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Official websites use. Share sensitive information only on official, secure websites. Corresponding Authors: E-mail: jinthong chungbuk. Limonene is a cyclic terpene found in citrus essential oils and inhibits methamphetamine-induced locomotor activity. Drug dependence is a severe neuropsychiatric condition that depends in part on changes in neurotransmission and neuroadaptation, induced by exposure to recreational drugs such as morphine and methamphetamine. In this study, we investigated the effects of limonene on the psychological dependence induced by drug abuse. Limonene inhibits methamphetamine-induced sensitization to locomotor activity. Expression of dopamine receptor supersensitivity induced by apomorphine, a dopamine receptor agonist, was significantly reduced in limonenepretreated rats. However, there was no significant difference in methamphetamine-induced conditioned place preferences between the limonene and control groups. These results suggest that limonene may ameliorate drug addiction-related behaviors by regulating postsynaptic dopamine receptor supersensitivity. Keywords: Dopamine receptor supersensitivity, Methamphetamine, Sensitization, Limonene. Limonene is a common terpene found in citrus fruits. This monoterpene is widely used as a flavor and fragrance and is listed to be generally recognized as safe in food by the Food and Drug Administration Flamm and Lehman-McKeeman, Limonene has been shown to exert anxiolytic effects, regulatory effects on neurotransmitters, and antinociceptive effects do Amaral et al. Recently, we have reported that limonene inhibits an acute single methamphetamine-induced hyperlocomotion in rats by regulating dopamine levels in the nucleus accumbens Yun, However, the potential for limonene in the treatment of drug dependence is largely unknown. Drug dependence is a condition that involves a cluster of behavioral, cognitive, and physiological symptoms that can develop following repeated substance use. Preclinical models have been shown to be useful in identifying many molecular and cellular targets of drug dependence. In rodents, acute administration of stimulants results in hyperactivity, whereas repeated administration results in progressive, enhanced locomotor activity Shimosato and Ohkuma, ; Filip et al. This phenomenon is also known as context-dependent behavioral sensitization, and this may play a role in the development of compulsive drug-seeking behaviors Hooks et al. It has been suggested that enhanced mesolimbic dopaminergic neuronal transmission is responsible for the development of behavioral sensitization to an abused drug Pak et al. It has also been reported that chronic abuse of drugs can cause the development of postsynaptic dopamine receptor supersensitivity in the central nervous system CNS Martin and Takemori, ; Ujike et al. This increased sensitivity can be detected as a hypersensitivity to direct-acting dopamine agonists and as an increase in the affinity of dopamine receptors Martin and Takemori, ; Woo et al. Many drugs that are liable to lead to dependence are known to induce CPP, including morphine, heroin Bozarth and Wise, ; Blander et al. These drugs produce a reinforcing effect, which, according to some hypotheses, may be because they commonly facilitate dopaminergic transmissions, either by stimulating the release of dopamine or inhibiting dopamine uptake Kim et al. In this study, we investigated the effect of limonene on methamphetamine-induced behavioral sensitization and CPP in rats. The rats were given a solid diet and tap water, ad libitum. All drugs were dissolved in distilled water 0. To test the degree of sensitization development, all groups were challenged with methamphetamines on day 5. Each rat was placed in an activity chamber The locomotor activity of the rats was measured using a photo-beam infrared activity chamber for 1 h, immediately after the injection of methamphetamine. The development and inhibition of sensitization was evidenced by enhanced and reduced response to methamphetamine, respectively. Dosages in this study are considered to have no toxicity in human as well as animals, which is accompanied with previous report Sun, Additional groups of rats, which underwent the same chronic methamphetamine and limonene treatment, were used to determine the effects of these treatments on the development of postsynaptic Dopamine receptor supersensitivity. The degree of methamphetamine-induced postsynaptic dopamine receptor supersensitivity developed was determined by measuring the enhanced locomotor activity induced by apomorphine on day 5, 24 h after the final injection of methamphetamine. Each rat was placed in an activity chamber and, after an adaptation period of 10 min, received 0. The locomotor activity of the rats was measured using an infrared photo-beam activity chamber for 1 h, from immediately after the injection of apomorphine. Development of methamphetamine-induced sensitization and postsynaptic dopamine receptor supersensitivity. The apparatus and procedure used for the CPP test have been published previously Kim et al. The two-side conditioning chambers interior dimensions: One conditioning chamber had white walls and a stainless-steel mesh floor 1. Removal of the guillotine doors during the pretesting and the final testing phases allowed the animals to have free access to both compartments, and the time spent by the individual rats in each of the two compartments was recorded using infrared detectors interfaced with an IBM-compatible PC. All conditioning or test sessions were conducted under ambient light 20—30 lux. To establish conditioning, we paired methamphetamine with the white compartment. The vehicle rats received an i. Methamphetamine was administered immediately before the rats were placed in the white compartment. To test the effect of limonene on the CPP induced by methamphetamine, limonene was administered 40 min prior to the methamphetamine injection. Pretesting phase: on day 1, the rats were pre-exposed to the test apparatus for 15 min. The guillotine doors were raised and each animal was allowed to move freely between the two compartments. On day 2, baseline preference for either of the two sides was determined for 15 min. Conditioning phase: on days 3, 5, 7, and 9, the rats were injected with methamphetamine prior to confinement in the white compartment, the non-preferred side, for 30 min. On days 4, 6, 8, and 10, the rats were injected with saline before they were confined to the black compartment, the preferred side, for 30 min. Testing phase: on day 11, the guillotine doors were raised. The rats were placed in the tunnel in the central part of the apparatus and the time spent by the rats in the two compartments was recorded for 15 min. The scores were calculated from the changes noted between the testing phase and the pre-testing phase in the white compartment. An increase in time in the drug-paired compartment indicated that the animal spent more time in the originally less-preferred compartment, presumably due to the reinforcing effects of the morphine that were conditioned to this environment Kim et al. Limonene was administered once a day for 4 days and the striatum was sampled 24 hours after last injection. Immunoreactive proteins were detected with an enhanced chemiluminescence Western blotting detection system. Locomotor sensitization, induced by repeated administration of a drug of abuse, is associated with the mechanism underlying the development of drug dependence Bello et al. Furthermore, apomorphine 0. Limonene treatment did not inhibit hyperactivity induced by a single methamphetamine injection on day 1 Fig. However, the locomotor sensitization induced by meth-amphetamine on day 5 was reduced in the rats pretreated with methamphetamine and limonene Fig. These results suggest that limonene inhibits methamphetamine-induced behavioral sensitization. Inhibitory effect of limonene on methamphetamine-induced sensitization of locomotion. The total distance on A day 1 and B day 5 is shown. These results suggest that limonene inhibits the development of postsynaptic dopamine receptor supersensitivity in methamphetamine-induced sensitized rats. Inhibitory effect of limonene on methamphetamine-induced postsynaptic dopamine receptor supersensitivity. On day 5, all groups were administered apomorphine 0. The methamphetamine group showed a significant increase in CPP score, as compared with the vehicle group Fig. Effect of limonene on CPP induced by methamphetamine. The preferences were calculated from the changes of the testing phase 15 min and the pre-testing phase 15 min in the white compartment. Because it has been reported that limonene regulates GABA expression, we measured expression levels of Gad67 protein which is involved in synthesis of GABA in striatum. Administration of limonene significantly increased the expression levels of Gad67 Fig. This observation suggest that the increased level of Gad67 protein induced by limonene play a role in the reduced sensitization. Effect of limonene on protein expression of Gad The expression of Gad67 was detected by Western blotting using specific antibodies in striatum. Each blot is representative of three experiments. We demonstrated that limonene may have therapeutic potential for the treatment of methamphetamine dependence. We have previously reported that limonene inhibits methamphetamineinduced hyperactivity Yun, ; in the present study, limonene administration also reduced the development of sensitization to methamphetamine-induced locomotor activity. Furthermore, the limonene-treated groups showed a decreasing trend in their place preference in the methamphetamine-induced CPP test, even though this was not significant. Sensitization to locomotor activity and CPP are associated with an increase in mesolimbic dopaminergic neurotransmission, which is a mechanism underlying drug dependence Pak et al. We also previously reported that limonene may reverse methamphetamine-induced elevation of dopamine levels in the nucleus accumbens of rats, by regulating GABA levels and activating GABA B receptors Yun, Therefore, the results from the present study suggest that the inhibitory effect of limonene on methamphetamine-induced dopamine release may play a role in the reduction of sensitization. It has previously been reported that an enhanced response to apomorphine, a direct-acting dopamine receptor agonist, results from the development of postsynaptic dopamine receptor supersensitivity after repeated administration of a drug of abuse Ritzmann et al. Overall, evidence indicates that postsynaptic dopamine receptor supersensitivity may be associated with behavioral effects, such as the CPP and sensitization induced by morphine, cocaine, and amphetamines Wolf et al. In this study, limonene inhibited the development of postsynaptic dopamine receptor super-sensitivity in the methamphetamine-induced sensitized rats, although the mechanism underlying the limonene-mediated reversal of supersensitivity development remains unclear. Limonene had no effect on the acute behavioral effects of apomorphine Supplementary Data 1 and the role of dopamine receptors in the development of methamphetamine-induced sensitization remains controversial Reed et al. However, other neurotransmitter systems, including GABAergic, 5-HTergic, and glutamatergic systems, are also associated with methamphetamine-induced locomotor sensitization and postsynaptic dopamine receptor supersensitivity Ohmori et al. Therefore, we suggest that limonene may inhibit the development of postsynaptic dopamine receptor supersensitivity in methamphetamine-induced sensitized rats via regulation of GABAergic and serotonergic modulation of dopaminergic neuronal transmission. In another study, Zhou et al. Methamphetamine-induced behavioral sensitization down-regulated Gad67 levels in the nucleus accumbens Zhang et al. Furthermore, we observed that a dopamine agonist, apomorphine-induced stereotype behavior was potentiated in Gad67 knock-down animal data not shown. Pharmacologic increases in brain GABA levels have been reported to block the increase in dopamine levels elicited by morphine or cocaine injection Klitenick et al. Therefore, limonene may reduce the development of physiological dependence by regulating GABAergic and dopaminergic neuronal transmission. In conclusion, these results suggest that limonene is a promising candidate in the treatment of drug dependence. 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Cheongju where can I buy cocaine