mRNA levels [F( ) = 3.93, P < .05] in 2, 17 qRT-PCR analysis showed significant alterations in Bdnf mRNA both SR and SS rats compared with controls. No changes in fosb levels [F( ) = 7.86, P < .01], with SS rats showing significant mRNA levels [F( ) = 0.30, P = .74] were observed. There were 2, 17 2, 18 increases compared with saline controls and SR rats (P < .01) also significant increases in Egr1 [F( ) = 9.0, P < .01] and Egr2 2, 18 (Figure 2a). Ngf mRNA levels were nonsignificantly higher in SS [F( = 13.52, P < .01] mRNA levels in SR rats compared with SS 2, 18) rats compared with SR rats [F( ) = 1.78, P = .21]. Gfra2 mRNA rats and controls (Figure 2c). There were no significant changes 2, 17 levels were also increased [F( ) = 7.97, P < .01] in SS rats rela- in Egr3 mRNA levels [F( ) = 0.53, P < .59]. 2, 18 2, 18 tive to SR and saline control rats. Interestingly, SS rats displayed a significant decrease in Trka [F( ) = 6.39, P < .01] mRNA lev- 2, 18 Differential Expression of Neurotrophin-Related els compared with SR rats. Our PCR analyses also confirmed Proteins in the Dorsal Striatum of SR and SS Rats the upregulation of some, but not all, neuropeptide-associated genes. Crhr1 mRNA levels were increased in SS rats [F( ) = 5.14, To better elucidate the neuroplastic bases for the SR from SS phe- 2, 17 notypes, we tested if changes in the striatal expression of neu- P < .05] (Figure 2b) but showed no changes in SR rats. Differential changes were also observed for Crhbp [F( ) = 3.7, P < .05] and rotrophin mRNA levels were also associated with corresponding 2, 18 changes in protein products. There were significant decreases in Ucn2 [F( ) = 3.9, P < .05] mRNA levels, with SS rats displaying 2, 18 Downloaded from https://academic.oup.com/ijnp/article-abstract/21/3/281/4642156 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Torres et al. | 285 Figure 3. Expression of BDNF- and NGF-related proteins in the dorsal striatum following 30 days after methamphetamine (METH) self-administration (SA). (a) Significantly decreased pro-BDNF levels in shock-resistant (SR) rats compared with saline controls. (b) Increased mature BDNF in SR and shock-sensitive (SS) rats com- pared with saline controls. (c) TrkB levels are slightly increased in SS rats compared with SR rats. (d) Similar expression of pTrkB protein levels in SR and SS phenotypes. (e) No changes in pro-NGF levels in SR and SS rats. (f) Increased mature NGF protein levels in both SR and SS rats, with SS showing larger increases. (g) Comparable upregulated TrkA levels in SR and SS rats. (h) Increased pTrkA expression in SS rats compared with saline controls. (i) Increased of p75NTR expression in SS rats com- pared with saline controls and SR rats. (j) Similar levels of sortilin expression between SR and SS rats. Values represent means ±SEM of fold changes relative to the # ## controls. Key to statistics: *P < .05, **P < .01, ***P < .001 compared with saline controls; P < .05, P < .01 compared with SR rats. striatal proBDNF levels [F ( ) = 5.13, P < .05] in SR rats compared rats. Given that p75NTR can interact with sortilin to cause cellular 2, 15 with controls (Figure 3a)F . igure 3b shows that there were also damage (Nykjaer and Willnow, 2012) and because METH is also increases in mature BDNF levels [F( ) = 11.80, P < .001] in both a known toxicant (Cadet and Krasnova, 2009), we measured stri- 2, 16 SR and SS rats. There were also significant changes in the BDNF atal sortilin levels. Figure 3j shows that there were no significant receptor, TrkB, protein levels [F( ) = 3.63, P < .05] (Figure 3c) but changes in sortilin levels [F( ) = 0.81, P = .46] in the 2 phenotypes 2, 15 2, 16 no significant changes in the phosphorylated form, pTrkB [F( (Figure 3j), supporting the idea that increased p75NTR may be 2, ) = 1.58, P = .23] (Figure 3d) between the SR and SS rats (Figure 3c). related to enhanced neuroplasticity in the SS phenotype but not We next focused our attention on proNGF, NGF, and TrkA pro- to the reported toxic effects of METH SA (Krasnova et al., 2010). tein levels. We detected no significant changes in proNGF levels [F( ) = 1.72, P = .21] (Figure 3e) but found significant increases 2, 15 Activation of the Ras/Raf/MEK/ERK Pathway in the in mature NGF levels [F( ) = 42.45, P < .001] in both SR and SS 2, 16 Dorsal Striatum of SS Rats groups compared with the control group (Figure 3f). However, mature NGF protein levels were significantly higher in the SS Neurotrophins exert their functions by activation of the Ras/ rats compared with the SR rats ( < P.05) (Figure 3f). There were no Raf/MEK/ERK intracellular signaling cascade through phos- significant differences in TrkA protein levels between the groups phorylation of several proteins in that cascade (Reichardt, (Figure 3g). However, there was increased abundance of phospho- 2006; Cargnello and Roux, 2011). Importantly, it is known rylated TrkA protein [F( ) = 5.10, P < .05] only in the SS pheno- that p75NTR can interact with TrkA to potentiate activation 2, 15 type (Figure 3h). Because NGF can also interact with the p75NTR of this cascade (Chao et al., 2006; Reichardt, 2006; Matusica receptor (Bucci et al., 2014), we tested the possibility that there et al., 2013), which is known to participate in the modulation might be differential protein expression of this receptor in the 2 of gene expression in response to neuronal activity (Flavell phenotypes. Figure 3i shows that there were indeed significant and Greenberg, 2008). We thus thought it likely that the SS changes in p75NTR protein levels [F( ) = 6.13, P < .05], with the SS phenotype might also show increased phosphorylation of 2, 15 rats showing increased expression compared with SR and control proteins of the MAPK cascade. Indeed, Figure 4a showed a Downloaded from https://academic.oup.com/ijnp/article-abstract/21/3/281/4642156 by Ed 'DeepDyve' Gillespie user on 16 March 2018 286 | International Journal of Neuropsychopharmacology, 2018 Figure 4. Activation of the MAPK/ERK intracellular signaling cascade in the dorsal striatum of shock-sensitive (SS) rats. (a) p-cRaf expression in SS rats compared with controls and SR rats. (b) Increased pMEK1/2 abundance in both SR and SS rats compared with saline controls. (c) Increased pERK 1/2 expression in SS rats compared with SR rats. (d) Increased pMSK1 expression in SS rats compared with saline controls and SR rats. (e) Increased pCREB expression in SS rats compared with saline controls and SR rats. (f) Increased p-mTOR levels in SS rats compared with control rats. (g) Increased H3ac levels in SS rats compared with saline controls and SR rats. (h) Increased p-MeCP2 expression in SS rats compared with saline controls and SR rats. Key to statistics: *P < .05, **P < .01, ***P < .001 compared with saline controls; # ## ### P < .05, P < .01, P < .001 compared with SR rats. trend [F( ) = 3.51, P = .06] of increased p-Raf abundance Discussion 2, 15 in SS rats, with planned comparisons revealing signifi- Recent work in our laboratory has indicated that, even in rats cant increases compared with SR rats ( P < .05). Figure 4b that had escalated their intake of METH during SA procedures, also shows significant increases in pMEK1/2 abundance footshock punishment can lead to the segregation of distinct [F( ) = 18.87, P < .001] in both SR and SS rats relative to 2, 16 subgroups of rats that either continue to take the drug com- controls.F igure 4c illustrates a trend [F( ) = 3.34, P = .06] 2, 15 pulsively or suppress their responding for the drug (Cadet et towards increased pERK abundance, with planned compari- al., 2017; Krasnova et al., 2017; Torres et al., 2017). Here, we sons revealing significant increases in the SS rats compared report that SS rats showed increased activation of multiple with SR rats (P < .05). There were significant increases [F( 2, proteins involved with the NGF-TrkA/p75NTR/MAPK signal- ) = 6.78, P < .01] in pMSK1 abundance in SS rats compared ing cascade in the dorsal striatum after 30 days of withdrawal with SR and control rats (Figure 4d). Similarly, CREB phos- from METH SA and punishment (Figure 5). SS rats also showed phorylation was significantly [F( ) = 22.55, P < .01] increased 2, 16 increases in the expression of neuropeptide and neurotrophic only in the SS phenotype (Figure 4e). genes compared with SR rats. Specifically, neuropeptide- Neurotrophins are also known to increase activation of related genes that were increased in SS rats included Crhr, mTOR complexes via mTOR phosphorylation with second- Crhbp, and Ucn2, whereas neurotrophic-associated genes that ary increase in translation processes (Laplante and Sabatini, showed upregulation included Bdnf and Gfra2. These observa- 2012). Because such an increase in translation may provide a tions are interesting given that UCN and its receptors serve partial explanation for the increased p75NTR protein expres- to integrate physiological stress responses that might have sion observed only in the sensitive phenotype, we measured served as triggers for the appearance of the SS phenotype in mTOR phosphorylation and found significant increases in reaction to negative stimuli. phosphorylated mTOR abundance [F( ) = 4.22, P < .05] in 2, 13 Our behavioral studies are in line with the reports of SS rats compared with controls (Figure 4f). We also meas- other authors who have developed SA methods to identify ured the abundance of total histone 3 acetylation (H3ac) in rats with persistent drug-seeking behaviors despite adverse the dorsal striatum and found significant increases in H3ac consequences (Deroche-Gamonet et al., 2004; Pelloux et al., abundance [F( ) = 4.67, P < .05] in SS rats compared with SR 2, 16 2007; Chen et al., 2013) or despite environmental signals and saline controls (Figure 4g). Phosphorylated MeCP2 pro- of potential adversity (Vanderschuren and Everitt, 2004) to tein levels were also increased in SS rats compared with SR drug taking. Our studies have used this approach to identify and controls (Figure 4h). Downloaded from https://academic.oup.com/ijnp/article-abstract/21/3/281/4642156 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Torres et al. | 287 Figure 5. Preferential activation of the NGF signaling pathway in shock-sensitive methamphetamine (METH) self-administering (SA) rats. The figure indicates that METH SA is accompanied by increased signaling in excitatory synapses in all rats. Yet contingent footshocks led to the identification of 2 METH SA phenotypes: rats that continued to press an active lever to receive METH (shock-resistant, SR) and those that reduced their lever pressing, thereby reducing their METH intake (shock-sensi- tive, SS). Both sets of rats showed increased BDNF, whereas rats that reduce their lever pressing exhibited increased mature nerve growth factor (NGF) levels and greater abundance of phopshorylated TrkA, a receptor for NGF. Importantly, the levels of P75NTR, another NGF receptor, were also increased only in the genetically prone shock-sensitive rats. In addition, several phospho-proteins that participate in the NGF/RAF/ERK/MSK cascade were activated only in the shock-sensitive rats. Moreover, the shock-sensitive rats showed increased CREB phosphorylation in the dorsal striatum. Phosphorylated CREB is known to recruit the histone acetyl-transferase, CREB binding protein (CBP), an event that leads to increased H3 histone acetylation, as observed in the shock-sensitive rats. These series of molecular events could have led to increased GABAergic tone in the dorsal striatum and subsequent suppression of METH SA in the shock-sensitive animals. Therefore, the development of molecules that can specifically activate this striatal NGF-mediated phosphorylation cascade may be of therapeutic benefit to METH-addicted individuals. distinct molecular profiles between persistent drug-seeking Because BDNF and TrkB protein levels did not account for rats and those that reduce their METH intake. For example, neuronal differences between SS and SR rats, the possibil- we have previously demonstrated that SS rats are character - ity arose that NGF and its receptor, TrkA, might play a more ized by differential changes in DNA hydroxymethylation in prominent role in discriminating the 2 phenotypes. Indeed, the nucleus accumbens (Cadet et al., 2017). Within this same we observed increases in NGF protein levels accompanied by region, we also demonstrated that SS rats show increased selective increases in phosphorylated TrkA and p75NTR lev- mRNA levels of various histone deacetylases that partici- els in the SS phenotype compared with the SR rats. Although pate in gene regulation (Cadet et al., 2016a). In a subsequent NGF was originally described as a neurotrophic factor required report, we also documented that SR rats exhibited increases for cell proliferation (Cohen et al., 1954), it is now clear that in nucleus accumbens proenkephalin and prodynorphin NGF can also participate in a number of neurobiological events mRNA levels (Cadet et al., 2016b). Herein, we expand on our (Conner et al., 2009; Manni et al., 2013). For example, within the previous work by demonstrating that, in the dorsal striatum, striatum NGF is produced by GABAergic interneurons (Bizon neurotrophins and activation of their downstream signaling et al., 1999) and has significant protective and plastic effects cascade distinguishes SS from SR phenotypes following pro- on striatal cholinergic neurons under normal and patho- longed abstinence from METH intake. logical conditions (Fischer et al., 1998Gr ; atacos et al., 2001). Neurotrophins play important roles in regulating diverse Additionally, NGF can cause hypertrophy of striatal cholinergic neuronal processes including synaptic plasticity, cell sur - neurons, increased levels of choline acetyltransferase mRNA, vival, differentiation, and neuronal growth (Alder et al., 2003; and reduced spontaneous neuronal activity (Forander et al., Bekinschtein et al., 2008). Our observations of increased mature 1996). Moreover, the biological effects of NGF occur through BDNF protein levels in SR and SS rats are consistent with pre- its binding to TrkA and p75NTR, with distinct functional and vious reports showing increased BDNF expression in rats that structural interactions between the 2 receptors (Matusica self-administered METH chronically (Krasnova et al., 2013 Li ; et al., 2013; Bucci et al., 2014; Covaceuszach et al., 2015). For et al., 2015). These observations suggest that increased BDNF instance, p75NTR can co-precipitate along with TrkA (Bibel expression may be a consequence of long-term METH expo- et al., 1999), with TrkA affinity for NGF increasing in the pres- sure but do not necessarily reflect molecular adaptations that ence of p75NTR (Esposito et al., 2001). p75NTR can also prolong would help to distinguish compulsive from controlled drug- cell-surface TrkA-dependent signaling (Makkerh et al., 2005), taking behaviors. This conclusion is supported by our findings thereby enhancing TrkA signaling capacity (Verdi et al., 1994; that there were no differential changes in TrkB phosphoryla- Epa et al., 2004). Interestingly, knockdown of p75NTR expres- tion between the two phenotypes. sion significantly reduced excessive alcohol intake in rats Downloaded from https://academic.oup.com/ijnp/article-abstract/21/3/281/4642156 by Ed 'DeepDyve' Gillespie user on 16 March 2018 288 | International Journal of Neuropsychopharmacology, 2018 (Darcq et al., 2016), whereas our own findings suggest that findings implicate potentially distinct roles of this protein in increased p75NTR might be involved in suppressing METH- various brain regions following METH SA. Taken together, our seeking behavior, since the SS rats also show less cue-induced findings and those of others suggest that increased neuro- drug seeking (Torres et al., 2017). This statement hints to the trophic factors and activation of the Ras/Raf/MEK/ERK pathway possibility that SS rats might have a better ability to learn and may serve to prevent the development of plastic changes that establish memory for adverse events through the activation of promote compulsive METH intake. the NGF signaling cascade. In support of this hypothesis, a pre- In conclusion, we found that rats that reduce their METH vious report suggested that enhancement of contextual fear intake in the presence of punishment show significant increases memory in rodents is mediated by neurotrophic-dependent in striatal NGF levels, TrkA phosphorylation, p75NTR expression, activation of the Erk1/2(MAPK) pathway (Revest et al., 2014). and phosphorylation of the Ras/Raf/MEK/ERK signaling cascade. Similarly, increased neurotrophic factors in the dorsal stri- These molecular adaptations implicate neurotrophin-mediated atum appear to be associated with enhanced performance on signaling pathways during late stages of withdrawal from METH the lever-press escape/avoidance paradigm in rats (Albeck et SA in a brain region associated with habitual and compulsive al., 2005). behaviors. Thus, our punishment-based model highlights the Given that stimulation of TrkA by NGF induces auto-phos- possibility of identifying specific molecular alterations that may phorylation of this receptor and promotes ERK1/2 activation help to distinguish rats with distinct profiles of drug intake after (Diolaiti et al., 2007), we thought it likely that NGF/TrkA inter - periods of drug withdrawal when a propensity to relapse might actions might differentially activate downstream signaling be pronounced. Therefore, the use of such models may be quite between the 2 phenotypes. This supposition was confirmed by useful in the development of therapeutic modalities against our findings that only striatal tissues from the SS rats showed drug addiction. increased phosphorylation of proteins associated with the MAPK/MEK/ERK intracellular cascade. NGF-TrkA interactions Supplementary Material are known to active multiple intracellular signaling pathways including the Ras/MAPK, PI3K, and PLC γ cascades (Marlin and Supplementary data are available at International Journal of Li, 2015). However, the Ras/MAPK cascade has received much Neuropsychopharmacology online. attention due to the prominent role it plays in neuronal plas- ticity (Bruel-Jungerman et al., 2007Car ; gnello and Roux, 2011; Correa et al., 2012), memory formation (Adams and Sweatt, Acknowledgments 2002), and transcriptional responses (Davis et al., 2000). In neur - This research was supported by funds of the Intramural Research onal cells, the binding of mature NGF onto TrkA activates the Program of the DHHS/NIH/NIDA. adaptor GRB2-SOS protein complex, which increases the rate of GDP-GTP exchange on Ras, leading to Ras activation (Bucci et al., 2014; Marlin and Li, 2015). Activation of Ras induces a sequential Statement of Interest activation of Raf, a MAPK kinase kinase. Activation of Raf sub- None. types induces phosphorylation of MEK that then promotes the phosphorylation of ERK1/2 (Plotnikov et al., 2011 Ciccar ; elli and Giustetto, 2014). Translocation of pERK1/2 into the cell nucleus References results in the phosphorylation of MSK1 (Plotnikov et al., 2011). Adams JP, Sweatt JD (2002) Molecular psychology: roles for the Phosphorylated-MSK1 directly causes the phosphorylation of ERK MAP kinase cascade in memory. Annu Rev Pharmacol CREB (Arthur and Cohen, 2000) that binds onto cAMP response Toxicol 42:135–163. elements. Phosphorylated-CREB then recruits histone acetyl- Albeck DS, Beck KD, Kung LH, Sano K, Brennan FX (2005) transferases that promote histone acetylation and increase Leverpress escape/avoidance training increases neurotro- accessibility of the genome for molecular machinery to initi- phin levels in rat brain. Integr Physiol Behav Sci 40:28–34. ate transcription (Nestler, 2012). This discussion is compatible Alder J, Thakker-Varia S, Bangasser DA, Kuroiwa M, Plummer MR, with our observations of increased phosphorylation of Raf, MEK, Shors TJ, Black IB (2003) Brain-derived neurotrophic factor- ERK, and MSK1 with subsequent increases in CREB phosphoryl- induced gene expression reveals novel actions of VGF in hip- ation in SS rats. In addition, our finding of increased H3ac in SS pocampal synaptic plasticity. J Neurosci 23:10800–10808. rats agrees with the above discussion and postulates a select- Arthur JS, Cohen P (2000) MSK1 is required for CREB phosphor - ive activation of long-lasting plasticity events that enhance ylation in response to mitogens in mouse embryonic stem memory formation in this group of animals. The finding that cells. FEBS Lett 482:44–48. phospho-mTOR is increased in SS, but not SR, rats is also of Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, interest, since NGF is known to activate this protein (Zhang and Goldin A, Izquierdo I, Medina JH (2008) BDNF is essential to Ma, 2014; Wang et al., 2017) that can regulate translation rates, promote persistence of long-term memory storage. Proc Natl metabolic processes, and synaptic plasticity in neurons (Cho, Acad Sci USA 105:2711–2716. 2011). 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International Journal of Neuropsychopharmacology – Oxford University Press
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