June Bryan de la Peña

Methoxetamine, a ketamine derivative, produced conditioned place preference and was self-administered by rats: Evidence of its abuse potential.

Methoxetamine (MXE) is an N-methyl-d-aspartate (NMDA) receptor antagonist that is chemically and pharmacologically similar to ketamine. Recently, there have been many reports regarding its use/misuse in humans which have resulted in serious or even fatal outcomes. Despite these reports, MXE is not controlled or regulated in many countries which may be partly due to the lack of scientific evidence regarding its abuse potential. Thus, in the present study we evaluated the abuse potential (rewarding and reinforcing effects) of MXE through the conditioned place preference (CPP) and self-administration (SA) tests in Sprague-Dawley rats. In addition, locomotor activity during the conditioning phase of the CPP was also analyzed. Ketamine was used as a reference drug. MXE (2.5 and 5mg/kg) induced significant CPP in rats, an effect comparable to that of ketamine (5mg/kg). Interestingly, MXE did not produce any locomotor alterations while ketamine decreased the locomotor activity of rats. In the SA test, rats showed modest self-administration of MXE (0.25, 0.5, 1.0mg/kg/infusion), while ketamine (0.5mg/kg/infusion) was robustly self-administered. These results demonstrate that MXE, similar to ketamine, has rewarding and reinforcing effects in rats. The present study strongly suggests that MXE has a potential for human abuse. In addition, the discrepant effects of MXE and ketamine on locomotor activity and rate of self-administration propose that the psychopharmacological effects of these drugs may diverge in some aspects. More importantly, this study advocates the careful monitoring and prompt regulation of MXE and its related substances.

Rewarding and reinforcing effects of the NMDA receptor antagonist-benzodiazepine combination, Zoletil®: difference between acute and repeated exposure.

Zoletil(®) is a 1:1 combination of the N-methyl-d-aspartate (NMDA) receptor antagonist, tiletamine, and the benzodiazepine, zolazepam, commonly used as a veterinary anesthetic. There have been previous reports on the abuse of zoletil in humans, and these motivated us to investigate the rewarding and reinforcing effects of the drug. We experimented whether zoletil and its constituents, tiletamine and zolazepam, produces place preference and/or facilitates self-administration. Then we compared the effects of zoletil to that of the recreationally abused veterinary anesthetic, ketamine. We also delved into the consequences of drug pre-exposure, thus parallel experiments were performed on rats pre-treated with the drug for 14 days. Our findings indicated that zoletil produced neither reward nor reinforcement in drug-naïve rats; however, repeated pre-treatment of zoletil produced significant place preference and self-administration. Tiletamine generated both place preference and self-administration; while zolazepam induced place preference but was not self-administered, even in pre-treated animals. The rewarding and reinforcing effects produced by zoletil were comparable to that of ketamine. Therefore, zoletil per se, has no motivational effects but the changes in neuronal functions and behavior consequential to repeated zoletil treatment may contribute in part to the addiction liability of the drug. Furthermore, the present study suggests that complex interactions occur with acute or repeated treatment of an NMDA receptor antagonist-benzodiazepine combination.

Luteolin mediates the antidepressant-like effects of Cirsium japonicum in mice, possibly through modulation of the GABAA receptor

Cirsium japonicum (CJ) has been shown to possess antidepressant-like properties. In the present study, we sought to identify which constituent of CJ might be responsible for its antidepressant effects and determine probable mechanism of action. The ethanol extract of CJ was administered to mice then behavioral changes were evaluated in the forced-swimming test (FST) and open-field test (OFT). In addition, its effects on norepinephrine (NE) reuptake and intracellular chloride (Cl−) flux were determined, in vitro. The effects of CJ’s major constituents (linarin, pectolinarin, chlorogenic acid, luteolin) were also evaluated. CJ showed antidepressant-like effect by significantly reducing immobile behavior of mice in the FST, without increasing locomotor activity in the OFT. CJ had no effect on monoamine (NE) uptake, but it significantly promoted Cl− ion influx in human neuroblastoma cells. This CJ-induced Cl− influx was significantly blocked by co-administration of the competitive GABAA receptor antagonist, bicuculline. Among the major constituents of the CJ extract, only luteolin produced similar antidepressant-like effect, in vivo, and Cl− ion influx, in vitro. Altogether, the present results suggest that the antidepressant-like effect of CJ was most probably induced by its constituent luteolin, mediated through potentiation of the GABAA receptor-Cl− ion channel complex.

Rearing in an enriched environment attenuated hyperactivity and inattention in the Spontaneously Hypertensive Rats, an animal model of Attention-Deficit Hyperactivity Disorder

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder, characterized by symptoms of hyperactivity, inattention, and impulsivity. It is commonly treated with psychostimulants that typically begins during childhood and lasts for an extended period of time. However, there are concerns regarding the consequences of chronic psychostimulant treatment; thus, there is a growing search for an alternative management for ADHD. One non-pharmacological management that is gaining much interest is environmental enrichment. Here, we investigated the effects of rearing in an enriched environment (EE) on the expression of ADHD-like symptoms in the Spontaneously Hypertensive Rats (SHRs), an animal model of ADHD. SHRs were reared in EE or standard environment (SE) from post-natal day (PND) 21 until PND 49. Thereafter, behavioral tests that measure hyperactivity (open field test [OFT]), inattention (Y-maze task), and impulsivity (delay discounting task) were conducted. Additionally, electroencephalography (EEG) was employed to assess the effects of EE on rats brain activity. Wistar-Kyoto (WKY) rats, the normotensive counterpart of the SHRs, were used to determine whether the effects of EE were specific to a particular genetic background. EE improved the performance of the SHRs and WKY rats in the OFT and Y-maze task, but not the delay discounting task. Interestingly, EE induced significant EEG changes in WKY rats, but not in the SHRs. These findings show that rearing environment may play a role in the expression of ADHD-like symptoms in the SHRs and that EE may be considered as a putative complementary approach in managing ADHD symptoms.

Conditioned Place Preference and Self-Administration Induced by Nicotine in Adolescent and Adult Rats

Nicotine addiction is a worldwide problem. However, previous studies characterizing the rewarding and reinforcing effects of nicotine in animal models have reported inconsistent findings. It was observed that the addictive effects are variable on different factors (e.g. route, dose, and age). Here, we evaluated the rewarding and reinforcing effects of nicotine in different routes of administration, across a wide dose range, and in different age groups. Two of the most widely used animal models of drug addiction were employed: the conditioned place preference (CPP) and self-administration (SA) tests. Nicotine CPP was evaluated in different routes [intraperitoneal (i.p.) and subcutaneous (s.c.)], doses (0.05 to 1.0 mg/kg) and age [adolescent and adult rats]. Similarly, intravenous nicotine SA was assessed in different doses (0.01 to 0.06 mg/kg/infusion) and age (adolescent and adult rats). In the CPP test, s.c. nicotine produced greater response than i.p. The 0.2 mg/kg dose produced highest CPP response in adolescent, while 0.6 mg/kg in adult rats; which were also confirmed in 7 days pretreated rats. In the SA test, adolescent rats readily self-administer 0.03 mg/kg/infusion of nicotine. Doses that produced nicotine CPP and SA induced blood nicotine levels that corresponded well with human smokers. In conclusion, we have demonstrated that nicotine produces reliable CPP [0.2 mg/kg dose (s.c.)] in adolescents and [0.6 mg/kg dose (s.c.)] in adults, and SA [0.03 mg/kg/infusion] in adolescent rats. Both tests indicate that adolescent rats are more sensitive to the rewarding and reinforcing effects of nicotine.

Assessment of the Abuse Liability of Synthetic Cannabinoid Agonists JWH-030, JWH-175, and JWH-176.

The emergence and use of synthetic cannabinoids have greatly increased in recent years. These substances are easily dispensed over the internet and on the streets. Some synthetic cannabinoids were shown to have abuse liability and were subsequently regulated by authorities. However, there are compounds that are still not regulated probably due to the lack of abuse liability studies. In the present study, we assessed the abuse liability of three synthetic cannabinoids, namely JWH-030, JWH-175, and JWH-176. The abuse liability of these drugs was evaluated in two of the most widely used animal models for assessing the abuse potential of drugs, the conditioned place preference (CPP) and self-administration (SA) test. In addition, the open-field test was utilized to assess the effects of repeated (7 days) treatment and abrupt cessation of these drugs on the psychomotor activity of animals. Results showed that JWH-175 (0.5 mg/kg), but not JWH-030 or JWH-176 at any dose, significantly decreased the locomotor activity of mice. This alteration in locomotor activity was only evident during acute exposure to the drug and was not observed during repeated treatment and abstinence. Similarly, only JWH-175 (0.1 mg/kg) produced significant CPP in rats. On the other hand, none of the drugs tested was self-administered by rats. Taken together, the present results indicate that JWH-175, but not JWH-030 and JWH-176, may have abuse potential. More importantly, our findings indicate the complex psychopharmacological effects of synthetic cannabinoids and the need to closely monitor the production, dispensation, and use of these substances.

Adolescent nicotine or cigarette smoke exposure changes subsequent response to nicotine conditioned place preference and self-administration.

Nicotine/cigarette addiction starts young. Indeed, most smokers started when they were adolescents. Adolescence has been implicated to be a critical period for nicotine/cigarette addiction, thus it is important to understand the consequences of such early exposure. In the present study, we sought to characterize the effects of adolescent nicotine or cigarette smoke pre-exposure on the subsequent addictive effects of nicotine. The rewarding and reinforcing effects of nicotine were evaluated in drug-naïve, nicotine pre-exposed, or cigarette smoke pre-exposed adolescent and adult rats, through the conditioned place preference (CPP) and the self-administration (SA) tests. In the CPP test, drug-naïve adolescent rats demonstrated CPP for the 0.2mg/kg dose of nicotine, while drug-naïve adult rats showed CPP for the relatively higher dose of 0.6mg/kg. Pre-exposed adolescent rats showed diminished response for the 0.2mg/kg, instead significant CPP was observed for the higher dose (0.6mg/kg) of nicotine. No significant change was observed in pre-exposed adult rats. Interestingly, cigarette smoke pre-exposed adolescent rats showed substantially higher nicotine CPP (0.6mg/kg) than to its nicotine-pre-exposed or adult counterpart. In the SA test, drug-naïve adolescent rats reliably produced stable nicotine (0.03mg/kg/infusion) self-administration, but drug-naïve adult rats did not. Surprisingly, however, nicotine or cigarette smoke pre-exposed adolescent and adult rats showed decreased nicotine self-administration. These results conform with the growing notion that adolescents are more sensitive to the addictive effects of nicotine and that nicotine or cigarette smoke exposure during this period produces complex behavioral changes which may influence subsequent response to nicotine.

Pre-exposure to ethanol, but not to caffeine and nicotine, induced place preference and self-administration of the NMDA receptor antagonist-benzodiazepine combination, Zoletil®.

Zoletil® is an equal amount combination of the NMDA receptor antagonist, tiletamine, and the benzodiazepine, zolazepam, usually used as a veterinary anesthetic. Previous studies have shown that pre-exposure to Zoletil® and other psychoactive drugs (e.g. ketamine, diazepam) plays a significant role in the abuse liability of the compound. However, these studies were only focused on illicit psychoactive drugs and not on the more widely used licit psychoactive substances. Thus, the goal of the present work is to investigate whether pre-exposure to the three most commonly used licit psychoactive substances (caffeine, nicotine, and ethanol) affects the rewarding and reinforcing effects of Zoletil®. Rats were pretreated with caffeine (1.25 or 2.5 mg/kg), nicotine (125 or 250 μg/kg), ethanol (0.5, 2, or 4 g/kg), or saline (1 ml/kg) for 14 days, and evaluated for subsequent Zoletil® place preference (2.5 mg/kg) and self-administration (250 μg/kg). Zoletil® produced neither place preference nor self-administration in saline-pretreated rats. Pre-exposure to caffeine or nicotine does not have significant effects on Zoletil®s abuse potential. However, pretreatment of ethanol significantly produced Zoletil® place preference and self-administration. These results suggest that individuals who are exposed to ethanol may have a high propensity to use/abuse Zoletil®. More importantly, the present result advocates the careful monitoring on the use and dispensation of Zoletil® or related substances.

The psychopharmacological activities of Vietnamese ginseng in mice: characterization of its psychomotor, sedative–hypnotic, antistress, anxiolytic, and cognitive effects

Background Panax vietnamensis Ha et Grushv. or Vietnamese ginseng (VG) is a recently discovered ginseng species. Studies on its chemical constituents have shown that VG is remarkably rich in ginseng saponins, particularly ocotillol saponins. However, the psychopharmacological effects of VG have not been characterized. Thus, in the present study we screened the psychopharmacological activities of VG in mice. Methods VG extract (VGE) was orally administered to mice at various dosages to evaluate its psychomotor (open-field and rota-rod tests), sedative–hypnotic (pentobarbital-induced sleeping test), antistress (cold swimming test), anxiolytic (elevated plus-maze test), and cognitive (Y-maze and passive-avoidance tests) effects. Results VGE treatment increased the spontaneous locomotor activity, enhanced the endurance to stress, reduced the anxiety-like behavior, and ameliorated the scopolamine-induced memory impairments in mice. In addition, VGE treatment did not alter the motor balance and coordination of mice and did not potentiate pentobarbital-induced sleep, indicating that VGE has no sedative-hypnotic effects. The effects of VGE were comparable to those of the Korean Red Ginseng extract. Conclusion VG, like other ginseng products, has significant and potentially useful psychopharmacological effects. This includes, but is not limited to, psychomotor stimulation, anxiolytic, antistress, and memory enhancing effects.

A novel synthetic cathinone, 2-(methylamino)-1-(naphthalen-2-yl) propan-1-one (BMAPN), produced rewarding effects and altered striatal dopamine-related gene expression in mice

HighlightsWe designed and synthesized a new synthetic cathinone BMAPN.BMAPN is a synthetic cathinone with naphthalene substituent on the aromatic ring.BMAPN produced rewarding and reinforcing effects.BMPAN has the ability to alter dopamine‐related gene expression. ABSTRACT The recreational use of synthetic cathinones has grown rapidly which prompted concerns from legal authorities and health care providers. However, in response to legislative regulations, synthesis of novel synthetic cathinones by introducing substituents in cathinone molecule has dramatically increased the diversity of these substances. Based on current trends, the aromatic ring is one of the popular sites in cathinone molecule being explored by designer‐type modifications. In this study, we designed and synthesized a novel synthetic cathinone, 2‐(methylamino)‐1‐(naphthalen‐2‐yl) propan‐1‐one (BMAPN), which has a naphthalene substituent on the aromatic ring. Thereafter, we determined whether BMAPN has rewarding and reinforcing effects through the conditioned place preference (CPP) test in mice and self‐administration (SA) paradigm in rats. Locomotor sensitization was also assessed in mice during daily BMAPN treatment for 7 days and drug challenge. Furthermore, we investigated the effects on BMAPN on dopamine‐related genes in the striatum of mice using quantitative real‐time polymerase chain reaction (qRT‐PCR). BMAPN induced CPP at 10 and 30 mg/kg and was modestly self‐administered at 0.3 mg/kg/infusion. Repeated BMAPN (30 mg/kg) administration also produced locomotor sensitization. qRT‐PCR analyses revealed decreased dopamine transporter and increased dopamine receptor D2 gene expression in the striatum of the BMAPN‐treated mice. These data indicate that BMAPN has rewarding and reinforcing properties, which might be due to its effects on dopamine‐related genes. The present study suggests that these findings may be useful in predicting abuse potential of future cathinone entities with aromatic ring substitutions.