gy 573 (2007) 133–138www.elsevier.com/locate/ejphar

European Journal of Pharmacolo

Involvement of glucose and ATP-sensitive potassium (K+) channels onmorphine-induced conditioned place preference☆

Mohammad R. Zarrindast a,b,c,⁎, Manochehr Sattari-Naeini d, Azita Khalilzadeh a

a Department of Pharmacology and Iranian National Center for addiction Studies, Medical Sciences, University of Tehran, Iranb School of Cognitive Science, Institute for Studies in Theoretical Physics and Mathematics, Tehran, Iran

c Institute for Cognitive Science Studies, Tehran, Irand Islamic Azad University, Naein branch, Iran

Received 6 March 2007; received in revised form 23 June 2007; accepted 28 June 2007Available online 4 July 2007

Abstract

In the present study, the effects of glucose and ATP-sensitive K+ channel compounds on the acquisition of morphine-induced place preference inmale mice were investigated. Subcutaneous administration of different doses of morphine (2.5–7.5 mg/kg) produced a dose-dependent conditionedplace preference. With a 3-day conditioning schedule, it was found that glucose (100, 200, 500 and 1000 mg/kg), diazoxide (15, 30 and 60 mg/kg) orglibenclamide (3, 6 and 12 mg/kg) did not produce significant place preference or place aversion. Intraperitoneal administration of the glucose(1000mg/kg) or glibenclamide (6 and 12mg/kg) with a lower dose of morphine (0.5 mg/kg) elicited the significant conditioned place preference. Theresponse of glibenclamide (6 mg/kg) was reversed by diazoxide (15, 30 and 60 mg/kg). Drug injections had no effects on locomotor activity duringthe test sessions. It is concluded that glucose and the ATP-sensitive K+ channel may play an active role in morphine reward.© 2007 Elsevier B.V. All rights reserved.

Keywords: ATP-sensitive K+ channel; Glucose; Conditioned place preference (CPP); Morphine; (Mice)

1. Introduction

Conditioned place preference is commonly used to measurethe rewarding properties of drugs. This model can be used as aneffective tool to investigate the mechanisms underlying drug-induced reinstatement of drug seeking after extinction (Bardoet al., 1995; Olmstead and Franklin, 1997; Parker andMcDonald, 2000; Zarrindast et al., 2002; Zarrindast et al.,2003). Conditioned place preference is a learning paradigmrequiring the formation of associations between reward andparticular locations (Hoffman, 1989; Calcagnetti and Schechter,1991; Tzschentke, 1998). It has been suggested that learningand memory play an important role in the development of opiatereward (White, 1996). Systemic administration of glucose can

☆ This article is dedicated to the memory of Dr. Azita Khalilzadeh who died inFebruary 2007. Her premature death is a loss to pharmacology as well as to thosewho knew her.⁎ Corresponding author. Department of Pharmacology, School of Medicine,

Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran. Tel.:+98 21 6112801; fax: +98 21 6402569.

E-mail address: zarinmr@ams.ac.ir (M.R. Zarrindast).

0014-2999/$ - see front matter © 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.ejphar.2007.06.044

facilitate memory consolidation processes underlying theextinction of drug-induced place preference behaviour. Glucosehas been reported to interact with the morphine-inducedimpairment of memory (McNay and Gold, 1998) and attenuatesthe memory-impairing effects of cholinergic antagonists(Durkin et al., 1992; Ragozzino et al., 1998) and opioidergicagonists (Stone et al., 1991). It seems that glucose may enhancememory in laboratory animals via modulation of ATP-sensitivepotassium (KATP) channels (Rashidy-Pour, 2001).

Potassium (K+) channels represent the largest family of ionchannels. Among different types of K+ channels, KATPchannels are involved in several physiological functions. Theinvolvement of KATP channels in the memory processes hasbeen confirmed by some investigators (Inan et al., 2000;Rashidy-Pour, 2001). It has been demonstrated that theadministration of K+ channel openers provokes amnesia inthe mouse passive avoidance test and that K+ channel blockersare able to prevent drug-induced amnesia (Ghelardini et al.,1998). Several studies suggested that KATP channels areinvolved in the central nervous system and in the peripheralactions of morphine (Cohen et al., 2001; Gonzalez et al., 2001;

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Liang and Gross, 1999; Ocana et al., 1990; Poggioli et al.,1995). Moreover, our previous experiments indicate thatchannel modulators may be involved in the effects of morphineon learning processes (Zarrindast et al., 2004b,c).

The present study was designed to establish the role of theglucose and KATP channels on the rewarding effect ofmorphine, using the conditioned place preference paradigm.

2. Materials and methods

2.1. Animals

Male NMRI mice weighing 22–25 g were used. The animalswere housed in standard polypropylene cages colony main-tained at 22±2 °C under a 12:12-h light–dark cycle (lights on at07:00 h) and were allowed free access to food and water. Theanimals were allowed to adapt laboratory conditions for at least1 week before surgery. Each animal was used once only. Twelveanimals were used in each group of experiments. Theexperiments were carried out during the light phase of thecycle. All procedures were carried out in accordance withinstitutional guidelines for animal care and use.

2.2. Apparatus

The place conditioning apparatus was based on that usedpreviously (Zarrindast et al., 2004a). Compartments A and Bwere identical in size (40×30×30 cm) but differed in shading.Compartment A was white with black horizontal stripes 2-cmwide on the walls and also had a textured floor, whereascompartment (B) was black with vertical white stripes 2-cmwide and had a smooth floor. Compartment C (40×15×30 cm)was painted red and was attached to the rear of compartments Aand B; it had removable wooden partitions that separated it fromthe other compartments. When the partitions were removed, theanimal could freely move between the two compartments (Aand B) via compartment C.

2.3. Behavioral testing

2.3.1. Place conditioningConditioning place preference was conducted using an

unbiased procedure according to the method of Rodriguez DeFonseca et al. (1995). It consisted of a 5-day schedule with threedistinct phases: preconditioning, conditioning, and testing.

2.3.2. PreconditioningThe animals were placed in the middle of the apparatus and

were allowed to freely explore the three compartments for the15 min. The time spent by the animals in each compartment wasrecorded to assess unconditioned preference (the position of themice was defined by the position of its front paws). In theparticular experimental setup used in this study, the animals didnot show an unconditioned preference for either of thecompartments. Animals were then randomly assigned to oneof two groups for place conditioning and a total of twelveanimals were used for each subsequent experiments.

2.3.3. ConditioningPlace conditioning phase started 1 day after the precondi-

tioning phase. This phase consisted of six, 45-min sessions (3saline and 3 drug pairing). These sessions were conducted twiceeach day (from day 2 to 4) with a 6-h interval. On each of thesedays, animals received one conditioning session with drug andone with saline. During these sessions, the animals wereconfined to one compartment by closing the removable wall.Animals of each group were injected with drug and wereimmediately confined to one compartment of the apparatus for45 min. Six hours later, animals were administered saline andconfined to the other compartment for 45 min. Treatmentcompartment and the order of administration of drug and salinewere counterbalanced for each group, during conditioning.

2.3.4. TestingThe testing phase was carried out on day 5, 1 day after the

last conditioning session. Each animal was tested once only. Fortesting, the removable wall was raised, and the animals had afree choice in the apparatus for 15 min. The time spent in drug-paired compartment was recorded for each animal and thechange in preference was calculated as the difference (inseconds) between the time spent in the drug-paired compart-ment on the testing day and the time spent in this compartmenton the preconditioning day. The position of the animal wasdefined by the position of its forelimbs and head.

2.3.5. Locomotor testingLocomotor activity was measured, based on a method

previously used during the testing phase (Belzung and Barreau,2000; Zarrindast et al., 2002), in a morphine-free state. Locomotortesting was carried out on the fifth day of the schedule for mice thathad undergone place conditioning, using the conditioned placepreference apparatus. To measure locomotor activity, the groundarea of the conditioned place preference compartments was dividedinto four equal-sized squares. Locomotion was measured as thenumber of crossings from one square to another during 15 min.

2.4. Drugs

Morphine sulfate was purchased from Temad (Tehran, Iran).Diazoxide and Glibenclamide were a gift from Chemidaru(Tehran, Iran). D-Glucose was a gift from Merck (Darmstadt,Germany). Drugs were dissolved in 0.9% saline, exceptglibenclamide and diazoxide, which were dissolved in water/dimethylsulfoxide (9:1) solvent. The control animals receivedeither saline or vehicle (5 ml/kg).

2.5. Drug treatments

2.5.1. Morphine dose–response analysisThe effects of different doses of morphine (0.5, 2.5, 5 and

7.5 mg/kg, s.c.) on the induction of conditioned place preferencewas studied.Morphine or saline was injected according to a 3-dayconditioning schedule as described in detail in the experimentalprocedure. The time spent in the drug-paired compartment on thetesting day minus to that spent in this compartment on the

Fig. 1. Place preference produced by morphine. Different doses of morphine(0.5, 2.5, 5 and 7.5 mg/kg) and saline (5 ml/kg) were administeredsubcutaneously (s.c.) according to a 3-day conditioning schedule. On the testday, the animals were observed for a 15-min period. The change of preferencewas assessed as the difference between the time spent in one compartment on theday of testing and the time spent in the same compartment on the day of thepreconditioning session. Data are expressed as means±S.E.M. for 12 animalsper group.⁎⁎Pb0.01, ⁎⁎⁎Pb0.001 different from the saline control group.

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preconditioning day was calculated to assess the induction ofconditioned place preference. Animals were tested in a morphine-free state. This groupwas used as control. Locomotor activity wasalso measured in the testing phase (Fig. 1).

2.5.2. Effects of glucose, diazoxide and glibenclamide on theinduction of conditioned place preference

The effects of intraperitoneal (i.p.) injection of differentdoses of glucose, diazoxide, and glibenclamide on the inductionof conditioned place preference were determined as follows.Mice received saline, glucose (100, 200, 500 and 1000 mg/kg),

Fig. 2. Place preference produced by glucose, glibenclamide, or diazoxide. Theanimals received glucose (100, 200, 500 and 1000 mg/kg), glibenclamide (3, 6and 12 mg/kg) or diazoxide (15, 30 and 60 mg/kg) according to a 3-dayconditioning schedule. On the test day, the animals were observed for a 15-minperiod. The change of preference was assessed as the difference between thetime spent in one compartment on the day of testing and the time spent in thesame compartment on the day of the preconditioning session. Data are expressedas means±S.E.M. for 12 animals per group.

diazoxide (15, 30 and 60 mg/kg) or glibenclamide (3, 6 and12 mg/kg) once daily according to a 3-day conditioningschedule. On the test day, the time spent in the drug-pairedcompartment on the testing day minus to that spent in thiscompartment on the preconditioning day was calculated toassess the induction of conditioned place preference (Fig. 2).

2.5.3. Effects of glucose, diazoxide, and glibenclamide onacquisition of morphine-induced place preference

Animals received glucose (100, 200, 500 and 1000 mg/kg),diazoxide (15, 30 and 60 mg/kg) or glibenclamide (3, 6 and12 mg/kg) after the administration of morphine (0.5 mg/kg)during the conditioning sessions. The animals were tested 24 hafter the last conditioning session, with no preceding injection.Locomotor activity was also measured during testing (Fig. 3).

2.5.4. Effects of diazoxide in combination with glibenclamideon acquisition of morphine-induced place preference

Animals received diazoxide (15, 30 and 60 mg/kg) withglibenclamide (6 mg/kg), before the administration of morphine(0.5mg/kg) during the conditioning sessions. The animals were tested24 h after the last conditioning session, with no preceding injection.Locomotor activity was also measured during testing (Fig. 4).

3. Results

3.1. Dose–response curve for place preference conditioningproduced by morphine

Fig. 1 shows the dose–response curve for place conditioninginduced by morphine. Animals that received saline twice per

Fig. 3. The effects of glucose, glibenclamide, or diazoxide on the acquisition ofmorphine-induced place preference. All animals receivedmorphine (0.5mg/kg, s.c.)according to a 3-day conditioning schedule. On the test day, the different doses ofglucose (100, 200, 500 and 1000 mg/kg), glibenclamide (3, 6 and 12 mg/kg),diazoxide (15, 30 and 60 mg/kg), saline or vehicle (5 ml/kg) were administeredimmediately before testing and each animal was observed for a 15-min period. Thechange of preference was assessed as the difference between the time spent in onecompartment on the day of testing and the time spent in the same compartment on theday of the preconditioning session. Data are expressed as means±S.E.M. for 12animals per group. ⁎⁎Pb0.01, ⁎⁎⁎Pb0.001 compared to the saline or vehicle group.

Fig. 4. The effects glibenclamide combined with diazoxide on the acquisition ofmorphine-induced place preference. The animals receivedglibenclamide (6mg/kg)with i.p. injection of diazoxide (15, 30 and 60 mg/kg) and then they were injectedwith morphine (0.5 mg/kg, s.c.). On the test day, the animals were observed for a15-min period. The change of preference was assessed as the difference betweenthe time spent in one compartment on the day of testing and the time spent in thesame compartment on the day of the preconditioning session.Data are expressed asmeans±S.E.M. for 12 animals per group. ⁎Pb0.05, ⁎⁎Pb0.01, ⁎⁎⁎Pb0.001compared to the morphine/glibenclamide group, ++Pb0.01 compared to themorphine/saline group.

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day during six sessions exhibited no preference for eithercompartment. Administration of different doses of morphine(0.5, 2.5, 5 and 7.5 mg/kg) during conditioning changedpreference [one-way ANOVA; F(4, 55)=13.26, Pb0.001].Post-hoc analysis showed that morphine (2.5, 5 and 7.5 mg/kg)induced conditioned place preference. The maximum responsewas obtained with 7.5 mg/kg of the opioid.

3.2. Effects of glucose, diazoxide, and glibenclamide on theinduction of conditioned place preference

Fig. 2 shows the effects of glucose (100, 200, 500 and1000 mg/kg), glibenclamide (3, 6 and 12 mg/kg), and diazoxide(15, 30 and 60 mg/kg) on the acquisition of conditioned placepreference. One-way ANOVA revealed that drugs aloneinduced neither significant place preference nor place aversion[glucose F(4, 55)=0.68, PN0.05; glibenclamide F(3, 44)=0.8,PN0.05; diazoxide F(3, 44)=0.33, PN0.05].

3.3. Effects of glucose, diazoxide, and glibenclamide withmorphine on the acquisition of conditioned place preference

Fig. 3 shows the effects of glucose, glibenclamide anddiazoxide with morphine (0.5 mg/kg) on the acquisition ofconditioned place preference. One-way ANOVA revealedthat both glucose [F(4, 55)=8.93, Pb0.001] and glibenclamide[F(3, 44)=10.90, Pb0.001] potentiated the morphine-inducedplace preference. Diazoxide tended to decrease the morphineresponse, but this effect was not significant [F(3, 44)=2.2,PN0.05].

3.4. Effects of diazoxide in combination with glibenclamide onmorphine-induced place preference

Fig. 4 shows the effects of glibenclamide (6 mg/kg) incombination with diazoxide (15, 30 and 60 mg/kg) and morphine(0.5 mg/kg) on the acquisition of conditioned place preference.One-way ANOVA revealed that glibenclamide+diazoxide dosedependently inhibited the morphine-induced place preference[One-way ANOVA: F(4,55)=8.02, Pb0.001].

3.5. The effect of the drugs on locomotor activity

One-way ANOVA indicated that i.p. injection of the differentdoses of morphine (0.5, 2.5, 5 and 7.5 mg/kg) [F(4,55)=0.53,PN0.05], glucose (100, 200, 500 and 1000 mg/kg) [F(4,55)=0.49, PN0.05], glibenclamide (3, 6 and 18 mg/ kg) [F(3,44)=0.32, PN0.05], or diazoxide (15, 30 and 60 mg/kg) [F(3,44)=0.20, PN0.05] during the conditioning phase had no effect onlocomotor activity during the testing phase (data are not shown).

4. Discussion

In the present study, the conditioning treatments with differentdoses of morphine produced a dose-related place preference inmice. The data agree with those of previous reports which sug-gested that the conditioning procedure can be used to investigatethe rewarding effect of morphine (Lu et al., 2000; Rodriguez DeFonseca et al., 1995; Shippenberg and Herz, 1988; Tzschentke,1998). There is a growing body of evidence indicating that themesocorticolimbic dopaminergic system has an important role inthe acquisition of morphine-induced place preference (Olmsteadand Franklin, 1997). Our previous studies also showed that non-dopamine mechanism(s) may be involved in morphine reward(Zarrindast et al., 2002, 2003; Rezayof et al., 2007a,b). Somestudies have indicated that the KATP channel blockers (sulfonyl-urea) antagonize the antinociceptive effect of opioids, and thus itseems that the opening of KATP channel plays a role in opioid-mediated antinociception (Ocana et al., 1995; Ocana et al., 1990;Wild et al., 1991). Furthermore, KATP channel openers such aspinacidil and cromakalin also enhanced the antinociceptive effectof opioid agonists (Ocana et al., 1996; Vergoni et al., 1992).Previously, we have also shown thatKATP channelmodulators areinvolved in morphine state dependence learning through acholinergic system mechanism (Zarrindast et al., 2004b).Therefore, in the present experiments, we examined the effectsof intraperitoneal injection of glucose, a K+ channel blocker(glibenclamide), or a K+ channel opener (diazoxide) on theacquisition of morphine-induced place preference in mice, usingan unbiased conditioned place preference paradigm.

The present data showed that the administration of glucoseby itself did not alter conditioned place preference, whereas co-administration of glucose with an ineffective dose of morphine-induced place preference. Since conditioned place preference isa learning paradigm, it seems that co-administration of glucosewith morphine may increase learning. It has been shown thatglucose can improve memory in most memory tasks (Flint andRiccio, 1997; Gold, 1995; Parkes and White, 2000). Glucose

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also increases the morphine-induced memory enhancement bythree different mechanisms: cholinergic or opioidergic modu-lation or regulation of KATP channels (Jafari et al., 2004).

Furthermore, in this study intraperitoneal injection of a K+

channel blocker (glibenclamide) and a K+ channel opener(diazoxide) by alone during the conditioning phase did notalter conditioned place preference, while co-administration ofglibenclamide, but not diazoxide, with a lower dose of morphine(0.5 mg/kg, s.c.) increased the morphine response significantly.Therefore, KATP channels may be involved in the induction ofmorphine-induced place preference. This may be supported byour other results that pretreatment with diazoxide duringconditioning attenuated the decrease in morphine reward inducedby glibenclamide. However, diazoxide may also decrease theeffect of morphine by itself. In support of our hypothesis, it hasbeen shown that the modulation of KATP channels play animportant role in the regulation of memory processes (Ghelardiniet al., 1998). One possible mechanism by which glucose mightenhance memory is that glucose affects the activity of KATPchannels in and/or outside (such as those channels in pancreaticbeta cells) the central nervous system. These channels provide acritical link between neurotransmitter or insulin secretion andcellular glucose metabolism (Amoroso et al., 1990; Dunne et al.,1999; Panten et al., 1996; Seino et al., 2000). Both glucose andglibenclamide close KATP channels, and therefore it is notsurprising that both of them similarly increase place conditioninginduced by morphine. However, there are reports indicating thatthe KATP channels antagonize morphine-induced antinocicep-tive effect and locomotor activity (Ocana and Baeyens, 1993;Ocana et al., 1995). Therefore, the exact mechanism involved isnot clear and needs further investigation. The present dataindicate that the administration of morphine, glucose, glibencla-mide or diazoxide during the conditioning phase had no effect onlocomotor activity. Therefore, locomotor activity did not affectthe results obtained.

In conclusion, these results showed that glucose orglibenclamide can facilitate morphine-induced place prefer-ence, an effect which may be mediated by blocking KATPchannels.

Acknowledgment

This project was supported by a grant from Tehran Universityof Medical Sciences, Tehran, Iran.

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