Vulnerability factors for mephedrone-induced conditioned place preference in rats-the impact of sex differences, social-conditioning and stress.

RATIONALE: Mephedrone is a frequently overused drug of abuse that belongs to the group of novel psychoactive substances. Although its mechanism of action, as well as toxic and psychoactive effects, has been widely studied, the role of different factors that could contribute to the increased vulnerability to mephedrone abuse is still poorly understood. OBJECTIVES: The aim of the presented study was to assess the impact of several factors (sex differences, social-conditioning, and chronic mild unpredictable stress - CMUS) on the liability to mephedrone-induced reward in Wistar rats. METHODS: The rewarding effects of mephedrone in male and female rats were assessed using the conditioned place preference (CPP) procedure. Furthermore, the impact of social factor and stress was evaluated in male rats using social-CPP and CMUS-dependent CPP, respectively. RESULTS: Mephedrone induced classic-CPP in female (10 mg/kg), as well as in male (10 and 20 mg/kg) rats. However, the impact of mephedrone treatment during social-CPP was highly dose-dependent as the rewarding effects of low dose of mephedrone (5 mg/kg; non-active in classic-CPP) were potentiated when administered during social-conditioning. Interestingly, social-conditioning with a higher dose of 20 mg/kg (that induced classic-CPP) was able to reverse these effects. Finally, CMUS potentiated rewarding effects of a low dose of mephedrone (5 mg/kg) and increased the level of corticosterone in rats' prefrontal cortex and hippocampus. CONCLUSIONS: Altogether, the presented results give new insight into possible factors underlying the vulnerability to mephedrone abuse and can serve as a basis for further studies assessing mechanisms underlying observed effects.

Insight into Glutamatergic Involvement in Rewarding Effects of Mephedrone in Rats: In Vivo and Ex Vivo Study.

Mephedrone is a widely used drug of abuse, exerting its effects by interacting with monoamine transporters. Although this mechanism has been widely studied heretofore, little is known about the involvement of glutamatergic transmission in mephedrone effects. In this study, we comprehensively evaluated glutamatergic involvement in rewarding effects of mephedrone using an interdisciplinary approach including (1) behavioural study on effects of memantine (non-selective NMDA antagonist) on expression of mephedrone-induced conditioned place preference (CPP) in rats; (2) evaluation of glutamate concentrations in the hippocampus of rats following 6 days of mephedrone administration, using in vivo magnetic resonance spectroscopy (MRS); and (3) determination of glutamate levels in the hippocampus of rats treated with mephedrone and subjected to MRS, using ion-exchange chromatography. In the presented research, we confirmed priorly reported mephedrone-induced rewarding effects in the CPP paradigm and showed that memantine (5 mg/kg) was able to reverse the expression of this effect. MRS study showed that subchronic mephedrone administration increased glutamate level in the hippocampus when measured in vivo 24 h (5 mg/kg, 10 mg/kg and 20 mg/kg) and 2 weeks (5 mg/kg and 20 mg/kg) after last injection. Ex vivo chromatographic analysis did not show significant changes in hippocampal glutamate concentrations; however, it showed similar results as obtained in the MRS study proving its validity. Taken together, the presented study provides new insight into glutamatergic involvement in rewarding properties of mephedrone.

Zebrafish and mouse models for anxiety evaluation - A comparative study with xanthotoxin as a model compound.

The ever-present trend for introducing new drugs of natural origin with anxiolytic properties meets healthcare needs of the population, whose almost 34 % struggles with anxiety-related disorders. At the same time, animal assays that could serve as fast and reliable models of anxiety-like behaviors are of great interest to scientists. Thus, the aim of the present study was to evaluate the utility of the zebrafish model for assessing the influence of natural compounds on anxiety in comparison with the well-known mouse model. Secondly, this study is also the first attempt to investigate the influence of a naturally occurring metabolite, i.e. xanthotoxin, on anxiety-related behaviors. The anxiety level in zebrafish was assessed by measuring thigmotaxis, a specific animal behavior to move closer to the boundaries of an open area and to avoid its center. In mice, the elevated plus maze test was chosen to study anxiety-related behaviors. Our results show that xanthotoxin exerted reversed U-shape effect on anxiety behaviors in both models. The similar pattern of xanthotoxin-induced anxiety-related behaviors in both animal models not only confirms the pharmacological properties of xanthotoxin but also proves the predictive power of the zebrafish model for behavioral research of natural compounds.