Pre-exposure to related substances induced place preference and self-administration of the NMDA receptor antagonist-benzodiazepine combination, zoletil.

Previously, we have reported that the N-methyl-D-aspartate (NMDA) receptor antagonist-benzodiazepine veterinary anesthetic combination, zoletil, produced reward and reinforcement, but only in rats repeatedly pretreated with the drug and not in drug-naïve rats. Therefore, we hypothesized that previous drug exposure plays an important role in the abuse of zoletil. In the present study, we examined whether pre-exposure to related substances, NMDA receptor antagonists (tiletamine, ketamine), and benzodiazepines (zolazepam, diazepam) predisposes animals to abuse zoletil. We examined whether animals repeatedly pretreated with tiletamine, ketamine, zolazepam, or diazepam, for 14 days, would show locomotor activation, place preference, and self-administration in response to zoletil. Place preference was observed in groups pretreated with either an NMDA receptor antagonist (ketamine) or a benzodiazepine (diazepam). However, locomotor activation and self-administration were only observed in rats pretreated with NMDA receptor antagonists (tiletamine and ketamine). These results show that pre-exposure to related substances might have induced neurobiological changes that consequently led to the expression of the rewarding and reinforcing effects of zoletil. This provides evidence that zoletil may be used as a substitute drug by abusers of NMDA receptor antagonists or benzodiazepines.

RNA control in pain: Blame it on the messenger.

mRNA function is meticulously controlled. We provide an overview of the integral role that posttranscriptional controls play in the perception of painful stimuli by sensory neurons. These specialized cells, termed nociceptors, precisely regulate mRNA polarity, translation, and stability. A growing body of evidence has revealed that targeted disruption of mRNAs and RNA-binding proteins robustly diminishes pain-associated behaviors. We propose that the use of multiple independent regulatory paradigms facilitates robust temporal and spatial precision of protein expression in response to a range of pain-promoting stimuli. This article is categorized under: RNA in Disease and Development > RNA in Disease Translation > Translation Regulation RNA Turnover and Surveillance > Regulation of RNA Stability.

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.

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.

The involvement of magnoflorine in the sedative and anxiolytic effects of Sinomeni Caulis et Rhizoma in mice.

The present study seeks to evaluate the sedative and anxiolytic effects of the 70% ethanol extract of Sinomeni Caulis et Rhizoma (SR). The extract was orally administered to mice at dosages of 25, 50, 100, 200 or 400 mg/kg. The mice were then subjected to an array of behavioral tests to assess the sedative (open-field, rota-rod, and thiopental sodium-induced sleeping test) and anxiolytic (elevated plus maze test) effects of the substance. SR (100, 200 mg/kg) significantly reduced locomotor activity, decreased rota-rod performance, and potentiated thiopental sodium-induced sleeping in mice, all indicative of its sedative effects. SR (50, 100 mg/kg) also produced anxiolytic effects, as shown by an increase in entries and staying time on the open arm of the plus maze. SR's sedative and anxiolytic effects were comparable to that of the benzodiazepine, diazepam. Moreover, to identify SR's probable mechanism of action, intracellular Cl⁻ ion influx was observed in cultured human neuroblastoma cells. SR dose-dependently increased Cl⁻ influx, which was blocked by co-administration of the GABAA receptor competitive antagonist, bicuculline. Among the major constituents of SR, only magnoflorine showed a similar increment in Cl⁻ influx, which was also blocked by bicuculline. Altogether, the present results suggest that SR has sedative and anxiolytic effects, probably mediated by magnoflorine through a GABAergic mechanism of action.

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.

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.