The role of δ-opioid receptor subtypes in cocaine- and methamphetamine-induced place preferences

Life Sciences, Vol. 55, No. 17 pp. PL 339-344, 1994 Copyright © 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0024-3205/94 $6.00 + .00

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THE ROLE OF 6-OPIOID RECEPTOR SUBTYPES IN COCAINE- AND METHAMPHETAMINE-INDUCED PLACE PREFERENCES

Tsutomu Suzuki t, Tomohisa Mori 1, Minoru Tsuji 1, Miwa Misawa 1 and Hiroshi Nagase 2 1Department of Pharmacology, School of Pharmacy, Hoshi University, Shinagawa-ku, Tokyo 142, Japan 2Basic Research Laboratories, Toray Industries,Inc., 1111 Tebiro, Kamakura 248, Japan (Submitted July 11, 1994; accepted July 22, 1994; received in final form August 12, 1994)

Abstract: The effects of 6-receptor antagonists on cocaine- and methamphetamine-induced place preferences were examined in rats. Cocaine- and methamphetamine-induced place preferences were significantly attenuated by naltrindole (NTI: a non-selective 6-opioid receptor antagonist). Furthermore, naltriben (NTB: a selective 62-0pioid receptor antagonist), but not 7benzylidenenaltrexone (BNTX: a selective 61-opioid receptor antagonist), attenuated the cocaineand methamphetamine-induced place preferences. These results suggest that 6-0pioid receptors, particularly 62-opioid receptors, may be involved in the reinforcing effects of cocaine and methamphetamine. Key Words:

cocaine,methamphetamine,~5-opioidreceptor, naltrindole,naltriben, 7-benzylidenenaltrexone

Introduction The reinforcing effects of psychostimulants, such as cocaine, amphetamine and methamphetamine, have been demonstrated using self-administration and conditioned place preference paradigms in animals (1-5). In addition, it is well known that opioids and psychostimulants act on the mesolimbic dopaminergic system, and this action is closely related to their reinforcing effects. The possible involvement of opioid receptors in the reinforcing effects of psychostimulants has recently been investigated. For example, self-administration of cocaine is reduced or enhanced by non-selective opioid receptor antagonist naloxone or naltrexone (2,3,5). We also found that the cocaine-induced place preference was significantly suppressed by naltrexone and ~-opioid receptor agonist U50,488H (6). Furthermore, Menkens et al. (7) reported that the cocaine-induced place preference was blocked by the non-selective 6-opioid receptor antagonist naltrindole (NTI). These results suggest that endogenous opioids, especially 6-opioids, may be involved in the mediation of the reinforcing effects of psychostimulants. All correspondence to Tsutomu Suzuki, Ph.D.

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Recently, Portoghese et al. (8,9) synthesized selective antagonists for 6 - o p i o i d receptor subtypes, such as the ~52-opioid receptor antagonist naltriben (NTB) and the 61-opioid receptor antagonist 7-benzylidenenaltrexone (BNTX). In the present study, the role of 61- and 62opioid receptor subtypes in cocaine- and methamphetamine-induced place preferences in rats was examined using NTI, NTB and BNTX.

Methods Animal: Male Sprague-Dawley rats (Tokyo Experimental Animal, Inc., Tokyo, Japan) weighing 150-160 g were housed in groups of 2 - 3 in a temperature-controlled room (22 -+ 1 °C). They were maintained on a 12-h light/dark cycle with laboratory rat chow and water available ad libitum. Place conditioning: Place conditioning was conducted according to Suzuki et al. (10). The apparatus consisted of a shuttlebox (30 x 60 x 30 cm: w x 1 x h) which was divided into two compartments of equal size. One compartment was white with a textured floor and the other was black with a smooth floor. For conditioning, rats were confined to one compartment after drug injections and to the other compartment after saline injections. The order of the injections and the association between the injection (drug or saline) and the compartment (white or black) were counterbalanced across the subjects. Conditioning sessions (3 for drug: 3 for saline) were conducted once daily. In each session, the animals were confined to each compartment for 50 min. On day 7, tests of conditioning were performed as follows: the partition which separated the two compartments was raised to 12 cm above the floor, and a neutral platform was inserted along the seam separating the compartments. The time spent in each compartment during a 900 s session was then measured automatically in a blinded fashion by an infrared beam sensor (KN-80, Natsume Seisakusho, Tokyo, Japan). The position of the rat was defined by the position of its forelimbs and head. All sessions were conducted under conditions of dim illumination and masking white noise. Effects o f N T I , NTB and B N T X on c o c a i n e - and m e t h a m p h e t a m i n e - i n d u c e d place preference: Control rats were injcctcd with saline (1 mg/kg, i.p.) instead of drugs at each of the conditioning sessions; rats that had been injected with saline wcrc confined to one compartment on one day, and to the other compartment the next day, again after saline injection. This conditioning session was repeated 3 times. Either injection of saline was randomly regarded as a substitute for the drug before the start of the experiments. In thc test rats, drugs (4.0 mg/kg cocaine or 2.0 mg/kg methamphetamine) and saline (1.0 ml/kg) were injected i.p. on alternate days. The rats werc immediately confined to the respective compartment after the injection. NTI (0.3-3.0 mg/kg), BNTX (0.3-3.0 mg/kg), NTB (0.1-1.0 mg/kg) and saline were injected i.p. 45 rain before cocaine or mcthamphetaminc treatmcnt. Drugs: The drags used in the present study were cocaine hydrochlofide (Takeda Pharmaceutical Industries, Inc., Osaka, Japan), methamphetamine hydrochloride (Dainippon Pharmaceutical Co. Ltd., Osaka, Japan), naltrindole hydrochloride (NTI), naltriben methanesulfonate hydrate (NTB) and 7-benzylidenenaltrexone tartrate (BNTX). NTI, NTB and BNTX were synthesized by us. All of the drugs were dissolved in saline and injected in a volume of 1.0 ml/kg. Statistical analysis: Conditioning scores represent the time spent in the drug-paired place minus the time spent in the vehicle-paired place and are expressed as the mean _ S.E.M. The Wilcoxon test was used to determine whether individual doses produced significant conditioning.

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Place conditioning produced by naltrindole (NTI), naltriben (NTB) and 7 benzylidenenaltrexone (BNTX). Each column represents the mean conditioning score with S.E.M. of 7-8 rats.

Results E f f e c t s o f NTI, N T B and B N T X on c o c a i n e - and m e t h a m p h e t a m i n e - i n d u c e d place preference The saline-control rats exhibited no preference for either place. The mean conditioning score was -24.4 _+ 44.5 s. NTI (0.3-3.0 mg/kg), NTB (0.1-1.0 mg/kg) and BNTX (0.3-3.0 mg/kg) alone induced neither significant place preference nor place aversion (Fig. 1).

Cocaine (4.0 mg/kg) and methamphetamine (2.0 mg/kg) produced significant place preference, with mean conditioning scores of 249.8 _+39.8 s and 257.8 _+42.2 s, respectively (both P<0.01, Fig. 2A and 2B). The cocaine-induced place preference was significantly antagonized by pretreatment with 1.0 or 3.0 mg/kg NTI (both P<0.05, Fig. 2A and 2B) and 1.0 mg/kg NTB (P<0.05, Fig. 3A) in a dose-dependent manner. On the other hand, the cocaine-induced place preference was not influenced by pretreatment with BNTX (Fig. 3A). The m e t h a m p h e t a m i n e - i n d u c e d place preference was significantly antagonized by pretreatment with 3.0 mg/kg NTI (P<0.05, Fig. 2B) and 1.0 mg/kg NTB (P<0.05, Fig. 3A) in a dose-dependent manner. On the other hand, pretreatment with 3.0 mg/kg BNTX tended to inhibit the methamphetamine-induced place preference, but this inhibition was not significant (Fig. 3B).

Discussion

Psychostimulants, such as cocaine and methamphetamine, produce reinforcing effects in animals, which can provide information regarding abuse liability. Furthermore, the sensitivity of the conditioned place preference paradigm appears to be as great as or greater than those of other behavioral tests that are used to measure the reinforcing effects of drugs (11). We previously

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Effects of naltrindole (NTI) on cocaine ( A ) - and methamphetamine (B)-induced p l a c e p r e f e r e n c e c o n d i t i o n i n g in rats. E a c h c o l u m n r e p r e s e n t s the m e a n conditioning score with S.E.M. of 7 - 8 rats. ** = significant difference from the s a l i n e c o n t r o l ( P < 0 . 0 1 ) . # = s i g n i f i c a n t d i f f e r e n c e f r o m c o c a i n e ( A ) or methamphetamine (B) alone (P<0.05).

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Effects of naltriben (NTB) and 7-benzylidenenaltrexone (BNTX) on cocaine ( A ) and m e t h a m p h e t a m i n e ( B ) - i n d u c e d place preference conditioning in rats. Each c o l u m n r e p r e s e n t s the mean c o n d i t i o n i n g score with S . E . M . o f 7 - 8 rats. # = significant difference from cocaine (A) or methamphetamine (B) alone (P<0.05).

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demonstrated cocaine- and methamphetamine-induced place preferences in rats (4) using the same procedure as in the present study. In the present study, both cocaine (4.0 mg/kg) and methamphetamine (2.0 mg/kg) produced a significant place preference. On the other hand, NTI alone induced neither place preference nor place aversion. These results are consistent with previous reports using NTI (7) or ICI174,864 (12) in rats. In addition, the highly selective 6opioid receptor-subtype antagonists BNTX (for 6copioid receptors) and NTB (for 62-opioid receptors) also induced neither place preference nor place aversion. The present study demonstrated that NTI attenuates the cocaine-induced place preference. Our finding is consistent with the report by Menkens et al. (7). Furthermore, we found that the methamphetamine-induced place preference is also attenuated by NTI. Previous reports demonstrated that the non-selective opioid receptor antagonists or 6-opioid receptor antagonists reduced some cocaine- or amphetamine-induced behavioral effects, such as place preference (1), self-administration (2,3), discriminative stimulus properties (13) and hyperlocomotion (1,14,15), which are mainly thought to be mediated via the mesolimbic dopaminergic system. Furthermore, Hooks et al. (14) suggested that the attenuating effect of naloxone on amphetamine-induced behaviors may be related to opioid receptors other than kt-opioid receptors, since relatively high doses of naloxone are necessary to attenuate the behavioral effects of amphetamine. In view of these earlier results, our findings indicate that the reinforcing effects of cocaine and methamphetamine may, at least in part, result from the activation of opioid, especially 6-opioid, receptors by endogenous opioids. Our present findings, as well as those of a previous report (7), demonstrated that cocaine's reinforcing effects are attenuated by 6-opioid receptor antagonists. However it was also reported that the non-selective opioid receptor antagonists do not affect the self-administration of cocaine (16,17). On the other hand, De Vry et al. (2) demonstrated that naltrexone reduces the selfadministration of low doses, but not high doses, of cocaine. Recently, we found that NTI attenuated the discriminative stimulus properties of cocaine at doses lower than the training dose in rats that were trained to discriminate between cocaine (10 mg/kg) and saline (13). Therefore, our findings may have some bearing on the relative importance of the role of opioid (especially 6opioid) receptors in the behavioral effects of cocaine. In the present study, 1.0 mg/kg NTI attenuated cocaine-induced, but not methamphetamineinduced, place preference. It is believed that mesolimbic dopaminergic system plays an important role in the reinforcing effects of psychostimulants. On the other hand, amphetamine more potently increases dopamine concentration in nucleus accumbens, which is the terminal region of mesolimbic dopaminergic system, as compared with cocaine (18). Cocaine acts by mainly blocking the reuptake of dopamine released by nerve impulse (19), whereas methamphetamine and amphetamine produce a release of dopamine from dopaminergic nerve terminal (18). Thus, the difference exists between cocaine and methamphetamine in regard to dopamine release from the nerve terminal and these previous findings may explain why high dose of NTI requires to attenuate the methamphetamine-induced place preference rather than in the case of cocaineinduced place preference. In fact, 6-opioid receptor antagonists attenuated the discriminative stimulus properties of cocaine (13) more potent than that of methamphetamine (unpublished data). Evidence has been reported which supports the existence of at least two 6-opioid receptor subtypes: i.e., 61- and 62-opioid receptors (7). Recently, Portoghese et al. (7,8) synthesized selective antagonists for these 6-opioid receptor subtypes: BNTX (for 61-opioid receptor) and NTB (for 62-opioid receptor). In the present study, 1.0 mg/kg NTB significantly attenuated both the cocaine- and methamphetamine-induced place preferences, while 1.0 and 3.0 mg/kg BNTX did not. These results agree with our recent findings that these doses of NTB, but not BNTX, significantly attenuates the discriminative stimulus properties of cocaine, suggesting that blockade

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of 62-0pioid receptors may play an important role in the attenuation of the discriminative stimulus properties of cocaine (13). Furthermore, Izenwasser et al. (20) suggested that although both 61and 62-0pioid receptors regulate adenylyl cyclase activity, 62-0pioid receptors may play a more significant role in the nucleus accumbens. Their report is consistent with our findings that NTB, but not BNTX, significantly attenuated c o c a i n e - and m e t h a m p h e t a m i n e - i n d u c e d place preferences. Therefore, our findings suggest that 62-0pioid receptors, rather than 61-0pioid receptors, may play an important role in modulating the reinforcing effects of cocaine and methamphetamine. In summary, the 6-0pioid receptor antagonists NTI and NTB, but not BNTX, attenuated cocaine- and methamphetamine-induced place preferences, and this attenuation may be due to blockade of 62-0pioid receptors, rather than of 61-0pioid receptors. Acknowledgement We wish to thank Mr. Yuya Ise and Mr. Takane Kazama for their technical assistance. References 1. A.A. HOUDI, M.T. BARDO and G.R. VAN LOON, Brain Res. 497 195-198 (1989) 2. J. DE VRY, I. DONSELAAR and J.M. VAN REE, J. Pharmacol. Exp. Ther. 251 735-740 (1989) 3. G.J. SCHAEFER and R.P. MICHAEL, Psychopharmacology 102 236-268 (1990) 4. Y. MASUKAWA, T. SUZUKI and M. MISAWA, Psychopharmacology 111 139-143 (1993) 5. M.E. CARROLL, S.T.L. MICHAEL, J. WALKER, R. KRAGH and T. NEWMAN, J. Pharmacol. Exp. Ther. 238 1-7 (1986) 6. T. SUZUKI, Y. SHIOZAKIM, Y. MASUKAWA, M. MISAWA and H. NAGASE, Jpn. J. Pharmacol. 58 435-442 (1992) 7. K. MENKENS, E.J. BILSKY, K.D. WILD, P.S. PORTOGHESE, L.D. REID and F. PORRECA, Eur. J. Pharmacol. 219 345-346 (1992) 8. P.S. PORTOGHESE, M. SULTANA, H. NAGASE and A.E. TAKEMORI, Eur. J. Pharmacol. 218 195-196 (1992) 9. P.S. PORTOGHESE, H. NAGASE, K.E. MALONEY HUSS, C . - E . LIN and A.E. TAKEMORI, J. Med. Chem. 34 1715-1720 (1991) 10. T. SUZUKI, Y. MASUKAWA, Y. SHIOZAKI and M. MISAWA, Psychopharmacology 105 9-12 (1991) 11. M.D. SCHECHTER and D.J. CALCAHNETTI, Neurosci. Biobehav. Rev. 17 21-41 (1993) 12. T.S. SHIPPENBERG, R. BALS-KUBIK and A. HERTZ, Brain Res. 436 234-239 (1987) 13. T. SUZUKI, T. MORI, M. FUNADA, M. MISAWA and H. NAGASE, Eur. J. Pharmacol. (in press) 14. M.S. HOOKS, D.N.C. JONES, J.B. JUSTICE JR and S.T. HOLTZMAN, Pharmacol. Biochem. Behav. 42 765-770 (1992) 15. D.N.C. JONES, W.D. BOWEN, P.S. PORTOGHESE and S.T. HOLTZMAN, Eur. J. Pharmacol. 249 167-177 (1993) 16. A. ETI~NBERG, H.O. PETIT, B. BLOOM and G.F. KOOB, Psychopharmacology 78 204209 (1982) 17. S.R. GOLDBERG, J.H. WOODS and C.R. SHUSTER, J. Pharmacol. Exp. Ther. 176 464471 (1971) 18. G. DI CHIARA and A. IMPERATO, Proc. Natl. Acad. Sci USA 85 5274-5278 (1988) 19. C.E. JOHANSON and M.W. FISCHMAN, Pharmacol. Rev. 41 3-52 (1989) 20. S. IZENWASSER, B. BUZAS and M. COX, J. Pharmacol. Exp. Ther. 267 145-152 (1993)