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Morphine-induced place preference: Involvement of the central amygdala NMDA receptors
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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s
Research Report
Morphine-induced place preference: Involvement of the central amygdala NMDA receptors Ameneh Rezayof a,⁎, Farideh Golhasani-Keshtan a , Ali Haeri-Rohani a , Mohammad-Reza Zarrindast b,c,d a
School of Biology, University College of Science, University of Tehran, P. O. Box 14155-6455, Tehran, Iran Department of Pharmacology and Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran c School of Cognitive Science, Institute for Studies in Theoretical Physics and Mathematics, Tehran, Iran d Institute for Cognitive Science Studies, Tehran, Iran b
A R T I C LE I N FO
AB S T R A C T
Article history:
In the present study, the effects of bilateral injections of N-methyl-D-aspartate (NMDA)
Accepted 16 November 2006
receptor agonist and/or antagonist into the central amygdala (CeA) on the acquisition and
Available online 20 December 2006
expression of morphine-induced conditioned place preference (CPP) were investigated in male Wistar rats. Animals that received 3 daily subcutaneous (s.c.) injections of morphine
Keywords:
(1–9 mg/kg) or saline (1.0 ml/kg) indicated a significant preference for compartment paired
Morphine
with morphine in a dose dependent manner. Intra-CeA administration of the NMDA (0.01,
Conditioned place preference
0.1 or 1 μg/rat) with an ineffective dose of morphine (1 mg/kg, s.c.) elicited a significant
Central amygdala
CPP. Administration of the non-competitive NMDA receptor antagonist, MK-801 (0.1, 0.3 or
NMDA
0.5 μg/rat), into the central amygdala dose-dependently inhibited the morphine (6 mg/kg,
MK-801
s.c.)-induced place preference. Furthermore, intra-CeA administration of MK-801 (0.25, 0.5
Rat
or 1 μg/rat) reduced the response induced by NMDA (1 μg/rat, intra-CeA) plus morphine (1 mg/kg, s.c.). Neither NMDA nor MK-801 alone produce a significant place preference or place aversion. Moreover, intra-CeA injection of NMDA but not MK-801 before testing significantly increased the expression of morphine (6 mg/kg, s.c.)-induced place preference. NMDA or MK-801 injections into the CeA had no effects on locomotor activity on the testing sessions. These results suggest that the NMDA receptor mechanisms in the central amygdala may be involved in the acquisition and expression of morphine-induced place preference. © 2006 Elsevier B.V. All rights reserved.
1.
Introduction
Opiates elicits the rewarding effects at the level of the mesolimbic dopamine system that is originated from the ventral tegmental area (VTA) and projects to the nucleus accumbens (Nac; Wise, 1998; McBride et al., 1999). A large body of evidence demonstrated that the activation of VTA dopamine neurons via inhibition of GABAergic inhibitory inter-
neurons cause the increase of the DA neurotransmission to the Nac and induce morphine reward (Leone et al., 1991; Johnson and North, 1992; Olmstead and Franklin, 1997a,b; Wise, 1996; Manzanedo et al., 2001). The paradigm of conditioned place preference (CPP) has also been used recently to study the rewarding effects of opioids (Bardo et al., 1995; McBride et al., 1999; Tzschentke, 1998; Manzanedo et al., 2001). It is assumed that the paradigm of CPP is based
⁎ Corresponding author. Fax: +98 21 66405141. E-mail address: [email protected] (A. Rezayof). 0006-8993/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2006.11.049
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tigating the effects of NMDA receptor agonist and antagonist in the acquisition and expression of morphine-induced place preference.
Fig. 1 – Place preference produced by morphine. Different doses of morphine (1, 3, 6 or 9 mg/kg) and saline (1 ml/kg) were administered subcutaneously (s.c) in a 3-day schedule of conditioning. On the test day, the animals were observed for a 15-min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the pre-conditioning session. Data are expressed as mean ± SEM of 8 animals per group. *P < 0.05, ***P < 0.001; compared with the saline control group.
upon the idea that contextual stimuli can acquire conditioned rewarding properties when paired with addictive drugs, reflecting their liability to be abused (Riberio Do Couto et al., 2005). Our previous studies showed that this DA pathway may be not the only one which is responsible for morphineinduced place preference and the other neurotransmitter mechanisms may be involved in the development and maintenance of addiction to opiates (Zarrindast et al., 2002, 2004, 2005, 2006; Rezayof et al., 2006a,b). There are interactions between glutamatergic and dopaminergic system in the VTA and Nac (Kalivas, 1993; Kretschmer, 1999) that it seems to modulate the functioning of the mesolimbic dopamine system and induce opiate reward. Riberio Do Couto et al. (2004) reported that the glutamatergic system can mediate the rewarding properties of morphine in the place conditioning paradigm and glutamate N-methyl-D-aspartate (NMDA) receptors are implicated in different aspects of opioid addiction. Moreover, previous studies have shown that the NMDA receptors may be critically involved in the development of conditioned stimulant-like effects (Druhan and Wilent, 1999) and drug dependence (Vetulani, 2001; Levi and Borne, 2002). The amygdala plays key roles in several aspects of addiction to drugs of abuse (Goussakov et al., 2006). It is noteworthy that the central amygdala (CeA) is a major component of the extended amygdala (Ono et al., 1995), which its involvement in reward-related processes is mediated by the Nac (Zahm et al., 1999; O'Dell et al., 1999). Considering DA and glutamate are clearly involved in the rewarding effects of opiates (Riberio Do Couto et al., 2004, 2005), the involvement of NMDA receptors in learning and memory processes and the importance of the central amygdala in reward-related learning (Lu et al., 2000), the present study aimed at inves-
2.
Results
2.1.
Experiment 1. Morphine-conditioned place preference
Results of morphine-induced place preference are summarized in Fig. 1. One-way ANOVA revealed that morphine (1, 3, 6 or 9 mg/kg, s.c.) caused a significant dose-related preference [F(4,35)= 12.9, P < 0.0001]. Significant conditioning was observed at doses of 3, 6 and 9 mg/kg.
2.2. Experiment 2. The effect of NMDA with or without morphine on the acquisition of CPP Fig. 2 shows the response of different doses of NMDA (0.01, 0.1 or 1 μg/rat) and morphine (1 mg/kg) on the acquisition of CPP. Two-way ANOVA indicates an interaction between morphine and NMDA in the acquisition of place preference [withingroup comparison: treatment effect: F(1,56) = 46.1, P < 0.001, dose effect: (3,48) = 6.4, P < 0.01, treatment × dose interaction: F(3,56) = 3.3, P < 0.05]. In addition, one-way ANOVA revealed that the lower dose of morphine (1 mg/kg) and NMDA (0.01, 0.1 or 1 μg/rat; intra-CeA) alone did not induce a significant place preference [F(4,35) = 0.5, P > 0.05]. Furthermore, NMDA potentiated the morphine (1 mg/kg)-induced place preference dose-dependently [F(3,28) = 20.4, P < 0.0001].
Fig. 2 – The effects of bilateral intra-CeA injection of NMDA, either alone or in combination with morphine, on the acquisition of a conditioned place preference. The animals received NMDA (0.01, 0.1 or 1 μg/rat) or saline (1 μl/rat) with or without morphine (1 mg/kg, s.c.) in a 3-day schedule of conditioning. On the test day, the animals were observed for a 15-min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the pre-conditioning session. Data are expressed as mean ± SEM of 8 animals per group. **P < 0.01, ***P < 0.001; compared with the saline/morphine control group.
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2.3. Experiment 3. The effect of MK-801 with or without morphine on the acquisition of CPP Fig. 3 shows the effect of bilateral intra-CeA injection of MK-801 (0.1, 0.3 or 0.5 μg/rat) in the absence or presence of morphine (6 mg/kg) on the acquisition of CPP. Two-way ANOVA shows that there is an interaction between morphine and MK-801 in the acquisition of place preference [withingroup comparison: treatment effect: F(1,56) = 38.3, P < 0.0001; dose effect: F(3,56) = 3.5, P < 0.05; interaction: F(3,56) = 3.4, P < 0.05]. Further analysis showed that the different doses of MK-801 (0.1, 0.3 or 0.5 μg/rat, intra-CeA) alone induced neither a significant place preference nor place aversion [one-way ANOVA, F(3,28) = 0.02, P > 0.05]. The administration of MK-801 inhibited the morphine (6 mg/kg)-induced place preference in a dose dependent manner [one-way ANOVA, F(3,28) = 6.1, P < 0.01].
2.4. Experiment 4. The effect of MK-801 on NMDA response during morphine conditioning Fig. 4 shows the effect of intra-CeA administration of MK801 on the induced changes by morphine (1 mg/kg) in combination with NMDA. One-way ANOVA indicated that different doses of MK-801 (0.25, 0.5 or 1 μg/rat, intra-CeA) altered the response induced by intra-CeA injection of NMDA (1 μg/rat) plus morphine (1 mg/kg, s.c.) [One-way ANOVA: F(3, 28) = 13.8, P < 0.0001]. Post hoc analysis showed that MK-801 reversed the effect of NMDA on morphine response.
Fig. 4 – The effects of bilateral intra-CeA injection of NMDA alone or combined with MK-801 on the acquisition of morphine-induced place preference. The animals received an intra-CeA injection of either saline (1 μl/rat) or different doses of MK-801 (0.25, 0.5 or 1 μg/rat) 5 min before intra-CeA injection of either saline (1 μl/rat) or NMDA (1 μg/rat) and then they were injected with morphine (1 mg/kg, s.c.) during conditioning. On the test day, the animals were observed for a 15-min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the pre-conditioning session. Data are expressed as mean ± SEM of 8 animals per group. ***P < 0.001; compared with the saline/saline/ morphine control group. ++P < 0.01, +++P < 0.001; compared with the saline/NMDA/morphine control group.
2.5. Experiment 5. The effect of NMDA or MK-801 on the expression of morphine-induced CPP Fig. 5 shows the effects of bilateral intra-CeA injection of NMDA (0.25, 0.5 or 1 μg/rat) or MK-801 (0.25, 0.5 or 1 μg/rat) on the expression of morphine-induced CPP. One-way ANOVA indicates that treatment with NMDA, but not MK-801 increased the expression of morphine (6 mg/kg)-induced place preference [F(6,49) = 3.7, P < 0.01]. Post hoc analysis indicates that the injection of different doses of NMDA (0.25, 0.5 or 1 μg/rat) can affect the morphine response (P < 0.05 and P < 0.001).
2.6. Fig. 3 – The effects of bilateral intra-CeA injection of MK-801, either alone or in combination with morphine, on the acquisition of a conditioned place preference. The animals received MK-801 (0.1, 0.3 or 0.5 μg/rat) or saline (1 μl/rat) with or without morphine (6 mg/kg, s.c.) in a 3-day schedule of conditioning. On the test day, the animals were observed for a 15-min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the pre-conditioning session. Data are expressed as mean ± SEM of 8 animals per group. ***P < 0.001; compared with the saline control group. + P < 0.05, ++P < 0.01; compared with the saline/morphine control group.
The effect of the drugs on locomotor activity
One-way ANOVA indicated that the different doses of morphine (1, 3, 6 or 9 mg/kg) [F(4,35) = 0.33, P > 0.05], NMDA (0.01, 0.1 or 1 μg/rat; intra-CeA)[F(3,28) = 1.9, P > 0.05] or MK-801 (0.1, 0.3 or 0.5 μg/rat; intra-CeA)[F(3,28) = 0.5, P > 0.05] alone had no effect on the locomotor activity during the testing phase. Besides, the bilateral intra-CeA injection of NMDA [F(3,28) = 1.9, P > 0.05] or MK-801 [F(3,28) = 1.8, P > 0.05] plus the subcutaneous injection of morphine did not induce any effect on locomotor activity during the testing phase (data not shown).
3.
Discussion
The present results show that systemic injection of morphine induces a dose-related conditioned place preference. These
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Fig. 5 – The effects of bilateral microinjection of NMDA or MK-801 into the CeA on the expression of morphine-induced place preference. All animals received morphine (6 mg/kg, s.c.) or saline (1 mg/kg, s.c.) in a 3-day schedule of conditioning. On the test day, the different doses of NMDA (0.25, 0.5 or 1 μg/rat), MK-801 (0.25, 0.5 or 1 μg/rat) or saline (1 μl/rat) was administered into the CeA immediately before testing and each animal was observed for a 15-min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the pre-conditioning session. Data are expressed as mean ± SEM of 8 animals per group. *P < 0.05, ***P < 0.001; compared with the saline/morphine control group.
findings supported the previous studies and demonstrated that the rewarding effects of morphine can be conditioned to environmental stimuli, which have previously signaled its administration (Shippenberg et al., 1996; Suzuki et al., 1995; Tzschentke, 1998). Opioids can activate μ-opioid receptors located in the ventral tegmental area (VTA), which indirectly stimulates the ascending mesocorticolimbic dopamine system (Kalivas, 1993; Olmstead and Franklin, 1997a; Van Ree et al., 1999). Morphine may inhibit VTA GABAergic interneurons to decrease GABA release and subsequently disinhibits VTA DA neurons, leading to an increase in nucleus accumbens DA release (Xi and Stein, 2002). Several results have been indicated the involvement of NMDA receptors in the opioids receptor-mediated functions such as antinociception, tolerance and dependence (For review see Mao, 1999). The most compelling evidence that NMDA may play a role in reward mechanisms is its ability to produce burst firing in dopamine neurons (Johnson et al., 1992). There is concordance between burst firing and behavioral arousal and motivation (Panos et al., 1999). In the present study, the effects of bilateral injections of NMDA receptor agonist and antagonist into the central amygdala (intra-CeA) on the acquisition and expression of morphine-induced place preference were investigated. We first evaluated the effect of bilateral microinjection of the glutamate NMDA receptor agents into the central amygdala (CeA) on the acquisition of conditioned place preference (CPP). There are reports indicating that systemic injection of NMDA produces CPP (Panos et al., 1999) and glutamate recep-
37
tor antagonists can block the development of CPP induced by rewarding drugs (Tzschentke and Schmidt, 1997). It has been also shown that NMDA increases dopamine transmission in both the mesocortical and mesolimbic dopaminergic system (Kalivas et al., 1989). Although the CeA is connected anatomically to the Nac, a structure that is critically involved in the process of reinforcement (Carr and White, 1986, 1987; Delfs et al., 1990; Salamone et al., 1997), but our results show that the microinjection of NMDA or MK-801 alone into the CeA could not produce a significant conditioned place preference or conditioned place aversion (CPA). Our data indicate that the bilateral microinjection of NMDA into the CeA by itself in conditioning sessions did not induce place preference, but co-administration of this drug with a lower dose of morphine (1 mg/kg, s.c.), which did not induce CPP by itself, significantly increased the morphine response and induced place preference. Therefore, glutamate NMDA mechanism in the central amygdala is involved in the mediating morphine reward. These findings support previous suggestions that NMDA receptor stimulation may be necessary for neuron adaptations underlying conditioning (Cervo and Samanin, 1996; Stewart and Druhan, 1993; Druhan and Wilent, 1999). It has been shown that NMDA receptors are also involved in the cocaine-induced CPP (Cervo and Samanin, 1995) and the glutamatergic system has an important role in the benzodiazepine-induced place preference (Gray et al., 1999). Furthermore, Hsu et al. (2002) suggested that druginduced conditioned place preference behavior requires memory for an association between environmental cues and the affective state produced by the drug treatment and amygdala mediates memory consolidation for a drug-induced place preference. Considering CPP is a learning paradigm and NMDA receptors are involved in learning, it seems possible that co-administration of NMDA and morphine may increase learning. The extensive involvement of NMDA receptors in modulation of the processes of neural plasticity (Danysz et al., 1995) could explain its ubiquitous role in learning processes underlying addictive states (Bisaga and Popik, 2000). Considerable evidence supports the hypothesis that the adaptations leading to addiction involve the same glutamate-dependent cellular mechanisms that enable learning and memory (for a review, see Wolf et al., 2004). Our experiments also show that MK-801 inhibits dosedependently morphine-induced CPP. There are several experiments showing that MK-801 induces opposite effect on morphine-induced responses. Behavioral studies have provided strong evidence for inhibitory effects of MK-801 on CPP induced by morphine, cocaine, methamphetamine and amphetamine (Del Pozo et al., 1996; Tzschentke and Schmidt, 1995, 1997; Tzschentke, 1998; Suzuki et al., 2000; Yonghui et al., 2006). Bisaga and Popik (2000) suggest that NMDA antagonists may attenuate the effect of the conditioned environmental stimuli that potentiate the reinforcing aspects of a drug in a given environment. It thus appears that the integrity of the central amygdala NMDA receptors function is important for the stimulus–reward association in the morphine CPP. Our results also indicate that the combination of MK-801 and morphine, it is possible to suppress the psychological dependence. The above results are in agreement with results reported by other investigators. Meli and See (1997) for exam-
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ple, have demonstrated that the lesion of the amygdala, which has dense glutamatergic projections to the limbic system, prevents cue-induced reinstatement of cocaine self-administration. Furthermore, our data indicate that the antagonist also decreased the NMDA-induced potentiation of the morphine response, which may further support the hypothesis that the effect of NMDA on morphine reward mediate through NMDA receptors. Considerable evidence suggests that there is an interaction between the dopamine D1 and glutamate receptors in mediating the reinforcing properties of various drugs of abuse (Criswell et al., 1990; Cervo and Samanin, 1995). It is interesting to note that intra-CeA administration of MK-801, like injection of the dopamine D1 receptor antagonist SCH 23390 into the central amygdala in our previous investigations (Zarrindast et al., 2003), blocked the acquisition of morphine CPP. Cervo and Samanin (1995) also showed that the blockade of dopamine D1 and glutamate NMDA receptors inhibited the acquisition of cocaine CPP. Moreover, it has been shown that both D1 (Graybiel et al., 1990; Young et al., 1991) and NMDA (Torres and Rivier, 1993) receptor antagonists block the induction of c-fos by cocaine in the rat brain. The results with MK-801 and SCH 23390 may suggest that different neuronal mechanisms underlie the acquisition of morphine (the present study) and cocaine (Cervo and Samanin, 1995) CPP. In a set of experiments, we also tested the effects of the administration of NMDA or MK-801 on the expression of morphine-induced place preference. The results show that bilateral intra-CeA injection of NMDA, but not MK-801, increased the expression of morphine (6 mg/kg)-induced place preference. Since the expression of a CPP on the drugfree test day presumably requires learning and memory (White and Carr, 1985) and NMDA facilitate memory, therefore intra-CeA injection of NMDA before the testing phase may increase learning, which in turn elicits a potentiated CPP. The fact that MK-801 inhibited the acquisition but not the expression of morphine-induced place preference is in agreement with the report of Cervo and Samanin (1995). They indicated that MK-801 blocked the acquisition of cocaine-CPP, but it had not any effect on the expression. Considerable evidence suggests that NMDA receptors are involved in the acquisition but not the expression of phenomena such as tolerance and sensitization after repeated exposure to stimulant drugs or opioids (Trujillo and Akil, 1991; Stewart and Druhan, 1993; Karler et al., 1994). However, NMDA may have a role in the expression of CPP, but it needs more experiment to clarify exact mechanism. In order to show if locomotor activity influence on testing phase, it has been measured as described before (Belzung and Barreau, 2000; Zarrindast et al., 2000). Our data indicate that subcutaneous injection of morphine and also the intra-CeA injections of the glutamatergic drugs at the doses used in our experiments did not alter the locomotor activity in comparison with the control groups during the testing phase. Therefore, the interaction of locomotor activity with the results obtained seems unlikely. Overall it can be concluded that glutamate NMDA receptors of the central amygdala may elicit an important role in the induction of morphine rewarding properties.
4.
Experimental procedures
4.1.
Animals
The experiments were carried out on male Wistar rats (Pasteur Institute; Tehran, Iran) weighing 240–280 g at the beginning of the surgery. The animals were kept under standard laboratory conditions (12:12-h light/dark cycle) with free access to tap water and lab chow and adapted to the laboratory conditions for at least 1 week. The rats were handled once a day for 5 days preceding the experiments. Each experimental group was consisted of 8 animals. Each animal was used once only. The experiments were performed between 8:00 a.m. and 5:00 p.m. All procedures were carried out in accordance with institutional guidelines for animal care and use.
4.2.
Drugs
The compounds tested were morphine sulfate (Temad Co., Tehran, Iran), NMDA and MK-801 (Tocris Cookson Ltd., UK). The drugs were dissolved in saline (0.9% NaCl), just before the experiment. Morphine was injected subcutaneously (s.c.) in a volume of 1 ml/kg. NMDA and MK-801 were bilaterally injected into the central amygdala (intra-CeA) in a volume of 1 μl/rat. Control groups received saline injections in the same volume and by the same route.
4.3.
Surgical and infusion procedures
The animals were anesthetized with intraperitoneal injection of ketamine hydrochloride (50 mg/kg) plus xylazine (4 mg/kg) and positioned in a stereotaxic instrument. Two 23-gauge (Outer diameter: 0.6 mm) stainless steel guide cannulae were implanted 1 mm above the central amygdala based on the Atlas of Paxinos and Watson (1986). The cannulae were chronically fixed to the skull using jeweler's screws and acrylic dental cement. Stereotaxic coordinates for the central amygdala were AP −2.2 mm from bregma, L ±4.1 mm from the sagittal suture and −7.8 mm from the skull surface. To prevent clogging, the stainless steel stylets (30 gauge) were placed in the guide cannulae until the animals were given the CeA injection. The animals were allowed 7 days to recover before place conditioning processes. For drug infusion, the stylets were withdrawn and replaced by the injection units (30 gauge stainless steel tubing; outer diameter: 0.3 mm), terminating 1 mm below the tip of the guides. Each injection unit was connected by polyethylene tubing to 1-μl Hamilton syringe. The left and right CeA were infused with a 0.5-μl solution on each side (1 μl/rat) over a 60-s period. The cannulae were left in place an additional 60 s to allow diffusion, then the stylets were reinserted into the guide cannulae. During the infusion procedure, the experimenter loosely held the animals.
4.4.
Apparatus
The testing apparatus for the conditioned place preference paradigm was similar to that used by Carr and White (1983). It was consisted of three wooden compartments. Two of the
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compartments (A and B) were identical in size (40 × 30 × 30 cm) but differed in shading and texture. Compartment A was white with black horizontal stripes 2 cm wide on the walls and also had a textured floor. The other compartment (B) was black with vertical white stripes 2 cm wide and also had a smooth floor. The third compartment (C) was a red tunnel (40 × 15 × 30 cm). It protruded from the rear of the two large compartments and connected the entrances to them.
4.5.
Behavioral testing
Conditioned place preference (CPP) was consisted of a 5-day schedule with three distinct phases: pre-conditioning, conditioning and testing. This method (unbiased design) was similar to that used in our previous experiments (Rezayof et al., 2006a,b; Zarrindast et al., 2004, 2005). The unbiased design is commonly used by other authors as an alternative to the unbiased design (De Fonseca et al., 1995; Shi et al., 2004).
4.5.1.
Pre-conditioning
During this phase (day 1), each animal was placed in the third compartment (C) with the guillotine doors removed to allow access to the entire apparatus for 15 min. The amount of time spent in each compartment was measured to assess unconditioned preference (the position of the rat was defined by the position of its front paws). In the particular experimental setup used in this study, the animals did not show an unconditioned preference for either of the compartments. Animals were then randomly assigned to one of two groups for place conditioning and a total of eight animals were used for each subsequent experiments.
4.5.2.
Conditioning
Place conditioning phase started 1 day after pre-conditioning phase. This phase consisted of six 45-min sessions (three saline and three drug pairing). These sessions were conducted twice each day (from day 2 to day 4) with a 6-h interval. On each of these days, separate groups of animals received one conditioning session with morphine and one with saline. During these sessions, the animals were confined to one compartment by closing the removable wall. Animals of each group were injected with morphine and were immediately confined to one compartment of the apparatus for 45 min. Following administration of saline, the animals were confined to the other compartment for 45 min. Treatment compartment and order of presentation of morphine and saline were counterbalanced for either group.
4.5.3.
Post-conditioning or testing
This phase was carried out on day 5, 1 day after the last conditioning session, in a morphine-free state. Each animal was tested only once. For testing, the removable wall was raised, and the animals had a free choice in the apparatus for 15 min. The time spent in drug-paired compartment was recorded for each animal and the change of preference was calculated as the difference (in seconds) between the time spent in the drug-paired compartment on the testing day and the time spent in this compartment in the pre-conditioning day (De Fonseca et al., 1995).
4.6.
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Locomotor testing
Locomotor activity was measured, based on a method we used previously (Rezayof et al., 2006a,b; Zarrindast et al., 2004, 2005), during the post-conditioning phase (Belzung and Barreau, 2000; Zarrindast et al., 2000), in a morphine-free state. For this purpose, the ground area of A and B compartments were divided into 4 equal sized squares. Locomotion was measured as the number of crossings from one square to another during 15 min.
4.7.
Drug treatments
4.7.1.
Experiment 1. Morphine-conditioned place preference
In this experiment, we produced a dose response function for morphine place conditioning. Four groups of animals were injected with morphine (1, 3, 6 or 9 mg/kg, s.c.) and saline (1 ml/ kg, s.c.) on alternate sessions. A separate group of animals was given saline (1 ml/kg, s.c.) only during the conditioning phase in order to confirm that the injections and the conditioning schedule were not affecting the time allotment in the apparatus. This group was used as control. Locomotor activity was also measured in the post-conditioning phase.
4.7.2. Experiment 2. Effects of NMDA and/or MK-801 with or without morphine on the acquisition of CPP Effects of intra-CeA injection of different doses of NMDA or MK-801 on the acquisition of the conditioned place preference induced by morphine were determined as follows. Rats received morphine or saline (s.c.) once daily in a 3-day schedule of conditioning. NMDA (0.01, 0.1 or 1 μg/rat; Fig. 2) or MK-801 (0.1, 0.3 or 0.5 μg/rat; Fig. 3) was injected into the central amygdala once per day for 3 days, 5 min before the administration of morphine (three sessions); the conditioning scores then were measured in a drug-free state (testing day). Intra-CeA injections of the same (above mentioned) doses of all drugs without morphine, during conditioning, were also used to assess their effects on CPP. The conditioning scores were then measured in a drug-free state on the test day. To determine the probable reversal effect of MK-801 on the response induced by NMDA, MK-801 (0.25, 0.5 or 1 μg/rat) was administered into the central amygdala, 5 min prior to the administration of NMDA at 1 μg/rat in the same experiment (Fig. 4). Locomotor activity was also evaluated during testing in these groups.
4.7.3. Experiment 3. The effects of NMDA or MK-801 on the expression of morphine-induced place preference Seven groups of animals underwent the experimental procedure of place conditioning with morphine (6 mg/kg, s.c.). On the 5th day, 5 min before testing, six groups were injected with NMDA (0.25, 0.5 or 1 μg/rat, intra-CeA) or MK-801 (0.25, 0.5 or 1 μg/rat, intra-CeA) and one group received saline (1 μl/rat, intra-CeA). Locomotor activity was also measured in the postconditioning phase (Fig. 5).
4.8.
Verification of cannulae placements
After completion of the experimental sessions, each animal was killed with an overdose of chloroform. Subsequently, 1.0 μl of ink was injected into the central amygdala by a 30-
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gauge injection cannula, which projected a further 1 mm ventral to the tip of the guide to aid in histological verification. The brains were removed and perfused with a 10% formalin solution 10 days before sectioning. Sections were examined to determine location of the cannulae aimed for the central amygdala. The cannula placements were verified using the atlas of Paxinos and Watson (1986). Data from rats with cannula placements outside the central amygdala were excluded from the analyses.
4.9.
Statistics
The data are expressed as means ± SEM. The statistical analyses were performed using one- and two-way analyses of variance (ANOVA) with score (i.e., the differences between post-conditioning and pre-conditioning time spent in the drug-associated compartment) as the dependent factor. Post hoc comparison of means was carried out with the Tukey test for multiple comparisons, when appropriate. The level of statistical significance was set at P < 0.05. Calculations were performed using the SPSS statistical package.
Acknowledgments The authors would like to express thanks to Yassaman Rassouli and Ladan Delphi for their skillful assistance.
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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s
Research Report
Morphine-induced place preference: Involvement of the central amygdala NMDA receptors Ameneh Rezayof a,⁎, Farideh Golhasani-Keshtan a , Ali Haeri-Rohani a , Mohammad-Reza Zarrindast b,c,d a
School of Biology, University College of Science, University of Tehran, P. O. Box 14155-6455, Tehran, Iran Department of Pharmacology and Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran c School of Cognitive Science, Institute for Studies in Theoretical Physics and Mathematics, Tehran, Iran d Institute for Cognitive Science Studies, Tehran, Iran b
A R T I C LE I N FO
AB S T R A C T
Article history:
In the present study, the effects of bilateral injections of N-methyl-D-aspartate (NMDA)
Accepted 16 November 2006
receptor agonist and/or antagonist into the central amygdala (CeA) on the acquisition and
Available online 20 December 2006
expression of morphine-induced conditioned place preference (CPP) were investigated in male Wistar rats. Animals that received 3 daily subcutaneous (s.c.) injections of morphine
Keywords:
(1–9 mg/kg) or saline (1.0 ml/kg) indicated a significant preference for compartment paired
Morphine
with morphine in a dose dependent manner. Intra-CeA administration of the NMDA (0.01,
Conditioned place preference
0.1 or 1 μg/rat) with an ineffective dose of morphine (1 mg/kg, s.c.) elicited a significant
Central amygdala
CPP. Administration of the non-competitive NMDA receptor antagonist, MK-801 (0.1, 0.3 or
NMDA
0.5 μg/rat), into the central amygdala dose-dependently inhibited the morphine (6 mg/kg,
MK-801
s.c.)-induced place preference. Furthermore, intra-CeA administration of MK-801 (0.25, 0.5
Rat
or 1 μg/rat) reduced the response induced by NMDA (1 μg/rat, intra-CeA) plus morphine (1 mg/kg, s.c.). Neither NMDA nor MK-801 alone produce a significant place preference or place aversion. Moreover, intra-CeA injection of NMDA but not MK-801 before testing significantly increased the expression of morphine (6 mg/kg, s.c.)-induced place preference. NMDA or MK-801 injections into the CeA had no effects on locomotor activity on the testing sessions. These results suggest that the NMDA receptor mechanisms in the central amygdala may be involved in the acquisition and expression of morphine-induced place preference. © 2006 Elsevier B.V. All rights reserved.
1.
Introduction
Opiates elicits the rewarding effects at the level of the mesolimbic dopamine system that is originated from the ventral tegmental area (VTA) and projects to the nucleus accumbens (Nac; Wise, 1998; McBride et al., 1999). A large body of evidence demonstrated that the activation of VTA dopamine neurons via inhibition of GABAergic inhibitory inter-
neurons cause the increase of the DA neurotransmission to the Nac and induce morphine reward (Leone et al., 1991; Johnson and North, 1992; Olmstead and Franklin, 1997a,b; Wise, 1996; Manzanedo et al., 2001). The paradigm of conditioned place preference (CPP) has also been used recently to study the rewarding effects of opioids (Bardo et al., 1995; McBride et al., 1999; Tzschentke, 1998; Manzanedo et al., 2001). It is assumed that the paradigm of CPP is based
⁎ Corresponding author. Fax: +98 21 66405141. E-mail address: [email protected] (A. Rezayof). 0006-8993/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2006.11.049
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tigating the effects of NMDA receptor agonist and antagonist in the acquisition and expression of morphine-induced place preference.
Fig. 1 – Place preference produced by morphine. Different doses of morphine (1, 3, 6 or 9 mg/kg) and saline (1 ml/kg) were administered subcutaneously (s.c) in a 3-day schedule of conditioning. On the test day, the animals were observed for a 15-min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the pre-conditioning session. Data are expressed as mean ± SEM of 8 animals per group. *P < 0.05, ***P < 0.001; compared with the saline control group.
upon the idea that contextual stimuli can acquire conditioned rewarding properties when paired with addictive drugs, reflecting their liability to be abused (Riberio Do Couto et al., 2005). Our previous studies showed that this DA pathway may be not the only one which is responsible for morphineinduced place preference and the other neurotransmitter mechanisms may be involved in the development and maintenance of addiction to opiates (Zarrindast et al., 2002, 2004, 2005, 2006; Rezayof et al., 2006a,b). There are interactions between glutamatergic and dopaminergic system in the VTA and Nac (Kalivas, 1993; Kretschmer, 1999) that it seems to modulate the functioning of the mesolimbic dopamine system and induce opiate reward. Riberio Do Couto et al. (2004) reported that the glutamatergic system can mediate the rewarding properties of morphine in the place conditioning paradigm and glutamate N-methyl-D-aspartate (NMDA) receptors are implicated in different aspects of opioid addiction. Moreover, previous studies have shown that the NMDA receptors may be critically involved in the development of conditioned stimulant-like effects (Druhan and Wilent, 1999) and drug dependence (Vetulani, 2001; Levi and Borne, 2002). The amygdala plays key roles in several aspects of addiction to drugs of abuse (Goussakov et al., 2006). It is noteworthy that the central amygdala (CeA) is a major component of the extended amygdala (Ono et al., 1995), which its involvement in reward-related processes is mediated by the Nac (Zahm et al., 1999; O'Dell et al., 1999). Considering DA and glutamate are clearly involved in the rewarding effects of opiates (Riberio Do Couto et al., 2004, 2005), the involvement of NMDA receptors in learning and memory processes and the importance of the central amygdala in reward-related learning (Lu et al., 2000), the present study aimed at inves-
2.
Results
2.1.
Experiment 1. Morphine-conditioned place preference
Results of morphine-induced place preference are summarized in Fig. 1. One-way ANOVA revealed that morphine (1, 3, 6 or 9 mg/kg, s.c.) caused a significant dose-related preference [F(4,35)= 12.9, P < 0.0001]. Significant conditioning was observed at doses of 3, 6 and 9 mg/kg.
2.2. Experiment 2. The effect of NMDA with or without morphine on the acquisition of CPP Fig. 2 shows the response of different doses of NMDA (0.01, 0.1 or 1 μg/rat) and morphine (1 mg/kg) on the acquisition of CPP. Two-way ANOVA indicates an interaction between morphine and NMDA in the acquisition of place preference [withingroup comparison: treatment effect: F(1,56) = 46.1, P < 0.001, dose effect: (3,48) = 6.4, P < 0.01, treatment × dose interaction: F(3,56) = 3.3, P < 0.05]. In addition, one-way ANOVA revealed that the lower dose of morphine (1 mg/kg) and NMDA (0.01, 0.1 or 1 μg/rat; intra-CeA) alone did not induce a significant place preference [F(4,35) = 0.5, P > 0.05]. Furthermore, NMDA potentiated the morphine (1 mg/kg)-induced place preference dose-dependently [F(3,28) = 20.4, P < 0.0001].
Fig. 2 – The effects of bilateral intra-CeA injection of NMDA, either alone or in combination with morphine, on the acquisition of a conditioned place preference. The animals received NMDA (0.01, 0.1 or 1 μg/rat) or saline (1 μl/rat) with or without morphine (1 mg/kg, s.c.) in a 3-day schedule of conditioning. On the test day, the animals were observed for a 15-min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the pre-conditioning session. Data are expressed as mean ± SEM of 8 animals per group. **P < 0.01, ***P < 0.001; compared with the saline/morphine control group.
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2.3. Experiment 3. The effect of MK-801 with or without morphine on the acquisition of CPP Fig. 3 shows the effect of bilateral intra-CeA injection of MK-801 (0.1, 0.3 or 0.5 μg/rat) in the absence or presence of morphine (6 mg/kg) on the acquisition of CPP. Two-way ANOVA shows that there is an interaction between morphine and MK-801 in the acquisition of place preference [withingroup comparison: treatment effect: F(1,56) = 38.3, P < 0.0001; dose effect: F(3,56) = 3.5, P < 0.05; interaction: F(3,56) = 3.4, P < 0.05]. Further analysis showed that the different doses of MK-801 (0.1, 0.3 or 0.5 μg/rat, intra-CeA) alone induced neither a significant place preference nor place aversion [one-way ANOVA, F(3,28) = 0.02, P > 0.05]. The administration of MK-801 inhibited the morphine (6 mg/kg)-induced place preference in a dose dependent manner [one-way ANOVA, F(3,28) = 6.1, P < 0.01].
2.4. Experiment 4. The effect of MK-801 on NMDA response during morphine conditioning Fig. 4 shows the effect of intra-CeA administration of MK801 on the induced changes by morphine (1 mg/kg) in combination with NMDA. One-way ANOVA indicated that different doses of MK-801 (0.25, 0.5 or 1 μg/rat, intra-CeA) altered the response induced by intra-CeA injection of NMDA (1 μg/rat) plus morphine (1 mg/kg, s.c.) [One-way ANOVA: F(3, 28) = 13.8, P < 0.0001]. Post hoc analysis showed that MK-801 reversed the effect of NMDA on morphine response.
Fig. 4 – The effects of bilateral intra-CeA injection of NMDA alone or combined with MK-801 on the acquisition of morphine-induced place preference. The animals received an intra-CeA injection of either saline (1 μl/rat) or different doses of MK-801 (0.25, 0.5 or 1 μg/rat) 5 min before intra-CeA injection of either saline (1 μl/rat) or NMDA (1 μg/rat) and then they were injected with morphine (1 mg/kg, s.c.) during conditioning. On the test day, the animals were observed for a 15-min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the pre-conditioning session. Data are expressed as mean ± SEM of 8 animals per group. ***P < 0.001; compared with the saline/saline/ morphine control group. ++P < 0.01, +++P < 0.001; compared with the saline/NMDA/morphine control group.
2.5. Experiment 5. The effect of NMDA or MK-801 on the expression of morphine-induced CPP Fig. 5 shows the effects of bilateral intra-CeA injection of NMDA (0.25, 0.5 or 1 μg/rat) or MK-801 (0.25, 0.5 or 1 μg/rat) on the expression of morphine-induced CPP. One-way ANOVA indicates that treatment with NMDA, but not MK-801 increased the expression of morphine (6 mg/kg)-induced place preference [F(6,49) = 3.7, P < 0.01]. Post hoc analysis indicates that the injection of different doses of NMDA (0.25, 0.5 or 1 μg/rat) can affect the morphine response (P < 0.05 and P < 0.001).
2.6. Fig. 3 – The effects of bilateral intra-CeA injection of MK-801, either alone or in combination with morphine, on the acquisition of a conditioned place preference. The animals received MK-801 (0.1, 0.3 or 0.5 μg/rat) or saline (1 μl/rat) with or without morphine (6 mg/kg, s.c.) in a 3-day schedule of conditioning. On the test day, the animals were observed for a 15-min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the pre-conditioning session. Data are expressed as mean ± SEM of 8 animals per group. ***P < 0.001; compared with the saline control group. + P < 0.05, ++P < 0.01; compared with the saline/morphine control group.
The effect of the drugs on locomotor activity
One-way ANOVA indicated that the different doses of morphine (1, 3, 6 or 9 mg/kg) [F(4,35) = 0.33, P > 0.05], NMDA (0.01, 0.1 or 1 μg/rat; intra-CeA)[F(3,28) = 1.9, P > 0.05] or MK-801 (0.1, 0.3 or 0.5 μg/rat; intra-CeA)[F(3,28) = 0.5, P > 0.05] alone had no effect on the locomotor activity during the testing phase. Besides, the bilateral intra-CeA injection of NMDA [F(3,28) = 1.9, P > 0.05] or MK-801 [F(3,28) = 1.8, P > 0.05] plus the subcutaneous injection of morphine did not induce any effect on locomotor activity during the testing phase (data not shown).
3.
Discussion
The present results show that systemic injection of morphine induces a dose-related conditioned place preference. These
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Fig. 5 – The effects of bilateral microinjection of NMDA or MK-801 into the CeA on the expression of morphine-induced place preference. All animals received morphine (6 mg/kg, s.c.) or saline (1 mg/kg, s.c.) in a 3-day schedule of conditioning. On the test day, the different doses of NMDA (0.25, 0.5 or 1 μg/rat), MK-801 (0.25, 0.5 or 1 μg/rat) or saline (1 μl/rat) was administered into the CeA immediately before testing and each animal was observed for a 15-min period. The change of preference was assessed as the difference between the time spent in the drug-paired compartment on the day of testing and the time spent in the drug-paired compartment on the day of the pre-conditioning session. Data are expressed as mean ± SEM of 8 animals per group. *P < 0.05, ***P < 0.001; compared with the saline/morphine control group.
findings supported the previous studies and demonstrated that the rewarding effects of morphine can be conditioned to environmental stimuli, which have previously signaled its administration (Shippenberg et al., 1996; Suzuki et al., 1995; Tzschentke, 1998). Opioids can activate μ-opioid receptors located in the ventral tegmental area (VTA), which indirectly stimulates the ascending mesocorticolimbic dopamine system (Kalivas, 1993; Olmstead and Franklin, 1997a; Van Ree et al., 1999). Morphine may inhibit VTA GABAergic interneurons to decrease GABA release and subsequently disinhibits VTA DA neurons, leading to an increase in nucleus accumbens DA release (Xi and Stein, 2002). Several results have been indicated the involvement of NMDA receptors in the opioids receptor-mediated functions such as antinociception, tolerance and dependence (For review see Mao, 1999). The most compelling evidence that NMDA may play a role in reward mechanisms is its ability to produce burst firing in dopamine neurons (Johnson et al., 1992). There is concordance between burst firing and behavioral arousal and motivation (Panos et al., 1999). In the present study, the effects of bilateral injections of NMDA receptor agonist and antagonist into the central amygdala (intra-CeA) on the acquisition and expression of morphine-induced place preference were investigated. We first evaluated the effect of bilateral microinjection of the glutamate NMDA receptor agents into the central amygdala (CeA) on the acquisition of conditioned place preference (CPP). There are reports indicating that systemic injection of NMDA produces CPP (Panos et al., 1999) and glutamate recep-
37
tor antagonists can block the development of CPP induced by rewarding drugs (Tzschentke and Schmidt, 1997). It has been also shown that NMDA increases dopamine transmission in both the mesocortical and mesolimbic dopaminergic system (Kalivas et al., 1989). Although the CeA is connected anatomically to the Nac, a structure that is critically involved in the process of reinforcement (Carr and White, 1986, 1987; Delfs et al., 1990; Salamone et al., 1997), but our results show that the microinjection of NMDA or MK-801 alone into the CeA could not produce a significant conditioned place preference or conditioned place aversion (CPA). Our data indicate that the bilateral microinjection of NMDA into the CeA by itself in conditioning sessions did not induce place preference, but co-administration of this drug with a lower dose of morphine (1 mg/kg, s.c.), which did not induce CPP by itself, significantly increased the morphine response and induced place preference. Therefore, glutamate NMDA mechanism in the central amygdala is involved in the mediating morphine reward. These findings support previous suggestions that NMDA receptor stimulation may be necessary for neuron adaptations underlying conditioning (Cervo and Samanin, 1996; Stewart and Druhan, 1993; Druhan and Wilent, 1999). It has been shown that NMDA receptors are also involved in the cocaine-induced CPP (Cervo and Samanin, 1995) and the glutamatergic system has an important role in the benzodiazepine-induced place preference (Gray et al., 1999). Furthermore, Hsu et al. (2002) suggested that druginduced conditioned place preference behavior requires memory for an association between environmental cues and the affective state produced by the drug treatment and amygdala mediates memory consolidation for a drug-induced place preference. Considering CPP is a learning paradigm and NMDA receptors are involved in learning, it seems possible that co-administration of NMDA and morphine may increase learning. The extensive involvement of NMDA receptors in modulation of the processes of neural plasticity (Danysz et al., 1995) could explain its ubiquitous role in learning processes underlying addictive states (Bisaga and Popik, 2000). Considerable evidence supports the hypothesis that the adaptations leading to addiction involve the same glutamate-dependent cellular mechanisms that enable learning and memory (for a review, see Wolf et al., 2004). Our experiments also show that MK-801 inhibits dosedependently morphine-induced CPP. There are several experiments showing that MK-801 induces opposite effect on morphine-induced responses. Behavioral studies have provided strong evidence for inhibitory effects of MK-801 on CPP induced by morphine, cocaine, methamphetamine and amphetamine (Del Pozo et al., 1996; Tzschentke and Schmidt, 1995, 1997; Tzschentke, 1998; Suzuki et al., 2000; Yonghui et al., 2006). Bisaga and Popik (2000) suggest that NMDA antagonists may attenuate the effect of the conditioned environmental stimuli that potentiate the reinforcing aspects of a drug in a given environment. It thus appears that the integrity of the central amygdala NMDA receptors function is important for the stimulus–reward association in the morphine CPP. Our results also indicate that the combination of MK-801 and morphine, it is possible to suppress the psychological dependence. The above results are in agreement with results reported by other investigators. Meli and See (1997) for exam-
38
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ple, have demonstrated that the lesion of the amygdala, which has dense glutamatergic projections to the limbic system, prevents cue-induced reinstatement of cocaine self-administration. Furthermore, our data indicate that the antagonist also decreased the NMDA-induced potentiation of the morphine response, which may further support the hypothesis that the effect of NMDA on morphine reward mediate through NMDA receptors. Considerable evidence suggests that there is an interaction between the dopamine D1 and glutamate receptors in mediating the reinforcing properties of various drugs of abuse (Criswell et al., 1990; Cervo and Samanin, 1995). It is interesting to note that intra-CeA administration of MK-801, like injection of the dopamine D1 receptor antagonist SCH 23390 into the central amygdala in our previous investigations (Zarrindast et al., 2003), blocked the acquisition of morphine CPP. Cervo and Samanin (1995) also showed that the blockade of dopamine D1 and glutamate NMDA receptors inhibited the acquisition of cocaine CPP. Moreover, it has been shown that both D1 (Graybiel et al., 1990; Young et al., 1991) and NMDA (Torres and Rivier, 1993) receptor antagonists block the induction of c-fos by cocaine in the rat brain. The results with MK-801 and SCH 23390 may suggest that different neuronal mechanisms underlie the acquisition of morphine (the present study) and cocaine (Cervo and Samanin, 1995) CPP. In a set of experiments, we also tested the effects of the administration of NMDA or MK-801 on the expression of morphine-induced place preference. The results show that bilateral intra-CeA injection of NMDA, but not MK-801, increased the expression of morphine (6 mg/kg)-induced place preference. Since the expression of a CPP on the drugfree test day presumably requires learning and memory (White and Carr, 1985) and NMDA facilitate memory, therefore intra-CeA injection of NMDA before the testing phase may increase learning, which in turn elicits a potentiated CPP. The fact that MK-801 inhibited the acquisition but not the expression of morphine-induced place preference is in agreement with the report of Cervo and Samanin (1995). They indicated that MK-801 blocked the acquisition of cocaine-CPP, but it had not any effect on the expression. Considerable evidence suggests that NMDA receptors are involved in the acquisition but not the expression of phenomena such as tolerance and sensitization after repeated exposure to stimulant drugs or opioids (Trujillo and Akil, 1991; Stewart and Druhan, 1993; Karler et al., 1994). However, NMDA may have a role in the expression of CPP, but it needs more experiment to clarify exact mechanism. In order to show if locomotor activity influence on testing phase, it has been measured as described before (Belzung and Barreau, 2000; Zarrindast et al., 2000). Our data indicate that subcutaneous injection of morphine and also the intra-CeA injections of the glutamatergic drugs at the doses used in our experiments did not alter the locomotor activity in comparison with the control groups during the testing phase. Therefore, the interaction of locomotor activity with the results obtained seems unlikely. Overall it can be concluded that glutamate NMDA receptors of the central amygdala may elicit an important role in the induction of morphine rewarding properties.
4.
Experimental procedures
4.1.
Animals
The experiments were carried out on male Wistar rats (Pasteur Institute; Tehran, Iran) weighing 240–280 g at the beginning of the surgery. The animals were kept under standard laboratory conditions (12:12-h light/dark cycle) with free access to tap water and lab chow and adapted to the laboratory conditions for at least 1 week. The rats were handled once a day for 5 days preceding the experiments. Each experimental group was consisted of 8 animals. Each animal was used once only. The experiments were performed between 8:00 a.m. and 5:00 p.m. All procedures were carried out in accordance with institutional guidelines for animal care and use.
4.2.
Drugs
The compounds tested were morphine sulfate (Temad Co., Tehran, Iran), NMDA and MK-801 (Tocris Cookson Ltd., UK). The drugs were dissolved in saline (0.9% NaCl), just before the experiment. Morphine was injected subcutaneously (s.c.) in a volume of 1 ml/kg. NMDA and MK-801 were bilaterally injected into the central amygdala (intra-CeA) in a volume of 1 μl/rat. Control groups received saline injections in the same volume and by the same route.
4.3.
Surgical and infusion procedures
The animals were anesthetized with intraperitoneal injection of ketamine hydrochloride (50 mg/kg) plus xylazine (4 mg/kg) and positioned in a stereotaxic instrument. Two 23-gauge (Outer diameter: 0.6 mm) stainless steel guide cannulae were implanted 1 mm above the central amygdala based on the Atlas of Paxinos and Watson (1986). The cannulae were chronically fixed to the skull using jeweler's screws and acrylic dental cement. Stereotaxic coordinates for the central amygdala were AP −2.2 mm from bregma, L ±4.1 mm from the sagittal suture and −7.8 mm from the skull surface. To prevent clogging, the stainless steel stylets (30 gauge) were placed in the guide cannulae until the animals were given the CeA injection. The animals were allowed 7 days to recover before place conditioning processes. For drug infusion, the stylets were withdrawn and replaced by the injection units (30 gauge stainless steel tubing; outer diameter: 0.3 mm), terminating 1 mm below the tip of the guides. Each injection unit was connected by polyethylene tubing to 1-μl Hamilton syringe. The left and right CeA were infused with a 0.5-μl solution on each side (1 μl/rat) over a 60-s period. The cannulae were left in place an additional 60 s to allow diffusion, then the stylets were reinserted into the guide cannulae. During the infusion procedure, the experimenter loosely held the animals.
4.4.
Apparatus
The testing apparatus for the conditioned place preference paradigm was similar to that used by Carr and White (1983). It was consisted of three wooden compartments. Two of the
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compartments (A and B) were identical in size (40 × 30 × 30 cm) but differed in shading and texture. Compartment A was white with black horizontal stripes 2 cm wide on the walls and also had a textured floor. The other compartment (B) was black with vertical white stripes 2 cm wide and also had a smooth floor. The third compartment (C) was a red tunnel (40 × 15 × 30 cm). It protruded from the rear of the two large compartments and connected the entrances to them.
4.5.
Behavioral testing
Conditioned place preference (CPP) was consisted of a 5-day schedule with three distinct phases: pre-conditioning, conditioning and testing. This method (unbiased design) was similar to that used in our previous experiments (Rezayof et al., 2006a,b; Zarrindast et al., 2004, 2005). The unbiased design is commonly used by other authors as an alternative to the unbiased design (De Fonseca et al., 1995; Shi et al., 2004).
4.5.1.
Pre-conditioning
During this phase (day 1), each animal was placed in the third compartment (C) with the guillotine doors removed to allow access to the entire apparatus for 15 min. The amount of time spent in each compartment was measured to assess unconditioned preference (the position of the rat was defined by the position of its front paws). In the particular experimental setup used in this study, the animals did not show an unconditioned preference for either of the compartments. Animals were then randomly assigned to one of two groups for place conditioning and a total of eight animals were used for each subsequent experiments.
4.5.2.
Conditioning
Place conditioning phase started 1 day after pre-conditioning phase. This phase consisted of six 45-min sessions (three saline and three drug pairing). These sessions were conducted twice each day (from day 2 to day 4) with a 6-h interval. On each of these days, separate groups of animals received one conditioning session with morphine and one with saline. During these sessions, the animals were confined to one compartment by closing the removable wall. Animals of each group were injected with morphine and were immediately confined to one compartment of the apparatus for 45 min. Following administration of saline, the animals were confined to the other compartment for 45 min. Treatment compartment and order of presentation of morphine and saline were counterbalanced for either group.
4.5.3.
Post-conditioning or testing
This phase was carried out on day 5, 1 day after the last conditioning session, in a morphine-free state. Each animal was tested only once. For testing, the removable wall was raised, and the animals had a free choice in the apparatus for 15 min. The time spent in drug-paired compartment was recorded for each animal and the change of preference was calculated as the difference (in seconds) between the time spent in the drug-paired compartment on the testing day and the time spent in this compartment in the pre-conditioning day (De Fonseca et al., 1995).
4.6.
39
Locomotor testing
Locomotor activity was measured, based on a method we used previously (Rezayof et al., 2006a,b; Zarrindast et al., 2004, 2005), during the post-conditioning phase (Belzung and Barreau, 2000; Zarrindast et al., 2000), in a morphine-free state. For this purpose, the ground area of A and B compartments were divided into 4 equal sized squares. Locomotion was measured as the number of crossings from one square to another during 15 min.
4.7.
Drug treatments
4.7.1.
Experiment 1. Morphine-conditioned place preference
In this experiment, we produced a dose response function for morphine place conditioning. Four groups of animals were injected with morphine (1, 3, 6 or 9 mg/kg, s.c.) and saline (1 ml/ kg, s.c.) on alternate sessions. A separate group of animals was given saline (1 ml/kg, s.c.) only during the conditioning phase in order to confirm that the injections and the conditioning schedule were not affecting the time allotment in the apparatus. This group was used as control. Locomotor activity was also measured in the post-conditioning phase.
4.7.2. Experiment 2. Effects of NMDA and/or MK-801 with or without morphine on the acquisition of CPP Effects of intra-CeA injection of different doses of NMDA or MK-801 on the acquisition of the conditioned place preference induced by morphine were determined as follows. Rats received morphine or saline (s.c.) once daily in a 3-day schedule of conditioning. NMDA (0.01, 0.1 or 1 μg/rat; Fig. 2) or MK-801 (0.1, 0.3 or 0.5 μg/rat; Fig. 3) was injected into the central amygdala once per day for 3 days, 5 min before the administration of morphine (three sessions); the conditioning scores then were measured in a drug-free state (testing day). Intra-CeA injections of the same (above mentioned) doses of all drugs without morphine, during conditioning, were also used to assess their effects on CPP. The conditioning scores were then measured in a drug-free state on the test day. To determine the probable reversal effect of MK-801 on the response induced by NMDA, MK-801 (0.25, 0.5 or 1 μg/rat) was administered into the central amygdala, 5 min prior to the administration of NMDA at 1 μg/rat in the same experiment (Fig. 4). Locomotor activity was also evaluated during testing in these groups.
4.7.3. Experiment 3. The effects of NMDA or MK-801 on the expression of morphine-induced place preference Seven groups of animals underwent the experimental procedure of place conditioning with morphine (6 mg/kg, s.c.). On the 5th day, 5 min before testing, six groups were injected with NMDA (0.25, 0.5 or 1 μg/rat, intra-CeA) or MK-801 (0.25, 0.5 or 1 μg/rat, intra-CeA) and one group received saline (1 μl/rat, intra-CeA). Locomotor activity was also measured in the postconditioning phase (Fig. 5).
4.8.
Verification of cannulae placements
After completion of the experimental sessions, each animal was killed with an overdose of chloroform. Subsequently, 1.0 μl of ink was injected into the central amygdala by a 30-
40
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gauge injection cannula, which projected a further 1 mm ventral to the tip of the guide to aid in histological verification. The brains were removed and perfused with a 10% formalin solution 10 days before sectioning. Sections were examined to determine location of the cannulae aimed for the central amygdala. The cannula placements were verified using the atlas of Paxinos and Watson (1986). Data from rats with cannula placements outside the central amygdala were excluded from the analyses.
4.9.
Statistics
The data are expressed as means ± SEM. The statistical analyses were performed using one- and two-way analyses of variance (ANOVA) with score (i.e., the differences between post-conditioning and pre-conditioning time spent in the drug-associated compartment) as the dependent factor. Post hoc comparison of means was carried out with the Tukey test for multiple comparisons, when appropriate. The level of statistical significance was set at P < 0.05. Calculations were performed using the SPSS statistical package.
Acknowledgments The authors would like to express thanks to Yassaman Rassouli and Ladan Delphi for their skillful assistance.
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