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Official websites use. Share sensitive information only on official, secure websites. Corresponding Author E-mail: jang skku. Currently, the expanding recreational use of synthetic cannabinoids SCBs threatens public health. SCBs produce psychoactive effects similar to those of tetrahydrocannabinol, the main component of cannabis, and additionally induce unexpected pharmacological side effects. SCBs are falsely advertised as legal and safe, but in reality, SCB abuse has been reported to cause acute intoxication and addictive disorders. However, because of the lack of scientific evidence to elucidate their dangerous pharmacological effects, SCBs are weakly regulated and continue to circulate in illegal drug markets. The number of inactive lever presses was significantly higher in the SCB groups AM and CB than that in the vehicle group, indicating their impulsive effects. In summary, these results demonstrated that SCBs have distinct pharmacological properties and abuse potential. Cannabis, also known as marijuana, is one of the oldest psychoactive drugs and is widely used for recreational purposes Carliner et al. Cannabis is abused because of its psychological effects e. As the pharmacological effects of THC have been revealed Gaoni and Mechoulam, , synthetic cannabinoids SCBs have been developed to mimic those effects Weissman et al. SCBs were initially developed as laboratory research tools to investigate the cannabinoid system Melvin et al. SCBs have been available on the illegal drug market since the early s, and they are often used for recreational purposes Papaseit et al. However, new analogs, which have alterations to their chemical structure to avoid these restrictions, are continually emerging Angerer et al. These drugs are sprayed on plant material and commercialized in herbal mixtures, creating the misinterpretation that these synthetic products are natural and safe Dresen et al. However, indeed, SCB use has caused unpredictable adverse effects, resulting in severe physical and psychological disabilities Hermanns-Clausen et al. Most case reports have linked the use of SCBs to acute intoxication, such as hypertension, tachycardia, seizure, amnesia, and unconsciousness Heath et al. By contrast, very few case reports have evaluated SCB abuse and potential addiction Grigg et al. And consequently, drug risk assessment has only focused on the toxic effects of drugs that can cause an emergency, whereas the abuse potential of drugs, which can be a primary cause of psychotropic drug abuse, is often overlooked. Drug addiction is an expected consequence of drug abuse with a reinforcing effect Wise and Koob, Even after one use of the drug, the memory of the euphoric experience can lead to compulsive drug cravings. The addicts typically lose control and continue to chronically use the drug despite the harm it inflicts. They may try to quit using the drug after suffering from severe mental and physical illness, but quitting is impossible because of severe withdrawal syndrome Budney and Hughes, Therefore, we consider the abuse potential of drugs to be the initial trigger of drug-related diseases and the most dangerous characteristic associated with risk assessment. Many cases of SCB addiction have been reported worldwide Inci et al. Several withdrawal symptoms such as craving, anxiety, headache and insomnia have been observed in SCB addicts Zimmermann et al. These dependence on SCB is considered to be due to its potent agonist activity on the cannabinoid receptor 1 CB1 , which is responsible for the psychoactive effects of cannabinoids Tai and Fantegrossi, In particular, activation of the CB1 specifically activates the dopaminergic system of the brain reward circuit, which can lead to drug addiction Covey et al. All three are known to act as potent agonists on the CB1 receptor Dziadulewicz et al. In many countries, their recreational use has been legally regulated Uchiyama et al. This is due to the lack of scientific evidence of their abuse potential, which is necessary for the strict regulation of these SCBs. Therefore, in the present study, we examined the addictive potential of these three SCBs through the intravenous self-administration IVSA test, which is the most validated experimental method for evaluating drug abuse liability in animals. Seoul, Korea for the self-administration SA test. The experiment began 1 week after their arrival and occurred at the same time each day during the light phase of the cycle between 9 a. The rats had free access to food and water, except during food training sessions, and weighed between and g at the start of the experiment. All animal care procedures were conducted according to the U. All efforts were made to minimize animal suffering, to reduce the number of animals used, and to utilize alternatives to in vivo techniques, if available. The selection of drug dose-range was based on previous studies Fattore et al. The IVSA test was performed with a slight modification of the previously reported experimental designs to evaluate the reinforcing effect of SCBs Hur et al. The specific experimental procedure is shown in Fig. Each chamber was equipped with response levers 4. A cue light was positioned above each response lever. The front door and the back wall of the chamber were made of transparent plastic, and the other walls were made of an opaque metal. The experimental sessions were controlled and recorded in the experimental room using a PC with a custom interface and software. To facilitate the acquisition of operant responding, the rats were initially trained to press a lever to receive 45 mg of food pellets Bio-Serv, Flemington, NJ, USA. The rats were deprived of food for 12 h prior to training and were then trained in 1 h daily sessions in standard operant chambers until criteria were satisfied 80 food pellets for three consecutive days. A silastic catheter 0. The rats were injected with 0. The drug IVSA test was performed under a fixed ratio 1 FR1 schedule of reinforcement for 2 h per day for seven consecutive days. During the experimental sessions, each rat was placed in a standard operant chamber Med Associates Inc. The house light was turned on at the start of each session, and two levers were placed in the chamber: the right lever was designated as the active lever, and the left lever was designated as the inactive lever. Pressing the right lever resulted in the delivery of 0. The house light was turned off during injection, and a cue light above the right lever was illuminated during the time-out period approximately 20 s that followed each injection. Pressing the right lever during this period did not initiate any response, but the number of lever presses was still recorded. The cue light was turned off at the end of the time-out period, and the house light was turned on, signaling that the next injection was possible. Pressing the left lever had no programmed consequences but was still recorded. Sessions were ended by withdrawing the two levers. To evaluate the reinforcing effects of the SCBs, the number of infusions, active lever presses, and inactive lever presses in the IVSA test were measured over a 2 h period. All analyses were performed using Prism 6. A p value of less than 0. Accordingly, the average of the total number of infusions expressed in Fig. All drugs were injected intravenously at a volume of 0. A Number of infusions during a daily session. B Number of active lever presses during a daily session. C Number of inactive lever presses during a daily session. D Average total number of infusions over 7 days. E Average total number of active lever presses over 7 days. F Average total number of inactive lever presses over 7 days. Accordingly, the average of the total active lever presses expressed in Fig. Accordingly, the average of the total inactive lever presses expressed in Fig. There was no significant difference in the number of inactive lever presses between the PB groups and the vehicle group. Accordingly, there was no significant difference in the average of the total inactive lever presses Fig. This assumption is supported by case reports that note that, although the development of THC dependence is rare Carlini, , chronic use of SCBs can lead to dependence Zimmermann et al. This difference in pharmacological effects may be due to the difference in pharmacodynamic properties between THC and SCB. Although more research is needed to elucidate the mechanisms that enhance the reinforcing effect of SCB, through this study, we have demonstrated that three SCBs have strong addictive potential. Active lever pressing is a reward-related operant behavior, which is highly established during IVSA if the drug acts as a reinforcement. This behavior was often observed, even in the vehicle group, in the early IVSA sessions when reward-related memories formed during food training Table 1. In the meantime, the AM and CB groups demonstrated their reinforcement-enhancing effects by having many more active lever presses than those in the vehicle group in the early sessions. This supportive reinforcing effect, which promotes the abuse of other psychotropic substances, has also been confirmed in THC Solinas et al. Considering that SCBs are commercialized as a complex mixture Langer et al. These results indicate that SCBs have a dual reinforcing effect supportive and direct , which has also been reported regarding other addictive substances Brianna Sheppard et al. The low number of inactive lever presses is presented as a control to demonstrate that rats pressed the active lever as a drug seeking behavior. In all groups, the lever discrimination ratio was predominantly higher for active than for inactive presses, demonstrating reasonable IVSA. Meanwhile, the AM and CB groups displayed significantly higher numbers of inactive lever presses than the vehicle group. These results may reflect that the administration of these SCBs triggered impulsive behavior, which has been commonly observed in SCB users Ozten et al. Additionally, these impulsive effects of SCBs are supported by previous studies that cannabinoid receptors are responsible for impulsive behavior Leffa et al. Through a comprehensive comparison of the infusion patterns during the daily IVSA test, we discovered that each SCB had a distinct pharmacological effect Table 2. This may be due to the accumulation of CB through daily drug intake, inducing high concentrations of CB, which can lead to cannabimimetic aversive effects, in the late IVSA sessions. This assumption is supported by previous studies that note that high concentrations of CB treatment resulted in negative responses such as catalepsy, hypothermia, and hypomotility Dziadulewicz et al. Considering a previous study that revealed that PB causes dose-dependent depressant effects Gatch and Forster, , the high dose of PB may have suppressed IVSA through a stronger aversion effect than reinforcing effect. In summary, through these analyses, we found that each SCB not only has a unique molecular structure but also induces a distinct pharmacological effect. These differences may be due to various factors, such as differences in affinity for cannabinoid receptors, unique cell signaling through non-cannabinoid receptors, or differences in bioavailability and other pharmacokinetic parameters Fantegrossi et al. Therefore, further studies are needed to determine the exact pharmacological effects of each SCB. In the present study, we demonstrated that SCBs have reinforcing effects, reinforcement-enhancing effects, and impulsive effects in rodents. Based on these scientific confirmations of the pharmacological effects of SCB, recreational abuse of SCB should be strictly regulated by law, and users should be aware that SCBs are dangerous and illegal drugs that can cause variable side effects and severe addiction. As a library, NLM provides access to scientific literature. Biomol Ther Seoul. Find articles by Kwang-Hyun Hur. Find articles by Shi-Xun Ma. Find articles by Bo-Ram Lee. Find articles by Yong-Hyun Ko. Find articles by Jee-Yeon Seo. Find articles by Hye Won Ryu. Find articles by Hye Jin Kim. Find articles by Seolmin Yoon. Find articles by Yong-Sup Lee. Find articles by Seok-Yong Lee. Find articles by Choon-Gon Jang. Open in a new tab. Number of active lever presses during early and late IVSA test sessions. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Vehicle a. Day 1. Day 2. Day 3. Day 4. Day 5. Day 6. Day 7.

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