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Morphine sensitization increases the extracellular level of glutamate in CA1 of rat hippocampus via μ-opioid receptor
Neuroscience Letters 494 (2011) 130–134
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Morphine sensitization increases the extracellular level of glutamate in CA1 of rat hippocampus via -opioid receptor Maryam Farahmandfar a,e , Seyed Morteza Karimian a , Mohammad-Reza Zarrindast b , Mehdi Kadivar c , Hossein Afrouzi d , Nasser Naghdi e,∗ a
Department of Physiology, Tehran University of Medical Sciences, Tehran, Iran Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran c Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran d Darou Pakhsh Pharmaceutical Research Center, Tehran, Iran e Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran b
a r t i c l e
i n f o
Article history: Received 9 October 2010 Received in revised form 1 February 2011 Accepted 26 February 2011 Keywords: Morphine Behavioral sensitization Glutamate Hippocampus Microdialysis
a b s t r a c t Repeated administration of abuse drugs such as morphine elicits a progressive enhancement of druginduced behavioral responses, a phenomenon termed behavioral sensitization. These changes in behavior may reflect plastic changes requiring regulation of glutamatergic system in the brain. In this study, we investigated the effect of morphine sensitization on extracellular glutamate concentration in the hippocampus, a brain region rich in glutamatergic neurons. Sensitization was induced by subcutaneous (s.c.) injection of morphine, once daily for 3 days followed by 5 days free of the opioid treatment. The results showed that extracellular glutamate concentration in the CA1 was decreased following administration of morphine in non-sensitized rats. However, morphine-induced behavioral sensitization significantly increased the extracellular glutamate concentration in this area. The enhancement of glutamate in morphine sensitized rats was prevented by administration of naloxone 30 min before each of three daily doses of morphine. These results suggest an adaptation of the glutamatergic neuronal transmission in the hippocampus after morphine sensitization and it is postulated that opioid receptors may play an important role in this effect. © 2011 Elsevier Ireland Ltd. All rights reserved.
Behavioral sensitization refers to the progressive and persistent enhancement of locomotor activity, stereotypic behavior, reward or memory expression elicited by repeated administration of drugs [29,35,39]. This phenomenon is a critical factor in the development of drug addiction and plays a significant role in the high rate of relapse seen in drug addicts even after very long periods of abstinence [24,39]. A large body of evidence indicates that the dopaminergic system is strongly involved in the drug reward, reinforcement and development of behavioral sensitization [2,28,32,37]. In addition, it has been postulated that behavioral sensitization could reflect drug-induced neuroadaptive changes in the certain circuits in the brain including nucleus accumbens, ventral tegmental area, basolateral amygdala, prefrontal cortex and the hippocampus [33]. Therefore like other forms of synaptic plasticity, excitatory amino acid transmission may play a crucial role in behavioral sensitization [35]. Chronic exposure of opiates sig-
∗ Corresponding author at: Department of Physiology and Pharmacology, Pasteur Institute of Iran, P.O. Box 1316943551, Tehran 13164, Iran. Tel.: +98 21 6646 5132; fax: +98 21 6646 5132. E-mail address: Nasser [email protected] (N. Naghdi). 0304-3940/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2011.02.074
nificantly alters the glutamatergic synaptic transmission which involves functional modulation of NMDA receptor [15] and glutamate transporter (GLT1) [36]. On the other hand, the regulation of the glutamatergic system, such as blocking receptors [5] or activation of transporters [14], prevents or attenuates the development of opiate-induced tolerance and dependence. It has been shown that morphine administration changes the extracellular neurotransmitter concentration in many addiction-associated regions in the brain such as nucleus accumbens [27], ventral tegmental area [13] and locus coeruleus [30]. Acute administration of morphine increases dopamine but decreases acetylcholine and glutamate in nucleus accumbens of rats [22,23,27]. Naloxone injections in morphinedependent rats increase glutamate and acetylcholine and decrease dopamine in the nucleus accumbens [19,22,27]. There is some evidence that investigates the effects of glutamatergic receptors on sensitization to opioid and stimulants. It has been demonstrated that both NMDA [9,26] and AMPA [25] receptors are involved in the development phase of opioid sensitization. Also, there are some studies which indicate that behavioral sensitization to opioids can alter the extracellular level of glutamate in different regions of the brain such as ventral tegmental area [17] and prefrontal cortex [7]. Our previous study revealed that morphine-induced impair-
M. Farahmandfar et al. / Neuroscience Letters 494 (2011) 130–134
ment of spatial memory reversed by morphine sensitization [4]. Since the hippocampus has an essential role in spatial memory and behavioral sensitization [33], we postulated that changes in glutamate concentration in this area may be responsible for our previous results. In the present study, we investigated the effect of morphine on extracellular glutamate concentration in the hippocampal CA1 area in non-sensitized and morphine-sensitized rats by using microdialysis via high performance liquid chromatography fluorescence detection (HPLC-FLD) method. Male Wistar rats (230 ± 20 g) were housed four per cage and maintained on a 12 h light–dark cycle in an air conditioned constant temperature (23 ± 1 ◦ C) room. Food and water made available ad libitum. All experiments were conducted in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23, USA) revised 1996. Morphine sulfate (Temad, Tehran, Iran) and naloxone hydrochloride (Tolid-Daru, Tehran, Iran) were dissolved in sterile 0.9% saline just before the experiment and were injected subcutaneously (s.c.). o-Phthalaldehyde (OPA) was purchased from Sigma–Aldrich and other reagents and solvents were HPLC-quality and were obtained from Sigma–Aldrich or Merck (Germany). For the implantation of microdialysis guide cannula (MAB 4.15.IC, Microbiotech/se AB, Stockholm, Sweden), rats were anesthetized with a mixture of ketamine hydrochloride (Sigma, Germany) and xylazine (ketamine 60 mg/kg, xylazine 12 mg/kg, i.p.) and mounted in a stereotaxic frame (Stoelting, USA). The guide cannula was inserted into the hippocampal CA1 area with the following coordinates: 3.8 mm posterior to the bregma, ±2.2 laterals to midline and 2.7 ventral to the skull surface [18]. After surgery, at least a seven-day recovery period was supposed before any other intervention. On the experiment day, microdialysis probe (MAB 4.15.1.Cu, <6000 kDa, 1 mm membrane length, Microbiotech/se AB, Stockholm, Sweden) was inserted into the guide cannula and were connected to the microdialysis pump (WPI, SP 210, syringe pump) and perfused with artificial cerebrospinal fluid (ACSF: 114 mM NaCl, 3 mM KCl, 1 mM CaCl2 , 2 mM MgSO4 , 1.25 mM NaH2 PO4 , 26 mM NaHCO3 , 1 mM NaOH, 10 mM glucose and pH = 7.4) at a flow rate of 2 l/min. Following a 20-min equilibration period, six consecutive 10-min samples were collected for determination of basal glutamate level. Subsequently, saline or morphine was administered and dialysate samples were collected every 10 min for 1 h and were put on ice and instantly placed in −80 ◦ C. The amino acids were measured by reverse-phase highpressure liquid chromatography (Column: Shim-pack VP-ODS, 250 L × 4.6 mm, 5 m; Pump: LC-10AD, Shimadzu, Japan) coupled to fluorescence detector (RF-10 AXL, Shimadzu, Japan, set at wavelength: EX. = 340 nm, EM. = 475 nm), following pre-column derivatization with o-phthaladialdehyde (OPA) according to the method described by de Freitas Silva et al. [3]. The mobile phase consisted of 0.05 M sodium acetate, tetrahydrofuran and methanol (50:1:49, v/v) adjusted to pH 4.0. The mobile phase was filtered through Millipore 0.45 m Durapore membrane filters and vacuum degassed prior to use. Chromatographic analyses were performed at 25 ± 2 ◦ C. Compounds were eluted isocratically over a 9 min runtime at a flow rate of 1 mL/min. Following microdialysis experiments, animals were sacrificed by decapitation and brains were removed. For histological examination of guide cannula and microdialysis probe placement in CA1, 100 m thick sections were taken, mounted on slides, stained with cresyl violet and the guide cannula and probe track was examined for each rat. Only rats with correct placement were included in data analysis. After recovery period of animals, rats were administered according to the group treatment. In the first experiment we examined
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Fig. 1. The basal levels of glutamate in non-sensitized (A), morphine sensitized (B) and morphine-sensitized rats in combination with naloxone (C) groups. The basal contents of glutamate in the samples were the mean ± SEM of the averages of the six baseline samples in five rats.
the effects of acute administration of morphine on the extracellular level of glutamate in CA1 area in non-sensitized rats. Animals received subcutaneous (s.c.) administration of saline (1 ml/kg, s.c.) or morphine (5 mg/kg, s.c.) 60 min after collection of basal level of glutamate. In the second experiment the effects of morphine sensitization on the extracellular level of glutamate in CA1 area were examined. Induction of sensitization was based on previous reports [37–39]. Animals received for 3 days, once daily saline (1 ml/kg, s.c.) or morphine (20 mg/kg, s.c.) and after 5 days (no drug treatment), microdialysis experiments were performed and challenge dose of morphine (5 mg/kg, s.c.) was injected 60 min after collection of basal level of glutamate. In the third experiment we investigated the effect of morphine sensitization on the extracellular level of glutamate in CA1 area of rats in the presence or absence of naloxone. For this purpose animals received once daily injections of saline (1 ml/kg, s.c.) or the opioid receptor antagonist, naloxone (2 mg/kg, s.c.), 30 min prior to s.c. injections of morphine (20 mg/kg/day × 3 days). After 5 days (no drug treatment), microdialysis experiments were performed and animals received challenge dose of morphine (5 mg/kg, s.c.), 60 min after collection of basal level of glutamate. Basal values of extracellular glutamate were the means of six consecutive samples and were expressed as nmol/L. The data of basal concentrations of glutamate were analyzed by Student’s t-test. The changes of glutamate concentration after different treatments were analyzed by repeated measures two-way analysis of variance (ANOVA) with the drug treatments as between group factors and time as within group factors. Results showing significant overall changes were subjected to post hoc Tukey’s test. The difference between groups in each time point was analyzed by Student’s t-test. The data were expressed as percentage of basal values. A probability level of P < 0.05 was regarded as statistically significant. As shown in Fig. 1, mean basal levels of glutamate in nonsensitized, morphine sensitized and morphine-sensitized rats in the presence or absence of naloxone showed no difference in the mean basal levels of glutamate in CA1 area as compared to their control groups, respectively (Fig. 1). Fig. 2 shows that acute administration of morphine (5 mg/kg) decreased the extracellular level of glutamate in CA1 area in non-sensitized rats by nearly 40–60% of baseline within 10–60 min after administration. Repeated measures ANOVA revealed a significant effects of group [F(1,8) = 135.19; P < 0.001], time [F(6,48) = 13.59; P < 0.01] and a significant interaction of group × time [F(6,48) = 6.06; P < 0.05]. Student’s t-test on each time point revealed significant effects of acute administration of mor-
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phine on 10, 30, 40, 60 min as compared to saline group [(P < 0.05), (P < 0.01), (P < 0.05) and (P < 0.01)], respectively (Fig. 2). Following repeated treatment with saline or morphine once daily for 3 days, after 5 days a challenge with morphine (5 mg/kg) increased extracellular glutamate levels by nearly 10–60% of baseline within 20–60 min after administration with a significant effect at 30 min (Fig. 3). Repeated measures ANOVA revealed a significant effects of group [F(1,8) = 84.03; P < 0.001], time [F(6,48) = 3.22; P < 0.05] and a significant interaction of group × time [F(6,48) = 16.34; P < 0.01]. Student’s t-test on each time point revealed significant effects of morphine sensitization on 20–60 min as compared to control group [(P < 0.01), (P < 0.001), (P < 0.01), (P < 0.001) and (P < 0.05)], respectively (Fig. 3). As shown in Fig. 4 increase in glutamate concentration in morphine-sensitized rats was prevented in animals that had previously received a 3-day morphine treatment regimen in combination with naloxone. Repeated measures ANOVA revealed a significant effects of group [F(1,8) = 147.77; P < 0.001], time [F(6,48) = 3.45; P < 0.05] and a significant interaction of group × time [F(6,48) = 6.2; P < 0.05]. Student’s t-test on each time point revealed significant effects of naloxone treatment on 10–60 min as compared to control group [(P < 0.001), (P < 0.001), (P < 0.001), (P < 0.01), (P < 0.001) and (P < 0.01)], respectively (Fig. 4).
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Fig. 2. Effect of acute injection of saline (1 ml/kg, s.c.) –– and morphine (5 mg/kg, s.c.) –– on basal extracellular glutamate level from the hippocampal CA1 area in non-sensitized rats. Results are expressed as means ± SEM of the percent of basal values (n = 5). *P < 0.05 significantly different from respective basal values. # P < 0.05 and ## P < 0.01 significantly different from the correspondent value of saline group.
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Time (min) Fig. 3. Effect of morphine (5 mg/kg, s.c.) challenge on basal extracellular glutamate level from the hippocampal CA1 area of saline (1 ml/kg, s.c.) –– and morphine (20 mg/kg) –– pre-treated rats. Results are expressed as means ± SEM of the percent of basal values (n = 5). *P < 0.05 significantly different from respective basal values. # P < 0.05, ## P < 0.01, ### P < 0.001 significantly different from the correspondent value of saline group.
Fig. 4. Effect of morphine (5 mg/kg s.c.) challenge on basal extracellular glutamate from the hippocampal CA1 area of saline (1 ml/kg, s.c.) + morphine (20 mg/kg s.c.) –– and naloxone (2 mg/kg s.c.) + morphine (20 mg/kg s.c.) –– pre-treated rats. Results are expressed as means ± SEM of the percent of basal values (n = 5). *P < 0.05 significantly different from respective basal values. ## P < 0.01 and ### P < 0.001 significantly different from the correspondent value of morphine group.
Accumulating evidence suggests that alteration in glutamatergic system can trigger a cascade of neuroadaptations underlying the physical and psychological dependence on morphine, or behavioral sensitization in animal models [10,35]. In the present experiments we evaluated the effects of morphine administration on the extracellular glutamate concentration in dorsal hippocampus of non-sensitized and morphine-sensitized rats by using microdialysis in freely moving animals and HPLC-FLD method. According to our previous study, single administration of morphine (2.5, 5 and 7.5 mg/kg), 30 min before training of Morris water maze task, decreased the spatial memory acquisition in non-sensitized rats with a maximum effect of 5 mg/kg of morphine [4]. In the present study, acute administration of morphine (5 mg/kg) decreased extracellular glutamate levels in CA1 area by 40–70% of baseline within 10–60 min after morphine administration with the nearly 60% reduction in 30 min after injection. This result is a direct verification that spatial learning deficit after acute injection of morphine is significantly correlate with the reduction of glutamate concentration in dorsal hippocampus [4]. Our data is also in agreement with the result of Guo et al. which has reported that acute injection of morphine (10 mg/kg) decreased the extracellular level of glutamate in the hippocampus of mice [6]. The circuitry involved in sensitization is complex [33], because sensitization represents a cascade of events involving different transmitter systems and different brain regions. [34]. A large number of studies have indicated that morphine sensitization can alter the level of dopamine concentration in various brain regions [1,11,16]. There are few studies considering the effect of morphine sensitization on the extracellular level of glutamate in addiction-associated regions. In one study Ojanen et al. reported that morphine sensitization increased the glutamate levels in the ventral tegmental area in alcohol-preferring AA rats [17]. In this area, Hao et al. showed that induction of morphine sensitization decreased the basal level of extracellular glutamate concentration in the medial prefrontal cortex in mice [7]. Although many investigations demonstrated that direct and indirect glutamatergic connections of the hippocampus to the nucleus accumbens may play an important role in behavioral sensitization and drug-seeking behavior [8], the role of the hippocampus in this phenomenon needs to be more elucidated. There are some evidences indicating that morphine sensitization can alter glutamate receptors in dorsal hippocampus [25,26]. Our finding indicates that morphine sensitization can significantly alter the extracellular level of glutamate in dorsal hippocampus of rats.
M. Farahmandfar et al. / Neuroscience Letters 494 (2011) 130–134
These data shows that reduction of extracellular glutamate concentration induced by morphine can restore in morphine-sensitized rats with a peak at 30 min after injection of morphine challenge dose. These findings are consistent with our previous observations that impairment of spatial memory acquisition induced by pretraining injection of morphine (5 mg/kg) was significantly reduced in morphine (20 mg/kg)-sensitized rats in Morris water maze task [4]. As hippocampal glutamatergic system has an essential role in learning and memory especially spatial memory and navigation [12], we suggest that alteration of glutamate levels in dorsal hippocampus following morphine sensitization maybe responsible for the effect of this phenomenon on the spatial memory paradigm. The present data also indicated that injection of naloxone during 3 days of sensitization and 30 min before morphine administration prevented the increase of glutamate concentration induced by morphine sensitization. Since it has been shown that morphine sensitization increases the -opioid receptor density in most of the brain regions [31], our findings imply that enhancement in the extracellular glutamate level in the hippocampus followed by morphine sensitization, may be mediated by the increase in -opioid receptors. Thus, the involvement of -opioid receptors in the sensitization processes and alteration of dorsal hippocampal glutamate concentration by morphine seems likely. Our findings provide an evidence of interaction between morphine and glutamatergic system in the hippocampus. This interaction also has been shown by electrophysiological studies which indicate morphine treatment can modulate synaptic plasticity in the hippocampal CA1 of rats via glutamatergic receptors [20,21]. The results of this study reflect the changes in extracellular concentration of glutamate in dorsal hippocampus which is maybe due to alteration in glutamate release from neuronal cells or functional modulation of glutamate transporters by morphine sensitization. It is clear that to investigation of morphine sensitization on neuronal content of glutamate, more studies are needed. In conclusion, the results of the presents study demonstrated an adaptation of glutamatergic neurotransmission induced by morphine sensitization and implied that -opioid receptors may play an important role in this process. Acknowledgments We wish to thank everyone who was contributed to the HPLC assays in Darou Pakhsh Pharmaceutical Research Center. References [1] C. Cadoni, G. Di Chiara, Reciprocal changes in dopamine responsiveness in the nucleus accumbens shell and core and in the dorsal caudate-putamen in rats sensitized to morphine, Neuroscience 90 (1999) 447–455. [2] J.W. Dalley, B.J. Everitt, Dopamine receptors in the learning, memory and drug reward circuitry, Semin. Cell Dev. Biol. 20 (2009) 403–410. [3] D.M. de Freitas Silva, V.P. Ferraz, A.M. Ribeiro, Improved high-performance liquid chromatographic method for GABA and glutamate determination in regions of the rodent brain, J. Neurosci. Methods 177 (2009) 289–293. [4] M. Farahmandfar, S.M. Karimian, N. Naghdi, M.R. Zarrindast, M. Kadivar, Morphine-induced impairment of spatial memory acquisition reversed by morphine sensitization in rats, Behav. Brain Res. 211 (2010) 156–163. [5] M.E. Fundytus, T.J. Coderre, Effect of activity at metabotropic, as well as ionotropic (NMDA), glutamate receptors on morphine dependence, Br. J. Pharmacol. 113 (1994) 1215–1220. [6] M. Guo, N.J. Xu, Y.T. Li, J.Y. Yang, C.F. Wu, G. Pei, Morphine modulates glutamate release in the hippocampal CA1 area in mice, Neurosci. Lett. 381 (2005) 12–15. [7] Y. Hao, J.Y. Yang, C.F. Wu, M.F. Wu, Pseudoginsenoside-F11 decreases morphine-induced behavioral sensitization and extracellular glutamate levels in the medial prefrontal cortex in mice, Pharmacol. Biochem. Behav. 86 (2007) 660–666.
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Morphine sensitization increases the extracellular level of glutamate in CA1 of rat hippocampus via -opioid receptor Maryam Farahmandfar a,e , Seyed Morteza Karimian a , Mohammad-Reza Zarrindast b , Mehdi Kadivar c , Hossein Afrouzi d , Nasser Naghdi e,∗ a
Department of Physiology, Tehran University of Medical Sciences, Tehran, Iran Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran c Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran d Darou Pakhsh Pharmaceutical Research Center, Tehran, Iran e Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran b
a r t i c l e
i n f o
Article history: Received 9 October 2010 Received in revised form 1 February 2011 Accepted 26 February 2011 Keywords: Morphine Behavioral sensitization Glutamate Hippocampus Microdialysis
a b s t r a c t Repeated administration of abuse drugs such as morphine elicits a progressive enhancement of druginduced behavioral responses, a phenomenon termed behavioral sensitization. These changes in behavior may reflect plastic changes requiring regulation of glutamatergic system in the brain. In this study, we investigated the effect of morphine sensitization on extracellular glutamate concentration in the hippocampus, a brain region rich in glutamatergic neurons. Sensitization was induced by subcutaneous (s.c.) injection of morphine, once daily for 3 days followed by 5 days free of the opioid treatment. The results showed that extracellular glutamate concentration in the CA1 was decreased following administration of morphine in non-sensitized rats. However, morphine-induced behavioral sensitization significantly increased the extracellular glutamate concentration in this area. The enhancement of glutamate in morphine sensitized rats was prevented by administration of naloxone 30 min before each of three daily doses of morphine. These results suggest an adaptation of the glutamatergic neuronal transmission in the hippocampus after morphine sensitization and it is postulated that opioid receptors may play an important role in this effect. © 2011 Elsevier Ireland Ltd. All rights reserved.
Behavioral sensitization refers to the progressive and persistent enhancement of locomotor activity, stereotypic behavior, reward or memory expression elicited by repeated administration of drugs [29,35,39]. This phenomenon is a critical factor in the development of drug addiction and plays a significant role in the high rate of relapse seen in drug addicts even after very long periods of abstinence [24,39]. A large body of evidence indicates that the dopaminergic system is strongly involved in the drug reward, reinforcement and development of behavioral sensitization [2,28,32,37]. In addition, it has been postulated that behavioral sensitization could reflect drug-induced neuroadaptive changes in the certain circuits in the brain including nucleus accumbens, ventral tegmental area, basolateral amygdala, prefrontal cortex and the hippocampus [33]. Therefore like other forms of synaptic plasticity, excitatory amino acid transmission may play a crucial role in behavioral sensitization [35]. Chronic exposure of opiates sig-
∗ Corresponding author at: Department of Physiology and Pharmacology, Pasteur Institute of Iran, P.O. Box 1316943551, Tehran 13164, Iran. Tel.: +98 21 6646 5132; fax: +98 21 6646 5132. E-mail address: Nasser [email protected] (N. Naghdi). 0304-3940/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2011.02.074
nificantly alters the glutamatergic synaptic transmission which involves functional modulation of NMDA receptor [15] and glutamate transporter (GLT1) [36]. On the other hand, the regulation of the glutamatergic system, such as blocking receptors [5] or activation of transporters [14], prevents or attenuates the development of opiate-induced tolerance and dependence. It has been shown that morphine administration changes the extracellular neurotransmitter concentration in many addiction-associated regions in the brain such as nucleus accumbens [27], ventral tegmental area [13] and locus coeruleus [30]. Acute administration of morphine increases dopamine but decreases acetylcholine and glutamate in nucleus accumbens of rats [22,23,27]. Naloxone injections in morphinedependent rats increase glutamate and acetylcholine and decrease dopamine in the nucleus accumbens [19,22,27]. There is some evidence that investigates the effects of glutamatergic receptors on sensitization to opioid and stimulants. It has been demonstrated that both NMDA [9,26] and AMPA [25] receptors are involved in the development phase of opioid sensitization. Also, there are some studies which indicate that behavioral sensitization to opioids can alter the extracellular level of glutamate in different regions of the brain such as ventral tegmental area [17] and prefrontal cortex [7]. Our previous study revealed that morphine-induced impair-
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ment of spatial memory reversed by morphine sensitization [4]. Since the hippocampus has an essential role in spatial memory and behavioral sensitization [33], we postulated that changes in glutamate concentration in this area may be responsible for our previous results. In the present study, we investigated the effect of morphine on extracellular glutamate concentration in the hippocampal CA1 area in non-sensitized and morphine-sensitized rats by using microdialysis via high performance liquid chromatography fluorescence detection (HPLC-FLD) method. Male Wistar rats (230 ± 20 g) were housed four per cage and maintained on a 12 h light–dark cycle in an air conditioned constant temperature (23 ± 1 ◦ C) room. Food and water made available ad libitum. All experiments were conducted in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23, USA) revised 1996. Morphine sulfate (Temad, Tehran, Iran) and naloxone hydrochloride (Tolid-Daru, Tehran, Iran) were dissolved in sterile 0.9% saline just before the experiment and were injected subcutaneously (s.c.). o-Phthalaldehyde (OPA) was purchased from Sigma–Aldrich and other reagents and solvents were HPLC-quality and were obtained from Sigma–Aldrich or Merck (Germany). For the implantation of microdialysis guide cannula (MAB 4.15.IC, Microbiotech/se AB, Stockholm, Sweden), rats were anesthetized with a mixture of ketamine hydrochloride (Sigma, Germany) and xylazine (ketamine 60 mg/kg, xylazine 12 mg/kg, i.p.) and mounted in a stereotaxic frame (Stoelting, USA). The guide cannula was inserted into the hippocampal CA1 area with the following coordinates: 3.8 mm posterior to the bregma, ±2.2 laterals to midline and 2.7 ventral to the skull surface [18]. After surgery, at least a seven-day recovery period was supposed before any other intervention. On the experiment day, microdialysis probe (MAB 4.15.1.Cu, <6000 kDa, 1 mm membrane length, Microbiotech/se AB, Stockholm, Sweden) was inserted into the guide cannula and were connected to the microdialysis pump (WPI, SP 210, syringe pump) and perfused with artificial cerebrospinal fluid (ACSF: 114 mM NaCl, 3 mM KCl, 1 mM CaCl2 , 2 mM MgSO4 , 1.25 mM NaH2 PO4 , 26 mM NaHCO3 , 1 mM NaOH, 10 mM glucose and pH = 7.4) at a flow rate of 2 l/min. Following a 20-min equilibration period, six consecutive 10-min samples were collected for determination of basal glutamate level. Subsequently, saline or morphine was administered and dialysate samples were collected every 10 min for 1 h and were put on ice and instantly placed in −80 ◦ C. The amino acids were measured by reverse-phase highpressure liquid chromatography (Column: Shim-pack VP-ODS, 250 L × 4.6 mm, 5 m; Pump: LC-10AD, Shimadzu, Japan) coupled to fluorescence detector (RF-10 AXL, Shimadzu, Japan, set at wavelength: EX. = 340 nm, EM. = 475 nm), following pre-column derivatization with o-phthaladialdehyde (OPA) according to the method described by de Freitas Silva et al. [3]. The mobile phase consisted of 0.05 M sodium acetate, tetrahydrofuran and methanol (50:1:49, v/v) adjusted to pH 4.0. The mobile phase was filtered through Millipore 0.45 m Durapore membrane filters and vacuum degassed prior to use. Chromatographic analyses were performed at 25 ± 2 ◦ C. Compounds were eluted isocratically over a 9 min runtime at a flow rate of 1 mL/min. Following microdialysis experiments, animals were sacrificed by decapitation and brains were removed. For histological examination of guide cannula and microdialysis probe placement in CA1, 100 m thick sections were taken, mounted on slides, stained with cresyl violet and the guide cannula and probe track was examined for each rat. Only rats with correct placement were included in data analysis. After recovery period of animals, rats were administered according to the group treatment. In the first experiment we examined
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Fig. 1. The basal levels of glutamate in non-sensitized (A), morphine sensitized (B) and morphine-sensitized rats in combination with naloxone (C) groups. The basal contents of glutamate in the samples were the mean ± SEM of the averages of the six baseline samples in five rats.
the effects of acute administration of morphine on the extracellular level of glutamate in CA1 area in non-sensitized rats. Animals received subcutaneous (s.c.) administration of saline (1 ml/kg, s.c.) or morphine (5 mg/kg, s.c.) 60 min after collection of basal level of glutamate. In the second experiment the effects of morphine sensitization on the extracellular level of glutamate in CA1 area were examined. Induction of sensitization was based on previous reports [37–39]. Animals received for 3 days, once daily saline (1 ml/kg, s.c.) or morphine (20 mg/kg, s.c.) and after 5 days (no drug treatment), microdialysis experiments were performed and challenge dose of morphine (5 mg/kg, s.c.) was injected 60 min after collection of basal level of glutamate. In the third experiment we investigated the effect of morphine sensitization on the extracellular level of glutamate in CA1 area of rats in the presence or absence of naloxone. For this purpose animals received once daily injections of saline (1 ml/kg, s.c.) or the opioid receptor antagonist, naloxone (2 mg/kg, s.c.), 30 min prior to s.c. injections of morphine (20 mg/kg/day × 3 days). After 5 days (no drug treatment), microdialysis experiments were performed and animals received challenge dose of morphine (5 mg/kg, s.c.), 60 min after collection of basal level of glutamate. Basal values of extracellular glutamate were the means of six consecutive samples and were expressed as nmol/L. The data of basal concentrations of glutamate were analyzed by Student’s t-test. The changes of glutamate concentration after different treatments were analyzed by repeated measures two-way analysis of variance (ANOVA) with the drug treatments as between group factors and time as within group factors. Results showing significant overall changes were subjected to post hoc Tukey’s test. The difference between groups in each time point was analyzed by Student’s t-test. The data were expressed as percentage of basal values. A probability level of P < 0.05 was regarded as statistically significant. As shown in Fig. 1, mean basal levels of glutamate in nonsensitized, morphine sensitized and morphine-sensitized rats in the presence or absence of naloxone showed no difference in the mean basal levels of glutamate in CA1 area as compared to their control groups, respectively (Fig. 1). Fig. 2 shows that acute administration of morphine (5 mg/kg) decreased the extracellular level of glutamate in CA1 area in non-sensitized rats by nearly 40–60% of baseline within 10–60 min after administration. Repeated measures ANOVA revealed a significant effects of group [F(1,8) = 135.19; P < 0.001], time [F(6,48) = 13.59; P < 0.01] and a significant interaction of group × time [F(6,48) = 6.06; P < 0.05]. Student’s t-test on each time point revealed significant effects of acute administration of mor-
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phine on 10, 30, 40, 60 min as compared to saline group [(P < 0.05), (P < 0.01), (P < 0.05) and (P < 0.01)], respectively (Fig. 2). Following repeated treatment with saline or morphine once daily for 3 days, after 5 days a challenge with morphine (5 mg/kg) increased extracellular glutamate levels by nearly 10–60% of baseline within 20–60 min after administration with a significant effect at 30 min (Fig. 3). Repeated measures ANOVA revealed a significant effects of group [F(1,8) = 84.03; P < 0.001], time [F(6,48) = 3.22; P < 0.05] and a significant interaction of group × time [F(6,48) = 16.34; P < 0.01]. Student’s t-test on each time point revealed significant effects of morphine sensitization on 20–60 min as compared to control group [(P < 0.01), (P < 0.001), (P < 0.01), (P < 0.001) and (P < 0.05)], respectively (Fig. 3). As shown in Fig. 4 increase in glutamate concentration in morphine-sensitized rats was prevented in animals that had previously received a 3-day morphine treatment regimen in combination with naloxone. Repeated measures ANOVA revealed a significant effects of group [F(1,8) = 147.77; P < 0.001], time [F(6,48) = 3.45; P < 0.05] and a significant interaction of group × time [F(6,48) = 6.2; P < 0.05]. Student’s t-test on each time point revealed significant effects of naloxone treatment on 10–60 min as compared to control group [(P < 0.001), (P < 0.001), (P < 0.001), (P < 0.01), (P < 0.001) and (P < 0.01)], respectively (Fig. 4).
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Fig. 2. Effect of acute injection of saline (1 ml/kg, s.c.) –– and morphine (5 mg/kg, s.c.) –– on basal extracellular glutamate level from the hippocampal CA1 area in non-sensitized rats. Results are expressed as means ± SEM of the percent of basal values (n = 5). *P < 0.05 significantly different from respective basal values. # P < 0.05 and ## P < 0.01 significantly different from the correspondent value of saline group.
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Time (min) Fig. 3. Effect of morphine (5 mg/kg, s.c.) challenge on basal extracellular glutamate level from the hippocampal CA1 area of saline (1 ml/kg, s.c.) –– and morphine (20 mg/kg) –– pre-treated rats. Results are expressed as means ± SEM of the percent of basal values (n = 5). *P < 0.05 significantly different from respective basal values. # P < 0.05, ## P < 0.01, ### P < 0.001 significantly different from the correspondent value of saline group.
Fig. 4. Effect of morphine (5 mg/kg s.c.) challenge on basal extracellular glutamate from the hippocampal CA1 area of saline (1 ml/kg, s.c.) + morphine (20 mg/kg s.c.) –– and naloxone (2 mg/kg s.c.) + morphine (20 mg/kg s.c.) –– pre-treated rats. Results are expressed as means ± SEM of the percent of basal values (n = 5). *P < 0.05 significantly different from respective basal values. ## P < 0.01 and ### P < 0.001 significantly different from the correspondent value of morphine group.
Accumulating evidence suggests that alteration in glutamatergic system can trigger a cascade of neuroadaptations underlying the physical and psychological dependence on morphine, or behavioral sensitization in animal models [10,35]. In the present experiments we evaluated the effects of morphine administration on the extracellular glutamate concentration in dorsal hippocampus of non-sensitized and morphine-sensitized rats by using microdialysis in freely moving animals and HPLC-FLD method. According to our previous study, single administration of morphine (2.5, 5 and 7.5 mg/kg), 30 min before training of Morris water maze task, decreased the spatial memory acquisition in non-sensitized rats with a maximum effect of 5 mg/kg of morphine [4]. In the present study, acute administration of morphine (5 mg/kg) decreased extracellular glutamate levels in CA1 area by 40–70% of baseline within 10–60 min after morphine administration with the nearly 60% reduction in 30 min after injection. This result is a direct verification that spatial learning deficit after acute injection of morphine is significantly correlate with the reduction of glutamate concentration in dorsal hippocampus [4]. Our data is also in agreement with the result of Guo et al. which has reported that acute injection of morphine (10 mg/kg) decreased the extracellular level of glutamate in the hippocampus of mice [6]. The circuitry involved in sensitization is complex [33], because sensitization represents a cascade of events involving different transmitter systems and different brain regions. [34]. A large number of studies have indicated that morphine sensitization can alter the level of dopamine concentration in various brain regions [1,11,16]. There are few studies considering the effect of morphine sensitization on the extracellular level of glutamate in addiction-associated regions. In one study Ojanen et al. reported that morphine sensitization increased the glutamate levels in the ventral tegmental area in alcohol-preferring AA rats [17]. In this area, Hao et al. showed that induction of morphine sensitization decreased the basal level of extracellular glutamate concentration in the medial prefrontal cortex in mice [7]. Although many investigations demonstrated that direct and indirect glutamatergic connections of the hippocampus to the nucleus accumbens may play an important role in behavioral sensitization and drug-seeking behavior [8], the role of the hippocampus in this phenomenon needs to be more elucidated. There are some evidences indicating that morphine sensitization can alter glutamate receptors in dorsal hippocampus [25,26]. Our finding indicates that morphine sensitization can significantly alter the extracellular level of glutamate in dorsal hippocampus of rats.
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These data shows that reduction of extracellular glutamate concentration induced by morphine can restore in morphine-sensitized rats with a peak at 30 min after injection of morphine challenge dose. These findings are consistent with our previous observations that impairment of spatial memory acquisition induced by pretraining injection of morphine (5 mg/kg) was significantly reduced in morphine (20 mg/kg)-sensitized rats in Morris water maze task [4]. As hippocampal glutamatergic system has an essential role in learning and memory especially spatial memory and navigation [12], we suggest that alteration of glutamate levels in dorsal hippocampus following morphine sensitization maybe responsible for the effect of this phenomenon on the spatial memory paradigm. The present data also indicated that injection of naloxone during 3 days of sensitization and 30 min before morphine administration prevented the increase of glutamate concentration induced by morphine sensitization. Since it has been shown that morphine sensitization increases the -opioid receptor density in most of the brain regions [31], our findings imply that enhancement in the extracellular glutamate level in the hippocampus followed by morphine sensitization, may be mediated by the increase in -opioid receptors. Thus, the involvement of -opioid receptors in the sensitization processes and alteration of dorsal hippocampal glutamate concentration by morphine seems likely. Our findings provide an evidence of interaction between morphine and glutamatergic system in the hippocampus. This interaction also has been shown by electrophysiological studies which indicate morphine treatment can modulate synaptic plasticity in the hippocampal CA1 of rats via glutamatergic receptors [20,21]. The results of this study reflect the changes in extracellular concentration of glutamate in dorsal hippocampus which is maybe due to alteration in glutamate release from neuronal cells or functional modulation of glutamate transporters by morphine sensitization. It is clear that to investigation of morphine sensitization on neuronal content of glutamate, more studies are needed. In conclusion, the results of the presents study demonstrated an adaptation of glutamatergic neurotransmission induced by morphine sensitization and implied that -opioid receptors may play an important role in this process. Acknowledgments We wish to thank everyone who was contributed to the HPLC assays in Darou Pakhsh Pharmaceutical Research Center. References [1] C. Cadoni, G. Di Chiara, Reciprocal changes in dopamine responsiveness in the nucleus accumbens shell and core and in the dorsal caudate-putamen in rats sensitized to morphine, Neuroscience 90 (1999) 447–455. [2] J.W. Dalley, B.J. Everitt, Dopamine receptors in the learning, memory and drug reward circuitry, Semin. Cell Dev. Biol. 20 (2009) 403–410. [3] D.M. de Freitas Silva, V.P. Ferraz, A.M. Ribeiro, Improved high-performance liquid chromatographic method for GABA and glutamate determination in regions of the rodent brain, J. Neurosci. Methods 177 (2009) 289–293. [4] M. Farahmandfar, S.M. Karimian, N. Naghdi, M.R. Zarrindast, M. Kadivar, Morphine-induced impairment of spatial memory acquisition reversed by morphine sensitization in rats, Behav. Brain Res. 211 (2010) 156–163. [5] M.E. Fundytus, T.J. Coderre, Effect of activity at metabotropic, as well as ionotropic (NMDA), glutamate receptors on morphine dependence, Br. J. Pharmacol. 113 (1994) 1215–1220. [6] M. Guo, N.J. Xu, Y.T. Li, J.Y. Yang, C.F. Wu, G. Pei, Morphine modulates glutamate release in the hippocampal CA1 area in mice, Neurosci. Lett. 381 (2005) 12–15. [7] Y. Hao, J.Y. Yang, C.F. Wu, M.F. Wu, Pseudoginsenoside-F11 decreases morphine-induced behavioral sensitization and extracellular glutamate levels in the medial prefrontal cortex in mice, Pharmacol. Biochem. Behav. 86 (2007) 660–666.
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