Chrislean Jun Botanas

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.

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.

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.

The abuse potential of two novel synthetic cathinones with modification on the alpha-carbon position, 2-cyclohexyl-2-(methylamino)-1-phenylethanone (MACHP) and 2-(methylamino)-1-phenyloctan-1-one (MAOP), and their effects on dopaminergic activity

ABSTRACT The recreational use of synthetic cathinones has dramatically increased in recent years, which is partly due to easy accessibility and ability of synthetic cathinones to exert rewarding effects similar to cocaine and methamphetamine. Many synthetic cathinones have already been scheduled in several countries; however, novel and diverse synthetic cathinones are emerging at an unprecedented rate, often outpacing regulatory processes. Recently, designer modifications of the basic cathinone molecule are usually performed on the alpha‐carbon position. In this study, we designed and synthesized two novel synthetic cathinones with substituents on alpha‐carbon position, [1] 2‐cyclohexyl‐2‐(methylamino)‐1‐phenylethanone (MACHP), and [2] 2‐(methylamino)‐1‐phenyloctan‐1‐one (MAOP). Then, we evaluated their rewarding and reinforcing effects through the conditioned place preference (CPP) in mice and self‐administration (SA) test in rats. Locomotor activity was also assessed in mice during daily MACHP or MAOP treatment for 7 days and drug challenge. qRT‐PCR analyses were conducted to determine their effects on dopamine‐related genes in the striatum. MACHP and MAOP produced CPP at 10 and 30 mg/kg. In the SA test, MACHP (1 mg/kg/infusion), but not MAOP, was self‐administered. Both MACHP and MAOP induced locomotor sensitization in mice. qRT‐PCR analyses showed that MACHP and MAOP reduced dopamine transporter gene expression in the striatum. These data indicate that MACHP and MAOP may have rewarding properties, which might be attributed to their ability to affect the dopaminergic activity. These findings may be useful in predicting the abuse potential and hasten the regulation of future cathinone entities with similar modifications. HighlightsWe synthesized two new synthetic cathinones MACHP and MAOP.MACHP and MAOP are synthetic cathinones with alpha‐carbon modification.MACHP and MAOP can produce rewarding effects.MACHP, but not MAOP, supports self‐administration.MACHP and MAOP have the ability to decrease DAT gene expression.

Exploring the Validity of Proposed Transgenic Animal Models of Attention-Deficit Hyperactivity Disorder (ADHD)

Attention-deficit/hyperactivity disorder (ADHD) is a common, behavioral, and heterogeneous neurodevelopmental condition characterized by hyperactivity, impulsivity, and inattention. Symptoms of this disorder are managed by treatment with methylphenidate, amphetamine, and/or atomoxetine. The cause of ADHD is unknown, but substantial evidence indicates that this disorder has a significant genetic component. Transgenic animals have become an essential tool in uncovering the genetic factors underlying ADHD. Although they cannot accurately reflect the human condition, they can provide insights into the disorder that cannot be obtained from human studies due to various limitations. An ideal animal model of ADHD must have face (similarity in symptoms), predictive (similarity in response to treatment or medications), and construct (similarity in etiology or underlying pathophysiological mechanism) validity. As the exact etiology of ADHD remains unclear, the construct validity of animal models of ADHD would always be limited. The proposed transgenic animal models of ADHD have substantially increased and diversified over the years. In this paper, we compiled and explored the validity of proposed transgenic animal models of ADHD. Each of the reviewed transgenic animal models has strengths and limitations. Some fulfill most of the validity criteria of an animal model of ADHD and have been extensively used, while there are others that require further validation. Nevertheless, these transgenic animal models of ADHD have provided and will continue to provide valuable insights into the genetic underpinnings of this complex disorder.

The Abuse Potential of α-Piperidinopropiophenone (PIPP) and α-Piperidinopentiothiophenone (PIVT), Two New Synthetic Cathinones with Piperidine Ring Substituent

A diversity of synthetic cathinones has flooded the recreational drug marketplace worldwide. This variety is often a response to legal control actions for one specific compound (e.g. methcathinone) which has resulted in the emergence of closely related replacement. Based on recent trends, the nitrogen atom is one of the sites in the cathinone molecule being explored by designer type modifications. In this study, we designed and synthesized two new synthetic cathinones, (1) α-piperidinopropiophenone (PIPP) and (2) α-piperidinopentiothiophenone (PIVT), which have piperidine ring substituent on their nitrogen atom. Thereafter, we evaluated whether these two compounds have an abuse potential through the conditioned place preference (CPP) in mice and self-administration (SA) in rats. We also investigated whether the substances can induce locomotor sensitization in mice following 7 days daily injection and challenge. qRT-PCR analyses were conducted to determine their effects on dopamine-related genes in the striatum. PIPP (10 and 30 mg/kg) induced CPP in mice, but not PIVT. However, both synthetic cathinones were not self-administered by the rats and did not induce locomotor sensitization in mice. qRT-PCR analyses showed that PIPP, but not PIVT, reduced dopamine transporter gene expression in the striatum. These data indicate that PIPP, but not PIVT, has rewarding effects, which may be attributed to its ability to affect dopamine transporter gene expression. Altogether, this study suggests that PIPP may have abuse potential. Careful monitoring of this type of cathinone and related drugs are advocated.