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. 2025 Nov 23;45(4):e70075. doi: 10.1002/npr2.70075

Possible Involvement of Hallucinogenic Effects in the Aversive Effects Induced by Kappa‐Opioid and 5‐HT2A /2C Receptor Agonists in Mice

Hideaki Kato 1,✉, Yoshimi Ichimaru 1, Masaaki Kurihara 1, Koushirou Sogawa 1, Masahiko Funada 1, Tsutomu Suzuki 1,✉
PMCID: PMC12640738  PMID: 41276415

ABSTRACT

Aim

The regulation of new psychoactive and dangerous abused substances is very important for the prevention of drug abuse. A simple and effective evaluation method using laboratory animals is needed to regulate designated drugs with high accuracy and speed.

Methods

In the present study, we used the typical κ‐opioid receptor agonist U50,488H and the typical 5‐HT2A/2C receptor agonist 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane hydrochloride (DOI), which have a similar mechanism of action to hallucinogenic drugs, in a conditioned place aversion (CPA) test in mice. In addition, because hallucinogenic drugs can cause emotional abnormalities during hallucinations, we performed a marble‐burying test in mice.

Results

In the CPA test, both κ‐opioid receptor and 5‐HT2A/2C receptor agonists produced significant aversive effects and abnormal behavior. These aversive effects and abnormal behavior were probably due in part to the hallucinogenic effects of these drugs.

Conclusion

Therefore, these tests using mice may be useful for evaluating hallucinogenic effects. We hope that these simple and rapid evaluation methods will be used to identify designated drugs.

Keywords: 5‐HT2A/2C receptor, conditioned place aversion, hallucinogenic drugs, kappa‐opioid

This study developed a simple way to test new psychoactive substances (NPS) in mice. Two drugs, U50,488H and DOI caused aversive and abnormal behaviors in mice, likely linked to their hallucinogenic properties. These results suggest such behavioral tests could help quickly identify and regulate harmful psychoactive drugs.

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1. Introduction

Psychoactive drugs, which are increasingly being abused and synthesized, known as new psychotropic substances (NPS), are regulated as “designated drugs” in Japan and other countries [1, 2]. In Japan, designated drugs are substances that act on the central nervous system and produce stimulant, depressant or hallucinogenic effects [1]. Whether designated drugs are considered central nervous system (CNS) stimulants or inhibitors is determined based on the presence of spontaneous motor activity, changes in brain amine levels, receptor binding experiments, etc., but it is very difficult to evaluate their hallucinogenic effects. It has been shown that 5‐HT2A/2C receptor agonists, which are known to have hallucinogenic effects, induce head‐twitching in mice [3, 4, 5, 6]. In addition, in a drug discrimination test to evaluate the subjective effects of drugs, it has been shown that 5‐HT2A/2C receptor agonists generalize to the discriminative stimulus effect of 3,4‐methylenedioxymethamphetamine (MDMA), which is known to have hallucinogenic effects, and thus may have similar subjective effects [7]. Furthermore, the κ‐opioid receptor agonist salvinorin A is regulated as a designated drug because it produces hallucinogenic effects [8]. κ‐Opioid receptor agonists generally show aversive effects in conditioned place preference tests [9, 10, 11, 12]. The development of simple and accurate evaluation methods is necessary for the rapid evaluation and timely regulation of hallucinogenic drugs that are synthesized and marketed for abuse. Furthermore, it is necessary to clarify the suitability of each of these methods for evaluating hallucinogenic drugs. In this study, we synthesized a typical κ‐opioid receptor agonist and a 5‐HT2A/2C receptor agonist for continuous use in animal studies. We then performed a mouse CPA test using the κ‐opioid receptor agonist U50,488H and the 5‐HT2A/2C receptor agonist DOI. We also conducted a mouse marble‐burying test because hallucinogens may cause emotional abnormalities.

2. Methods

2.1. Animals

Male ICR mice (20–25 g) were obtained from Japan SLC Inc. (Hamamatsu, Japan). Unless otherwise stated, the mice were group‐housed (3–6 mice). Animals were housed in a room maintained at 23°C ± 1°C with a 12‐h light/dark cycle (lights on from 8:00 a.m. to 8:00 p.m.). Food (CE‐2, CLEA Japan Inc., Tokyo, Japan) and water were available ad libitum.

2.2. Drugs

The trans‐(±)‐3,4‐dichloro‐N‐methyl‐N‐[2‐(1‐pyrrolidinyl)cyclohexyl]benzeneacetamide hydrochloride (U50,488H) and 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane hydrochloride (DOI) (Figure 1) used in this study were synthesized in‐house using the preparation methods used in previous studies. In brief, U50,488H was synthesized in 5 steps using 1,2‐epoxycyclohexane as a starting material [13, 14]. DOI was synthesized in 4 steps using 1,4‐dimethoxy‐2‐(2‐nitroprop‐1‐en‐1‐yl)benzene as a raw material [15, 16]. The 1H NMR charts of the synthesized compounds were consistent with the previously reported data, and the product with a purity of over 95% was used in animal experiments [13, 14, 15, 16]. U50,488H and DOI were dissolved in saline as a vehicle.

FIGURE 1.

FIGURE 1

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Chemical structures of U50,488H and DOI. We synthesized the κ‐opioid receptor agonist U50,488H (A) and the 5‐HT2A/2C receptor agonist DOI (B) and administered them to mice, respectively.

2.3. Behavioral Tests

2.3.1. Conditioned Place Aversion (CPA) Test Using CPP Apparatus

The conditioned place preference (CPP) apparatus was developed at Muromachi Kikai Co. Ltd. (Tokyo, Japan). Place conditioning was conducted as described previously [17, 18, 19]. The apparatus consisted of a shuttle box (15 cm wide × 30 cm long × 15 cm high) made of acrylic resin board and divided into two compartments of equal size. We used a two‐compartment CPP apparatus because we believe it provides a simple and reliable way to detect both rewarding and aversive effects. Additionally, this two‐compartment CPP apparatus offers the possibility of big data analyses [9, 10]. One compartment was white with a textured floor, and the other was black with a smooth floor to create compartments of approximately equal preference. The place conditioning schedule consisted of three phases (preconditioning test, conditioning, and postconditioning test). The preconditioning test was performed as follows: a partition board with a hole (8 cm wide × 3 cm high) was made in the center of the partition separating the two compartments, and an animal that had received neither drug nor saline was placed in the center of the two compartments. The time spent in each compartment box during a 900 s (15 min) session was then automatically recorded with an infrared beam sensor (Supermex sensor; Muromachi Kikai Co. Ltd., Tokyo, Japan). Conditioning was performed twice daily for 3 days (three times for saline in the morning and three times for drugs in the afternoon). Drug conditioning was performed using a combination of our own modified pre‐test and a counterbalance method. Mice were randomly stratified into groups based on the time spent in the black and white two‐compartment box (15 min) measured on the day before the start of drug conditioning (Day −1). This conditioning method was used to eliminate bias in the administration of drugs and the combination of each box (drug‐white, drug‐black, vehicle‐white, and vehicle‐black) between the test groups. Conditioning was performed as follows. In the morning (8:00–10:00 a.m.), the animals were administered saline (10 mL/kg mouse body) as a vehicle, and confined to the white or black box for 30 min. In the afternoon, after an 8‐h rest period, the mice were administered the drug and then placed in a different box from the one used in the morning for 30 min. In this CPA procedure, the vehicle was administered in the morning and the drug was given in the afternoon. This allowed for an 8‐h interval between the vehicle and drug and a 16‐h drug withdrawal period. These operations constituted one session, and this conditioning was repeated for three sessions (Days 1–3). The postconditioning tests were performed on Days 4, 7, and 14. In the postconditioning test, the time spent in the white or black compartment box (15 min; 900 s) was measured without drug or vehicle administration. For data analysis, a score was calculated by subtracting the time spent in the vehicle‐treated box from the time spent in the drug‐treated box, and the difference in time spent from the preconditioning test score was calculated as the CPA score (s). If these values were positive (+), the rewarding effect of the conditioned drug was expressed, and if they were negative (−), the animals were scored as avoiding the drug‐treated box, that is, the expression of an aversive effect. The experimental protocol is shown in Figure 2A.

FIGURE 2.

FIGURE 2

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Schedule of conditioned place aversion (CPA) and marble‐burying tests. In the present study, the CPA and marble‐burying tests were performed with U50,488H and DOI to establish a method for evaluating substances with hallucinogenic effects. U50,488H and DOI were administered acutely or once daily for 3 days. CPA tests were performed on Days 4, 7, and 14 (A). The marble‐burying test was performed after a single administration, and also on Days 4, 7, and 14 after the CPA test (B).

2.3.2. Marble‐Burying Test

To assess behaviors representative of abnormal emotions, including unstable emotions, anxiety, and irritability, which are thought to be associated with hallucinogenic‐like effects, a marble‐burying test was performed after acute administration and 1 h after the CPA test on Days 4, 7, and 14. Briefly, 25 blue glass marbles (17 mm in diameter; Matsuno Industry Co. Ltd., Osaka, Japan) were evenly distributed on 5 cm‐deep paper animal bedding (Paper Clean, Japan SLC Co. Ltd., Hamamatsu, Japan) in 5 × 5 grids in polycarbonate cages (28 cm wide × 44 cm long × 20.5 cm; KN‐601 U‐TPX, Natsume Seisakusho Co. Ltd., Tokyo, Japan). It is well known that mice have difficulty distinguishing colors. The choice of blue was intentional, as it provides a high visual contrast against the bedding material, particularly for albino strains, such as ICR mice. Each mouse was placed in a cage for 30 min immediately after drug administration. The number of marbles buried by the mice was then counted after 15 and 30 min using photographs (GoPro HERO13; GoPro Inc., San Mateo, CA, USA) taken from above. Marbles buried to at least two‐third of their depth were considered buried [20, 21]. The light intensity in the test room was 200 lux at 5 cm from the floor. The experimental protocol is shown in Figure 2B.

2.4. Statistical Analysis

The data are presented as the mean with S.E.M. The statistical significance of differences between individual doses that produced significant conditioning was assessed with an ANOVA followed by Dunnett's multiple comparisons test (GraphPad InStat ver. 3.06, GraphPad Software Inc., San Diego, CA). In all instances, p < 0.05 was considered statistically significant. ANOVA, followed by Dunnett's multiple comparisons test, was performed for combined data across multiple days (Days 4, 7, and 14) and additionally for each day individually. The same animals were used for the experiments conducted on Days 4, 7, and 14. However, as the objectives and conditions differed each day, an ANOVA followed by Dunnett's multiple comparisons test was performed for daily comparisons and for comparisons across multiple days.

3. Results

3.1. Conditioned Place Aversion (CPA) Test

The results on Days 4, 7, and 14 after U50,488H (0.3, 1 and 3 mg/kg, s.c.) conditioning (Days 1–3) are shown in Figure 3A–C. The U50,488H 1 mg/kg group had a significant CPA score compared with the saline control group on Days 4 (1 mg/kg; p < 0.01; daily analysis, p < 0.05; multiple‐day analysis) and 7 (1 mg/kg; p < 0.05; daily analysis), but not on Day 14. The results on Days 4, 7, and 14 after DOI (1 and 3 mg/kg, s.c.) conditioning (Days 1–3) are shown in Figure 4A–C. The DOI 3 mg/kg group had a significant CPA score compared with the saline control group on Day 4 (3 mg/kg; p < 0.01; daily statistics), but not on Days 7 and 14.

FIGURE 3.

FIGURE 3

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U50,488H‐induced place aversion in mice. Conditioned place aversion (CPA) tests were performed by administering U50,488H (0.3, 1, 3 mg/kg, s.c.) or saline to mice twice daily for 3 days, in the morning and afternoon. CPA scores for the test sessions were measured for 900 s each on Days 4, 7, and 14. CPA scores (s) for the time spent in each black or white box were calculated from the difference between the postconditioning and preconditioning test scores. Each column represents the mean scores with S.E.M. of eight to ten animals. *p < 0.05, **p < 0.01, versus saline control (Dunnett's multiple comparison test; daily analysis). #p < 0.05 versus saline control (Dunnett's multiple comparison test; multiple‐day analysis).

FIGURE 4.

FIGURE 4

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DOI‐induced place aversion in mice. Conditioned place aversion (CPA) tests were performed by administering DOI (1 and 3 mg/kg, s.c.) or saline to mice twice daily for 3 days, in the morning and afternoon. CPA scores for the test sessions were measured for 900 s each on Days 4, 7, and 14. CPA scores (s) for the time spent in each black or white box were calculated from the difference between the postconditioning and preconditioning test scores. Each column represents the mean scores with S.E.M. of ten to twelve animals. *p < 0.05, versus saline control (Dunnett's multiple comparison test; daily analysis).

3.2. Marble‐Burying Test

The effects of U50,488H (0.3, 1, and 3 mg/kg, s.c.) at 15 and 30 min immediately after acute administration are shown in Figure 5A. There was a significant reduction in the number of buried marbles for all doses of U50,488H at 15 (0.3, 1, and 3 mg/kg; p < 0.01) and 30 min (0.3 mg/kg; p < 0.05, 1 and 3 mg/kg; p < 0.01) compared with the saline control group. The effects of DOI (0.3, 1, and 3 mg/kg, s.c.) at 15 and 30 min immediately after acute administration are shown in Figure 5B. There was a significant reduction in the number of buried marbles for all doses of DOI at 15 (0.3 mg/kg; p < 0.05, 1 mg/kg; p < 0.01) and 30 min (1 mg/kg; p < 0.01, 3 mg/kg; p < 0.01) compared with the saline control group. The results in the U50,488H (0.3, 1, and 3 mg/kg, s.c.) conditioning groups at 1 h after the CPA test session on Days 4, 7, and 14 are shown in Figure 6A–C. On Day 4, the number of buried marbles was significantly greater than that in the saline control for only 30 min (1 mg/kg; p < 0.05) in the U50,488H 1 mg/kg conditioning group. The results in the DOI (1 and 3 mg/kg, s.c.) conditioning groups at 1 h after the CPA test session on Days 4, 7, and 14 are shown in Figure 7A–C. On Day 4, the number of buried marbles was significantly greater than that in the saline control for 15 (3 mg/kg; p < 0.05) and 30 min (1 and 3 mg/kg; p < 0.05) in the DOI conditioning groups. On Day 7, the number of buried marbles was significantly greater than that in the saline control for 15 (3 mg/kg; p < 0.05) in the DOI conditioning groups.

FIGURE 5.

FIGURE 5

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Marble‐burying behavior after acute administration of U50,488H and DOI. Acute administration of U‐50488 H (0.3, 1, and 3 mg/kg, s.c.) (A) and DOI (0.3, 1, and 3 mg/kg, s.c.) (B) was evaluated by marble‐burying test in mice. The number of marbles buried 15 and 30 min after administration of U‐50488H and DOI were counted. Twenty‐five marbles were placed in the field. Each column represents the mean counts with S.E.M. of nine (A) and 14 to 16 (B) animals. *p < 0.05, **p < 0.01, versus saline control (Dunnett's multiple comparison test; daily analysis).

FIGURE 6.

FIGURE 6

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Marble‐burying behavior in U50,488H‐conditioned mice. Marble‐burying tests were performed 1 h after the CPA postconditioning test in the U‐50488H (0.3, 1, and 3 mg/kg, s.c.) or saline‐conditioning groups in mice on Days 4 (A), 7 (B), and 14 (C). The number of buried marbles at 15 and 30 min were counted. Twenty‐five marbles were placed in the field. Each column represents the mean counts with S.E.M. of eight to ten animals. *p < 0.05, versus saline control (Dunnett's multiple comparison test; daily analysis).

FIGURE 7.

FIGURE 7

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Marble‐burying behavior in DOI‐conditioned mice. Marble‐burying tests were performed 1 h after the CPA test session in the DOI (1 and 3 mg/kg, s.c.) or saline‐conditioning groups in mice on Days 4 (A), 7 (B), and 14 (C). The number of buried marbles at 15 and 30 min were counted. Twenty‐five marbles were placed in the field. Each column represents the mean counts with S.E.M. of 10 and 12 animals. *p < 0.05, versus saline control (Dunnett's multiple comparison test; daily analysis).

4. Discussion

Designated drugs are defined as those that have a high probability of having an excitatory or inhibitory effect on the central nervous system or hallucinogenic effects, and that may cause health hazards when used on the human body [1]. In several developed countries, the abuse of the hallucinogenic plant Salvia divinorum by inhaling its vapor through a water pipe has become a problem, especially among the younger generation [8]. It has been used for over a thousand years by indigenous people, including the Masatec Indians of Mexico, for divinatory, religious, and physical healing purposes [22, 23]. In Japan, the hallucinogen salvinorin A and its plant Salvia divinorum have been regulated as designated drugs since 2007 under the “Act on Pharmaceuticals and Medical Devices” [24]. Salvinorin A, which has a characteristic chemical structure, was found to be a selective agonist for especially κ‐opioid receptors [25, 26, 27]. On the contrary, the best‐known hallucinogenic drugs are 5‐HT receptor agonists, like lysergic acid diethylamide (LSD) [28]. Additionally, N‐methyl‐D‐aspartate (NMDA) receptor antagonists and cannabinoid (CB) receptor agonists have hallucinogenic properties [28]. κ‐Opioid receptor agonists, such as salvinorin A, are known to produce aversive effects in laboratory animals [9, 10, 11, 12]. In humans, however, they produce hallucinogenic effects [8, 22, 23]. Therefore, we investigated the aversive effects of U50,488H under short‐term (3 days) simple conditioning, and at the same time, whether a marble‐burying test could be used to evaluate not only antianxiety but also hallucinogenic drugs. The aversive effects of U50,488H persisted until at least Day 7 after conditioning, suggesting that it may be used to evaluate drugs that produce hallucinogenic effects. In addition, the aversive effect of U50,488H disappeared at higher doses, which is consistent with previous reports, and sedation is also known to be observed at similar doses [10, 11]. The aversive effects were also examined with the typical 5‐HT2A/2C receptor agonist DOI, which produces hallucinogenic head‐twitch responses [6, 29]. DOI is a brain‐penetrating 5‐HT2A/2C receptor agonist (Ki values are 0.7 nM for 5‐HT2A receptors and 2.4 nM for 5‐HT2C receptors) and is a well‐known hallucinogen [6, 30, 31]. This study observed aversive effects with both DOI and U50,488H, possibly related to their hallucinogenic effects. Although this study did not directly evaluate the DOI‐induced head‐twitch response, a recognized indicator of 5‐HT2A/2C receptor activation and hallucinogenic effects, we have observed head‐twitch response at the same dosage in a separate study (unpublished data). Based on these findings, the place aversion observed after DOI administration in this study may indirectly indicate hallucinogenic activity. Therefore, observation by aversive effects may also be useful for the evaluation of hallucinogenic drugs involving 5‐HT receptors for the regulation of “designated drugs.” Hallucinogenic effects preferred by humans may be aversive to laboratory animals. We also observed whether memories of the aversive effects of U50,488H and DOI were maintained or enhanced until Day 14. The aversive effects of U50,488H and DOI were also reduced or eliminated. Therefore, at this time, it may not be appropriate to use the CPA method to evaluate the desire for re‐intake. Drug discrimination tests in rats have also been used to evaluate hallucinogens [7, 32]. Evaluation to identify drugs with hallucinogenic effects may be possible using rat drug discrimination tests. However, the evaluation process is time‐consuming and not straightforward. We then investigated whether the marble‐burying test could be used to evaluate hallucinogenic drugs. In general, marble‐burying behavior is an animal experimental model used to represent anxiety or obsessive‐compulsive disorder (OCD) behavior [20, 21]. It is based on the observation that rodents will bury either harmful or harmless objects in their bedding. The present study showed that after acute administration of U50,488H and DOI, marble‐burying behavior was significantly inhibited. These results suggest that the marble‐burying test is suitable for assessing at least κ‐opioid and 5‐HT2A/2C receptor‐mediated hallucinogenic effects and may well serve as a source of evidence for the regulation of designated drugs. The marble‐burying test may be particularly sensitive to the negative affective dimensions of hallucinogenic states, including the dysphoric or anxiety‐like components often associated with so‐called “bad trips.” One possible explanation is that under the acute administration of U50,488H and DOI, the hallucinogenic‐like effects of these compounds altered the animals' engagement with the marbles. The decrease in marble‐burying behavior may reflect emotional or cognitive alterations rather than a simple anxiolytic effect. This finding further supports the usefulness of the marble‐burying test for detecting the broad psychological effects of hallucinogenic compounds. However, we acknowledge that the CPA and marble‐burying tests do not directly measure hallucinations. These behavioral paradigms may also reflect emotional or cognitive alterations associated with receptor systems (κ‐opioid and 5‐HT2A/2C) involved in the effects of hallucinogenic drugs. Although the inclusion of typical hallucinogens, such as MDMA, LSD, or CB receptor agonists as positive controls would strengthen the interpretation, legal regulations in our country make it difficult to use these substances for research purposes. Therefore, in the current study, we focused on compounds with similar receptor profiles that are legally accessible. On the contrary, the results of the marble‐burying test after the CPA test in mice conditioned with U50,488H or DOI showed an increase in marble‐burying behavior. Thus, the aversive effects following hallucinogenic drug conditioning may be positively correlated with an increase in marble‐burying behavior. The increase in marble‐burying behavior may have caused an increase in anxiety or OCD behavior after treatment with hallucinogenic drugs. Improvements to the marble‐burying test method, such as the number of marbles and the size of the field, could make the evaluation of hallucinogenic drugs easier and more accurate and should be considered in the near future.

5. Conclusion

In summary, the current evaluation of hallucinogens with respect to designated drugs is mainly based on general behavioral observations and head‐twitch response. However, in this study, we found that the observation of aversive behavior and changes in marble‐burying behavior in mice may be useful in evaluating hallucinogenic effects. Although these tests do not directly assess hallucinations, they may reflect emotional or cognitive alterations linked to κ‐opioid and 5‐HT2A/2C receptor activation. We strongly hope that this simple and rapid method for evaluating hallucinogens can be widely used to regulate hallucinogens.

Author Contributions

Hideaki Kato: writing – review and editing, writing – original draft, methodology, formal analysis, conceptualization, project administration. Yoshimi Ichimaru and Masaaki Kurihara: compound synthesis, writing – review and editing. Koushirou Sogawa: writing – review and editing. Masahiko Funada: methodology, formal analysis, writing – review and editing. Tsutomu Suzuki: writing – review and editing, writing – original draft, methodology, conceptualization, project administration.

Disclosure

Animal studies: The present study was conducted in accordance with the Guiding Principles for the Care and Use of Laboratory Animals (Shonan University of Medical Sciences), as adopted by the Committee on Animal Research of Shonan University of Medical Sciences, which is accredited by the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The protocols were approved by the Institutional Ethics Committee at Shonan University of Medical Sciences. The approval numbers were 2024–8, 2024–11, and 2024–16. Every effort was made to minimize the number and suffering of animals used in the experiments. The protocol using animals met the Act on Welfare and Management of Animals and the Ministry of Education, Culture, Sports, Science and Technology (MEXT)'s Fundamental Guidelines for Proper Conduct of Animal Experiment and Related Activities in Academic Research Institutions.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1: npr270075‐sup‐0001‐DataS1.xlsx.

NPR2-45-e70075-s001.xlsx (51.5KB, xlsx)

Kato H., Ichimaru Y., Kurihara M., Sogawa K., Funada M., and Suzuki T., “Possible Involvement of Hallucinogenic Effects in the Aversive Effects Induced by Kappa‐Opioid and 5‐HT2A /2C Receptor Agonists in Mice,” Neuropsychopharmacology Reports 45, no. 4 (2025): e70075, 10.1002/npr2.70075.

Funding: This study was supported by a Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan (Grants No. JPMH22KC1005 and JPMH25KC1002).

Contributor Information

Hideaki Kato, Email: hideaki.kato@sums.ac.jp.

Tsutomu Suzuki, Email: tsutomu.suzuki@sums.ac.jp.

Data Availability Statement

The data that support the findings of this study are available in Supporting Information of this article.

References

  • 1. Ministry of Health, Labor and Welfare (Japan) , “Japan: Designated Drugs,” https://www.mhlw.go.jp/bunya/iyakuhin/yakubuturanyou/scheduled‐drug/index.html.
  • 2. Shafi A., Berry A. J., Sumnall H., Wood D. M., and Tracy D. K., “New Psychoactive Substances: A Review and Updates,” Therapeutic Advances in Psychopharmacology 10 (2020): 2045125320967197, 10.1177/2045125320967197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Fantegrossi W. E., Simoneau J., Cohen M. S., et al., “Interaction of 5‐HT2A and 5‐HT2C Receptors in R(−)‐2,5‐Dimethoxy‐4‐Iodoamphetamine‐Elicited Head Twitch Behavior in Mice,” Journal of Pharmacology and Experimental Therapeutics 335, no. 3 (2010): 728–734, 10.1124/jpet.110.172247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Smith D. A., Bailey J. M., Williams D., and Fantegrossi W. E., “Tolerance and Cross‐Tolerance to Head Twitch Behavior Elicited by Phenethylamine‐ and Tryptamine‐Derived Hallucinogens in Mice,” Journal of Pharmacology and Experimental Therapeutics 351, no. 3 (2014): 485–491, 10.1124/jpet.114.219337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Biezonski D. K., Courtemanche A. B., Hong S. B., Piper B. J., and Meyer J. S., “Repeated Adolescent MDMA (“Ecstasy”) Exposure in Rats Increases Behavioral and Neuroendocrine Responses to a 5‐HT2A/2C Agonist,” Brain Research 1252 (2009): 87–93, 10.1016/j.brainres.2008.11.045. [DOI] [PubMed] [Google Scholar]
  • 6. Benvenga M. J., Chaney S. F., Baez M., et al., “Metabotropic Glutamate2 Receptors Play a Key Role in Modulating Head Twitches Induced by a Serotonergic Hallucinogen in Mice,” Frontiers in Pharmacology 9 (2018): 208, 10.3389/fphar.2018.00208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Mori T., Uzawa N., Kazawa H., et al., “Differential Substitution for the Discriminative Stimulus Effects of 3,4‐Methylenedioxymethamphetamine and Methylphenidate in Rats,” Journal of Pharmacology and Experimental Therapeutics 350, no. 2 (2014): 403–411, 10.1124/jpet.114.214288. [DOI] [PubMed] [Google Scholar]
  • 8. Brito‐da‐Costa A. M., Dias‐da‐Silva D., Gomes N. G. M., Dinis‐Oliveira R. J., and Madureira‐Carvalho Á., “Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects,” Pharmaceuticals (Basel) 14, no. 2 (2021): 116, 10.3390/ph14020116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Suzuki T., Shiozaki Y., Masukawa Y., Misawa M., and Nagase H., “The Role of Mu‐ and Kappa‐Opioid Receptors in Cocaine‐Induced Conditioned Place Preference,” Japanese Journal of Pharmacology 58, no. 4 (1992): 435–442, 10.1254/jjp.58.435. [DOI] [PubMed] [Google Scholar]
  • 10. Funada M., Suzuki T., Narita M., Misawa M., and Nagase H., “Blockade of Morphine Reward Through the Activation of Kappa‐Opioid Receptors in Mice,” Neuropharmacology 32, no. 12 (1993): 1315–1323, 10.1016/0028-3908(93)90026-y. [DOI] [PubMed] [Google Scholar]
  • 11. Huang P., Gentile T. A., Muschamp J. W., and Liu‐Chen L. Y., “The Kappa Opioid Receptor Agonist U50,488H Did Not Affect Brain‐Stimulation Reward While It Elicited Conditioned Place Aversion in Mice,” BMC Research Notes 13, no. 1 (2020): 384, 10.1186/s13104-020-05227-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Ehrich J. M., Messinger D. I., Knakal C. R., et al., “Kappa Opioid Receptor‐Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons,” Journal of Neuroscience 35, no. 37 (2015): 12917–12931, 10.1523/JNEUROSCI.2444-15.2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. González‐Sabín J., Gotor V., and Rebolledo F., “Chemoenzymatic Preparation of Optically Active Trans‐Cyclohexane‐1,2‐Diamine Derivatives: An Efficient Synthesis of the Analgesic U‐(−)‐50,488,” Chemistry 10, no. 22 (2004): 5788–5794, 10.1002/chem.200400607. [DOI] [PubMed] [Google Scholar]
  • 14. Chesis P. L. and Welch M. J., “Comparison of Bromo‐ and Iodoalkyl Triflates for 18F‐Radiolabeling of Amines,” International Journal of Radiation Applications and Instrumentation. Part A 41, no. 3 (1990): 259–265, 10.1016/0883-2889(90)90189-n. [DOI] [PubMed] [Google Scholar]
  • 15. Coutts R. T. and Malicky J. L., “The Synthesis of Analogs of the Hallucinogen 1‐(2,5‐Dimethoxy‐4‐Methylphenyl)‐2‐Aminopropane (DOM). II. Some Ring‐Methoxylated 1‐Amino‐and 2‐Aminoindanes,” Canadian Journal of Chemistry 52, no. 3 (1974): 381–389, 10.1139/v74-061. [DOI] [Google Scholar]
  • 16. Mathis C. A., Hoffman A. J., Nichols D. E., and Shulgin A. T., “Synthesis of High Specific Activity 125I‐ and 123I‐Labelled Enantiomers of 2,5‐Dimethoxy‐4‐Iodophenylisopropylamine (DOI),” Journal of Labelled Compounds and Radiopharmaceuticals 25 (1988): 1255–1265, 10.1002/jlcr.2580251112. [DOI] [Google Scholar]
  • 17. Suzuki T., Masukawa Y., and Misawa M., “Drug Interactions in the Reinforcing Effects of Over‐The‐Counter Cough Syrups,” Psychopharmacology 102, no. 4 (1990): 438–442, 10.1007/BF02247122. [DOI] [PubMed] [Google Scholar]
  • 18. Nestler E. J., “Genes and Addiction,” Nature Genetics 26, no. 3 (2000): 277–281, 10.1038/81570. [DOI] [PubMed] [Google Scholar]
  • 19. Bardo M. T. and Bevins R. A., “Conditioned Place Preference: What Does It Add to Our Preclinical Understanding of Drug Reward?,” Psychopharmacology 153, no. 1 (2000): 31–43, 10.1007/s002130000569. [DOI] [PubMed] [Google Scholar]
  • 20. Yamada K., Wada E., Yamano M., et al., “Decreased Marble Burying Behavior in Female Mice Lacking Neuromedin‐B Receptor (NMB‐R) Implies the Involvement of NMB/NMB‐R in 5‐HT Neuron Function,” Brain Research 942, no. 1–2 (2002): 71–78, 10.1016/s0006-8993(02)02696-3. [DOI] [PubMed] [Google Scholar]
  • 21. Deacon R. M., “Digging and Marble Burying in Mice: Simple Methods for In Vivo Identification of Biological Impacts,” Nature Protocols 1, no. 1 (2006): 122–124, 10.1038/nprot.2006.20. [DOI] [PubMed] [Google Scholar]
  • 22. Valdés L. J., Díaz J. L., and Paul A. G., “Ethnopharmacology of Ska María Pastora (Salvia divinorum, Epling and Játiva‐M.),” Journal of Ethnopharmacology 7, no. 3 (1983): 287–312, 10.1016/0378-8741(83)90004-1. [DOI] [PubMed] [Google Scholar]
  • 23. Siebert D. J., “Salvia Divinorum and Salvinorin A: New Pharmacologic Findings,” Journal of Ethnopharmacology 43, no. 1 (1994): 53–56, 10.1016/0378-8741(94)90116-3. [DOI] [PubMed] [Google Scholar]
  • 24. Ministry of Health, Labor and Welfare (Japan) , “Japan: Designated Drugs List,” (2007), https://www.mhlw.go.jp/bunya/iyakuhin/yakubuturanyou/scheduled‐drug/list.html.
  • 25. Sheffler D. J. and Roth B. L., “Salvinorin A: The “Magic Mint” Hallucinogen Finds a Molecular Target in the Kappa Opioid Receptor,” Trends in Pharmacological Sciences 24, no. 3 (2003): 107–109, 10.1016/S0165-6147(03)00027-0. [DOI] [PubMed] [Google Scholar]
  • 26. Yan F. and Roth B. L., “Salvinorin A: A Novel and Highly Selective Kappa‐Opioid Receptor Agonist,” Life Sciences 75, no. 22 (2004): 2615–2619, 10.1016/j.lfs.2004.07.008. [DOI] [PubMed] [Google Scholar]
  • 27. Roth B. L., Baner K., Westkaemper R., et al., “Salvinorin A: A Potent Naturally Occurring Nonnitrogenous Kappa Opioid Selective Agonist,” Proceedings of the National Academy of Sciences of the United States of America 99, no. 18 (2002): 11934–11939, 10.1073/pnas.182234399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. De Gregorio D., Enns J. P., Nuñez N. A., Posa L., and Gobbi G., “D‐Lysergic Acid Diethylamide, Psilocybin, and Other Classic Hallucinogens: Mechanism of Action and Potential Therapeutic Applications in Mood Disorders,” Progress in Brain Research 242 (2018): 69–96, 10.1016/bs.pbr.2018.07.008. [DOI] [PubMed] [Google Scholar]
  • 29. Oppong‐Damoah A., Curry K. E., Blough B. E., Rice K. C., and Murnane K. S., “Effects of the Synthetic Psychedelic 2,5‐Dimethoxy‐4‐Iodoamphetamine (DOI) on Ethanol Consumption and Place Conditioning in Male Mice,” Psychopharmacology 236, no. 12 (2019): 3567–3578, 10.1007/s00213-019-05328-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Nelson D. L., Lucaites V. L., Wainscott D. B., and Glennon R. A., “Comparisons of Hallucinogenic Phenylisopropylamine Binding Affinities at Cloned Human 5‐HT2A, ‐HT(2B) and 5‐HT2C Receptors,” Naunyn‐Schmiedeberg's Archives of Pharmacology 359, no. 1 (1999): 1–6, 10.1007/pl00005315. [DOI] [PubMed] [Google Scholar]
  • 31. Shepheard S. L., Jordan D., and Ramage A. G., “Investigation of the Effects of IVth Ventricular Administration of the 5‐HT2 Agonist, 1‐(2,5‐Dimethoxy‐4‐Iodophenyl)‐2‐Aminopropane (DOI), on Autonomic Outflow in the Anaesthetized Cat,” British Journal of Pharmacology 104, no. 2 (1991): 367–372, 10.1111/j.1476-5381.1991.tb12437.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Mori T., Iwase Y., Uzawa N., et al., “Synergistic Effects of MDMA and Ethanol on Behavior: Possible Effects of Ethanol on Dopamine D2 ‐Receptor‐Related Signaling,” Addiction Biology 26, no. 4 (2021): e13000, 10.1111/adb.13000. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Data S1: npr270075‐sup‐0001‐DataS1.xlsx.

NPR2-45-e70075-s001.xlsx (51.5KB, xlsx)

Data Availability Statement

The data that support the findings of this study are available in Supporting Information of this article.

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