Psychopharmacology (2007) 195:407–414 DOI 10.1007/s00213-007-0922-9

ORIGINAL INVESTIGATION

Cocaine increases immunoglobulin heavy chain binding protein and caspase-12 expression in the rat dorsal striatum Sung Min Ahn & Soo Woon Kim & Eun Sang Choe

Received: 7 April 2007 / Accepted: 18 August 2007 / Published online: 13 September 2007 # Springer-Verlag 2007

Abstract Rationale Cocaine increases endoplasmic reticulum (ER) stress protein expression via glutamate and dopamine receptor activation in the dorsal striatum. Objectives The present study was performed to investigate ER stress response in the dorsal striatum in response to acute or repeated cocaine stimulation. It was hypothesized that cocaine upregulates the ER stress protein immunoglobulin heavy chain binding protein (BiP) and the ER stressassociated protein caspase-12 via N-methyl-D-aspartate (NMDA) and D1 dopamine receptor activation. Materials and methods Western immunoblot and immunohistochemical analyses were mainly performed to test this hypothesis in the rat dorsal striatum. Results The results showed that BiP and caspase-12 immunoreactivities were significantly increased at 30, 60, and 120 min after acute or repeated intraperitoneal (i.p.) injections of three doses (10, 20, 40 mg/kg) of cocaine for seven consecutive days. Intrastriatal (i.s.) infusion of the selective NMDA antagonist MK801 (2 nmol) or AP5 (2 nmol) significantly attenuated the increase in the immunoreactivity of caspase-12 in the dorsal striatum induced by repeated, but not acute, cocaine (20 mg/kg) administration. However, i.p. injection of the selective D1 antagonist SCH23390 (0.1 mg/kg) significantly attenuated the increase in the immunoreactivity of caspase-12 in the dorsal striatum induced by both acute and repeated cocaine (20 mg/kg) stimulation. Conclusion These findings suggest that acute or repeated cocaine administration can cause ER stress response in the dorsal striatum in which NMDA and D1 dopamine receptors participate in the mediation of the process. S. M. Ahn : S. W. Kim : E. S. Choe (*) Division of Biological Sciences, Pusan National University, 30 Jangjeon-dong, Kumjeong-gu, Pusan 609-735, South Korea e-mail: [email protected]

Keywords Dopamine . ER stress response . Glutamate . Psychostimulant . Striatum

Introduction Cocaine administration alters the levels of extracellular glutamate and dopamine in the dorsal striatum, which disrupts calcium homeostasis and causes an increase in the expression of endoplasmic reticulum (ER) stress proteins (Shin et al. 2007). The ER is the site of synthesis, folding and assembly of secretory proteins, which is controlled in part by immunoglobulin heavy chain binding protein (BiP), an ER heat shock protein 70 (Hsp 70) family member. Disturbances in normal cellular physiology can affect protein biosynthesis in the ER, resulting in the accumulation of unfolded proteins. Cells under ER stress activate a signaling cascade termed the unfolded protein response (UPR) to prevent the formation of insoluble protein aggregates (Kaufman 1999). The UPR pathway transmits information regarding protein-folding status in the ER lumen to the cytoplasm and the nucleus. Prolonged UPR activation leads to apoptotic cell death (Patil and Walter 2001). Caspase-12 is located on the cytoplasmic side of the ER, and it plays an important role in the regulation of cell death by inducing ER stress (Chen and Gao 2002; Hitomi et al. 2004; Jayanthi et al. 2004). Although no real evidence regarding cocaine-induced neuronal cell damage in the brain was provided so far, we recently demonstrated that either acute or repeated cocaine administration increases the levels of the ER stress proteins BiP, C/EBPhomologous protein (CHOP) and inositol-requiring enzyme-1alpha (Ire1α) in the rat dorsal striatum through the activation of dopamine and glutamate receptors (Shin et al. 2007). However, methamphetamine, another indirect dopamine agonist, has capability to induce neuronal cell

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death via ER-mediated apoptotic processes (Cadet et al. 2005). These findings suggest that cocaine is capable of causing neuronal cell damage through ER stress response in the brain. The present study was designed to investigate the routes for causing ER stress response by cocaine administration, as the medium dose of either acute or repeated cocaine (20 mg/kg) administration upregulates the expression of ER stress proteins in the dorsal striatum (Shin et al. 2007). It was therefore hypothesized that cocaine upregulates BiP and caspase-12 via N-methyl-D-aspartate (NMDA) and D1 dopamine receptor activation. Western immunoblot and immunohistochemical analyses were performed to test this hypothesis in the dorsal striatum in vivo by (1) intraperitoneal (i.p.) injection of three different doses of acute or repeated cocaine to understand whether cocaine alters BiP and caspase-12 induction and (2) blockade of NMDA or D1 receptor in response to acute or repeated cocaine administration to determine the involvement of the receptors in the regulation of the protein expression.

Materials and methods Animals Adult male Sprague–Dawley rats (200–250 g) were obtained from Hyo-Chang Science (Daegu, Korea). The rats were individually housed in a controlled environment during all experimental treatments. Food and water were provided ad libitum, and the rats were maintained on a 12-h light/dark cycle. On the day of the experiment, the injection was performed in a quiet room to minimize stress. All animal use procedures were approved by the Institutional Animal Care and Use Committee and were carried out in accordance with the provisions of the NIH “Guide for the Care and Use of Laboratory Animals.” Drugs All pharmacological drugs used in this study were purchased from Tocris Cookson (Ballwin, MO, USA) and were freshly prepared on the day of the experiment. Dizocilpine/ (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate (MK801; 2 nmol), DL-2amino-5-phosphonopentanoic acid (AP5; 2 nmol) and (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0.1 mg/kg) were dissolved in dimethylsulfoxide (DMSO) and then diluted in artificial cerebrospinal fluid (aCSF). DMSO in combination with aCSF was therefore used as the vehicle control for the respective agents. Solutions of all drugs were neutralized to pH 7.2–7.4 with 1 N NaOH if

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necessary. Cocaine (Belgopia, Louvain-La-Neuve, Belgium) was dissolved in physiological saline (0.9% sodium chloride) throughout the experiments. Experimental design Four separate experiments were conducted in this study. The first experiment was designed to investigate whether lower (10 mg/kg) or higher (40 mg/kg) doses of acute or repeated cocaine injections alter the expression of BiP and caspase-12 because our previous study showed that the medium dose (20 mg/kg) of both acute and repeated cocaine injections significantly increased the induction of ER stress proteins (Shin et al. 2007). The rats were randomly divided into eight groups (n=5–6 per group). For the acute cocaine injection, each rat received an i.p. injection of cocaine (10, 20, 40 mg/kg). For the repeated cocaine injections, the rats received i.p. injection of one of the three doses of cocaine once daily for seven consecutive days. As acute and repeated cocaine injections at three different doses significantly increased BiP and caspase-12 expression, the second and third experiments were designed to investigate the involvement of the NMDA and D1 receptors in the regulation of caspase-12 by acute or repeated cocaine (20 mg/kg) injections in the dorsal striatum. The rats were randomly divided into four groups (n=5–6 per group) for each experiment. The selective NMDA antagonist MK801 (2 nmol) or AP5 (2 nmol) was injected into the center of the dorsal striatum 5 min before the final injection of each dose of cocaine was administered. However, the selective D1 antagonist SCH23390 (0.1 mg/kg) was intraperitoneally delivered 30 min before the final injection of each dose of cocaine. Alterations of the immunoreactivity of caspase-12 were observed 30 min after acute or repeated cocaine in which BiP immunoreactivity was maximally increased as demonstrated in the first experiment. The doses of the antagonists were determined from the results of previous studies (Wang and McGinty 1995; Choe and Wang 2002; Shin et al. 2007). Intrastriatal drug infusion The rats were anesthetized with 8% chloral hydrate (6 ml/kg, i.p.) and placed in a Stoelting stereotaxic apparatus. Under aseptic conditions, a 23-gauge stainless steel guide cannula (inner diameter, 0.29 mm; 10 mm in length) was implanted at the coordinates of 1 mm anterior to the bregma, 2.5 mm to the right of the midline, and 4 mm below the surface of the skull. The guide cannula was sealed with a stainless steel wire of the same length. Rats were given 3 days to recover from the surgery. On the day of the experiment, the inner steel wire was replaced by a 30-gauge stainless steel

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injection cannula (inner diameter, 0.15 mm) with a length of 12.5 mm that protruded 2.5 mm beyond the guide cannula. MK801 or AP5 was unilaterally infused through the injection cannula into the central part of the right dorsal striatum in a volume of 1 μl at a rate of 0.2 μl/min in freely moving rats. The progress of the injection was monitored by observing the movement of a small air bubble through a length of precalibrated PE-10 tubing inserted between the injection cannula and a 2.5-μl Hamilton microsyringe. After the injection was completed, the injector was left in place for an additional 5 min to reduce any possible backflow of the solution along the injection tract. All injections were performed in the home cages. Western blot analysis The rats were deeply anesthetized with 8% chloral hydrate (6 ml/kg, i.p.) and decapitated at 30, 60, and 120 min after the final injection of saline or cocaine. To analyze the effects of MK801, AP5, and SCH23390, the rats were killed at 30 min after the final injection of saline or cocaine. The brains were removed, frozen in isopentane at −70°C, and stored in a deep freezer. Sections were serially cut in a cryostat, and the injected right dorsal striatum was removed with a steel borer (inner diameter, 2 mm). All tissue samples were lysed in sodium dodecyl sulfate (SDS) sample buffer for 5 min at 95°C. The samples were then sonicated on ice for 30 s and centrifuged at 700×g for 10 min at 4°C, and the pellet primarily containing nuclei and large debris was discarded. The supernatant was then centrifuged again at 12,000×g for 30 min at 4°C. The supernatant was resolved using 10% SDS-polyacrylamide gel electrophoresis (SDS-PAGE), and the separated proteins were transferred to a nitrocellulose membrane. The membrane was blocked with blocking buffer containing 5% skim milk. The membrane was probed with each rabbit primary antiserum against BiP (1:2,000), caspase-12 (1:1,000), or actin (1:1,000) overnight at 4°C on a shaker. BiP and actin antisera were purchased from Sigma-Aldrich (St. Louis, MO, USA), and caspase-12 antiserum was purchased from Santa Cruz Biotech (Santa Cruz, CA, USA). The membrane was then incubated with the appropriate secondary antiserum for 1 h at room temperature. Immunoreactive protein bands were detected using enhanced chemiluminescence reagents (ECL; Amersham Pharmacia Biotech, Piscataway, NJ, USA) on X-ray films. Immunohistochemistry As in the Western blot analysis, the rats were deeply anesthetized with 8% chloral hydrate (6 ml/kg, i.p.) 10 min before each time point. Briefly, the rats were transcardially perfused with 300 ml of 4% paraformaldehyde at 4°C. The

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brains were removed and post-fixed in 10% sucrose/4% paraformaldehyde for 2 h at 4°C and then placed in 20% sucrose/phosphate-buffered saline at 4°C overnight. Using a sliding microtome, 30-μm frozen sections were cut, and three sections per BiP or caspase-12 antiserum per brain were collected at striatal levels and processed for immunohistochemistry according to the method previously described (Choe et al. 2004). Briefly, sections were incubated with BiP or caspase-12 antiserum for 20 h at 4°C on a shaker. Sections were then incubated in goat anti-rabbit secondary antiserum (Kirkegaard and Perry Laboratories, Gaithersburg, MD, USA) for 1 h, followed by avidin–biotin– peroxidase reagents (Vector Elite Vectastain Kit, Vector Laboratories, Burlingame, CA, USA) for 1 h at room temperature. Diaminobenzidine was used as the chromagen, and NiCl2 was added to enhance the reaction product. Quantitation of immunoreactivity Immunoreactive protein bands on films were semi-quantified using an imaging digital camera and NIH Image 1.62 software. Briefly, the film background was measured and saved as a “blank field” to correct for uneven illumination. The upper limit of the density slice option was set to eliminate any background, and this value was used to measure all images. The lower limit was set at the bottom of the LUT scale. The immunoreactive protein bands were measured using a rectangle that covered the individual band. Statistics Statistical significance on the number of immunoreactive pixels per measured area between groups was determined using a one-way analysis of variance on ranked data followed by a Tukey’s honestly significant difference test in GraphPad Prism 4 (GraphPad Software, San Diego, CA, USA). The level of statistical significance was set at p<0.05.

Results Acute or repeated cocaine increased BiP and caspase-12 immunoreactivities in the dorsal striatum This experiment was designed to investigate whether acute or repeated cocaine administration alters BiP and caspase12 expression in the dorsal striatum. The changes in BiP and caspase-12 immunoreactivities in the dorsal striatum were monitored at 30, 60, and 120 min after the three different doses (10, 20, 40 mg/kg) of acute or repeated cocaine injections. The results showed that each dose of acute or repeated cocaine significantly increased the

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Fig. 1 Western immunoblot analysis for the effects of three different doses (10, 20, 40 mg/kg, i.p.) of acute (a, b, c) or repeated (d, e, f) cocaine on BiP immunoreactivity at 30, 60, and 120 min after the final cocaine injection. Semiquantitative analysis confirms that both acute and repeated cocaine administration caused an increase in BiP immunoreactivity in rat dorsal striatum (n=5–6 per group). *p<0.05 vs acute or repeated saline groups

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Fig. 2 Western immunoblot analysis for the effects of three different doses (10, 20, and 40 mg/kg, i.p.) of acute (a, b, c) or repeated (d, e, f) cocaine on caspase-12 immunoreactivity at 30, 60, and 120 min after the final injection of cocaine. Semiquantitative analysis confirms that both acute and repeated cocaine administration increased caspase-12 immunoreactivity in rat dorsal striatum (n=5–6 per group). *p<0.05 vs acute or repeated saline groups

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immunoreactivities of the proteins at all three time points. The BiP immunoreactivity was significantly increased at 30 min and was prolonged for up to 120 min after each dose of acute (Fig. 1a–c) or repeated cocaine (Fig. 1d–f) injections, with the exception of the acute cocaine (10 mg/kg) injection at the 30-min time point. Similar to BiP immunoreactivity, caspase-12 immunoreactivity also was significantly increased at 30 min and was prolonged for up to 120 min after the three different doses of acute (Fig. 2a–c) or repeated cocaine (Fig. 2d–f) injections. Caspase-12 immunoreactivity induced by repeated cocaine injections was enhanced in the cytoplasmic compartments of striatal neurons as compared to the levels in neurons treated with repeated saline injections (Fig. 3a, b). Similar results were shown in the acute cocaineinjected dorsal striatum (data not shown). Control actin immunoreactivity was not altered at any time point as shown in Figs. 1 and 2.

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MK801 or AP5 decreased repeated, but not acute, cocaine-stimulated caspase-12 immunoreactivity in the dorsal striatum As BiP and caspase-12 immunoreactivities in the dorsal striatum were significantly increased by each dose of acute and repeated cocaine injections at all of the time points, the NMDA antagonist MK801 (2 nmol, i.s.) or AP5 (2 nmol, i.s.) was infused to determine the involvement of the NMDA receptors in the regulation of caspase-12 induction by medium dose of either acute or repeated cocaine injected at the 30-min time point. As shown in Fig. 4 (a, b), acute or repeated cocaine injections significantly increased caspase12 immunoreactivity as compared to the saline-injected controls. As in the vehicle, MK801 or AP5 infusion alone did not alter the basal levels of caspase-12 immunoreactivity. The induction of caspase-12 immunoreactivity by repeated, but not acute, cocaine injections was much lower in the presence of MK801 or AP5. SCH23390 decreased acute or repeated cocaine-stimulated caspase-12 immunoreactivity in the dorsal striatum A separate study was carried out to evaluate the involvement of D1 dopamine receptors in the regulation of caspase-12 expression by acute or repeated cocaine administration. As in the vehicle control, SCH23390 (0.1 mg/kg, i.p.) pretreatment alone had no significant effects on the basal levels of caspase-12 immunoreactivity in the dorsal striatum. Pretreatment with SCH23390 significantly attenuated acute or repeated cocaine-induced caspase-12 immunoreactivity in the dorsal striatum (Fig. 4c, d). However, the levels of blockade were much less than those of MK801 or AP5. As seen in the immunoblot, immunohistochemical staining demonstrated that MK801, AP5, or SCH23390 attenuated the effects of acute or repeated cocaine-stimulated caspase-12 immunoreactivity in the cytoplasmic compartments of striatal neurons, as shown in Fig. 5. Similar results, except for MK801 or AP5, on acute cocaine were shown in the acute cocaine-injected dorsal striatum (data not shown).

Discussion

Fig. 3 Immunohistochemical localization of caspase-12 immunoreactivity in the cytoplasmic compartments of striatal neurons at 30 min after repeated saline (a) and repeated cocaine (b) injections. Caspase12 immunoreactivity was significantly increased by repeated cocaine administration as compared with repeated saline administration. Bar represents 100 μm

The results driven from the present study demonstrated that cocaine is able to increase the expression of the ER stress protein BiP. The present results also showed that caspase12, along with the NMDA and D1 dopamine receptors, participates in the mediation of the expression of ER stress proteins in response to acute or repeated cocaine injections in the dorsal striatum. The present data showed that three different doses of both acute and repeated cocaine injections significantly

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Fig. 5 Immunohistochemical staining illustrating the effects of the NMDA receptor antagonist MK801, AP5, or the D1 dopamine antagonist SCH23390 on caspase-12 immunoreactivity in response to repeated cocaine stimulation in rat striatal neurons. Caspase-12 immunoreactivity was significantly increased by repeated cocaine administration as compared with repeated saline administration (a, b). MK801 (2 nmol, i.s.), AP5 (2 nmol, i.s.), and SCH23390 (0.1 mg/kg, i.p.) significantly attenuated the repeated cocaineinduced increase in caspase-12 immunoreactivity in striatal neurons (c, d, e). Bar represents 50 (a, b) and 100 μm (c, d, e)

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Fig. 4 Western immunoblot analysis for the effect of the NMDA antagonist MK801 (2 nmol, i.s.), AP5 (2 nmol, i.s.), or the D1 antagonist SCH23390 (0.1 mg/kg, i.p.) on caspase-12 immunoreactivity at 30 min after medium dose of acute (a, c) or repeated (b, d) cocaine (20 mg/kg, i.p.) injection. Semiquantitative analysis confirms that pretreatment with MK801 or AP5 significantly attenuated repeated, but not acute, cocaine-stimulated caspase-12 immunoreactivity in rat dorsal striatum; however, SCH23390 significantly attenuated the increase in caspase-12 immunoreactivity by both acute and repeated cocaine injections in rat dorsal striatum (n=5–6 per group). *p<0.05 vs vehicle+ acute or repeated saline groups; #p<0.05 vs vehicle−acute or repeated cocaine groups

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increased the levels of BiP and caspase-12 immunoreactivities at three different time points, suggesting that lower to higher doses of cocaine are able to upregulate ER stress response in the dorsal striatum. The ER is an important organelle that participates in cellular homeostasis by regulating calcium signaling cascades and protein folding (Ermak and Davies 2002). The disruption of intracellular calcium homeostasis can cause ER stress in primary neuronal cell cultures and cell lines (McCullough et al. 2001; Paschen and Frandsen 2001). Recent studies have demonstrated that ER stress plays an important role in neuronal apoptosis (Hale et al. 1996; Sanders and Wride 1995; Vaux and Strasser 1996). Although the effect of cocaine on the induction of ER stress proteins in the brain remains to be documented, Nassogne et al. (1997) showed that methamphetamine increases BiP expression, which is considered to be associated with the UPR and to participate in ER-induced cell injury (Paschen and Frandsen 2001). The increase in BiP levels might serve a protective function because BiP overexpression protects cells against ER stress (Morris et al. 1997). A previous study delivered from our laboratory demonstrated that acute and repeated cocaine administration significantly increased BiP, CHOP and Ire1α immunoreactivities in the dorsal striatum (Shin et al. 2007). Consistent with BiP expression, caspase-12 expression also was increased in the dorsal striatum by all three doses of acute and repeated cocaine injections in this study. ER stress also is known to increase caspase-12 expression in neurons and glial cells (Chen and Gao 2002; Shimoke et al. 2004). Caspase-12 plays an important role in the activation of apoptosis-inducing factor via calcium-mediated protein misfolding in cultured cells (Sanges and Marigo 2006). These findings suggest that cocaine is closely related to the induction of ER stress response in the brain in vivo. However, the degree to regulate BiP and caspase-12 expression by repeated cocaine administration is not different than that after acute administration in this study. In this study, pretreatment with the NMDA antagonist MK801 or AP5 significantly attenuated the levels of caspase-12 immunoreactivity by repeated, but not acute, cocaine injection, suggesting that NMDA receptors are more sensitive to the repeated exposure of cocaine in the induction of caspase-12 in the dorsal striatum. Thus, the activation of NMDA in striatal neurons in response to repeated cocaine plays a critical role in upregulating the expression of ER stress response as demonstrated by our previous study (Shin et al. 2007). Similarly, the infusion of the selective D1 antagonist SCH23390 significantly attenuated either acute or repeated cocaine-induced caspase-12 immunoreactivity in the dorsal striatum. These data suggest that activation of D1 dopamine receptors by cocaine in striatal neurons also plays an important role in the

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upregulation of ER stress response through D1-coupled signaling cascades resulting in NMDA receptor activation (Choe and McGinty 2000; Shin et al. 2007). Activation of NMDA in turn alters calcium homeostasis and leads to ER stress response in striatal neurons.

Summary This study investigated the involvement of the NMDA and D1 dopamine receptors in the regulation of ER stress response by cocaine administration in the rat dorsal striatum. The results demonstrated that both acute and repeated cocaine administration significantly augmented caspase-12 expression via the activation of D1 dopamine and NMDA receptors. These data suggest that the stimulation of NMDA and D1 dopamine receptors by cocaine causes ER stress response in the dorsal striatum. Acknowledgments This work was supported by the Korea Research Foundation (KRF2006-311-H00001) and the Ministry of Health and Welfare (02-PJ3-PG6-EV05-0001), Korea.

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