Behavioral and Pharmacokinetic Profile of Indole-Derived Synthetic Cannabinoids JWH-073 and JWH-210 as Compared to the Phytocannabinoid Δ9-THC in Rats

Synthetic cannabinoid compounds are marketed as “legal” marijuana substitutes, even though little is known about their behavioral effects in relation to their pharmacokinetic profiles. Therefore, in the present study we assessed the behavioral effects of systemic treatment with the two synthetic cannabinoids JWH-073 and JWH-210 and the phytocannabinoid Δ9-THC on locomotor activity, anxiety-like phenotype (in the open field) and sensorimotor gating (measured as prepulse inhibition of the acoustic startle response, PPI), in relation to cannabinoid serum levels. Wistar rats were injected subcutaneously (sc.) with JWH-073 (0.1, 0.5, or 5 mg/kg), JWH-210 (0.1, 0.5, or 5 mg/kg), Δ9-THC (1 or 3 mg/kg) or vehicle (oleum helanti) in a volume of 0.5 ml/kg and tested in the open field and PPI. Although JWH-073, JWH-210, Δ9-THC (and its metabolites) were confirmed in serum, effects on sensorimotor gating were absent, and locomotor activity was only partially affected. Δ9-THC (3 mg/kg) elicited an anxiolytic-like effect as suggested by the increased time spent in the center of the open field (p < 0.05). Our results further support the potential anxiolytic-like effect of pharmacological modulation of the endocannabinoid system

Personality of common vole (\kur{Microtus arvalis}): behaviour in two behavioural tests.

The aim of the study was to examine individual differences in behaviour of common voles by the comparison of the results of two behavioural experiments {--} Open Field test and Radial Arm Maze test. Also the usability of the experimental device (RAM) as the aparatur for the study of animal personality was studied

Underlying causes and stability of intraspecific variation in behaviour of microtine rodents

Two crucial issues related to personality in non-human animals have been identified: firstly, the underlying 'causes' of personality and,secondly, the stability of behavioural repertoires (essentially the defining feature of personality) have both been the subject of long-standing debate. This thesis is focused on investigating stable inter- and intra- individual differences in the behaviour of wildcaught bank voles, Myodes glareolus (that varied according to mtDNA type), and in common voles, Microtus arvalis. The first study, using wild voles, revealed empirical evidence about the effects of sex and mtDNA type on individual differences in basal metabolic rate and in behaviour in the open field which provides measures of approach and avoidance (here, generically termed 'proactivity') and which relate to several theoretical conceptualisations of animal personality. The second study demonstrated the presence of stable individual differences in reactions to exposure to open field test and radial maze in common voles, which were shaped by the social environment and in turn, related to cognitive efficiency. The same species was used in the third study documenting the distinct temporal patterns of behavioural plasticity that manifested over repeated exposures to the open field test. We suggest that this distinct temporal patterning in habituation, whilst it varied over time, was predictable in nature and therefore a reflection of a stable underlying personality. To conclude, this body of thesis work draws together a number of influencing factors, and considers their contribution to animal personality

Early social environment affects development of personality traits in common vole \kur{(Microtus arvalis).}

The study investigated the effect of non-genetic social factors (represented by litter size, litter sex composition, and affinity to age cohort) on the development of consistent inter-specific differences in reaction to novelty in common voles (Microtus arvalis). The voles were tested in three behavioural experiments ? Forced Open Filed test (FOF), Unforced Open Field test (UFOF), and Radial-arm maze (RAM). A siginificant impact of compontents of social environment was detected

25CN-NBOMe Metabolites in Rat Urine, Human Liver Microsomes and C. elegans—Structure Determination and Synthesis of the Most Abundant Metabolites

N-Benzylphenethylamines are novel psychedelic substances increasingly used for research, diagnostic, or recreational purposes. To date, only a few metabolism studies have been conducted for N-2-methoxybenzylated compounds (NBOMes). Thus, the available 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe) metabolism data are limited. Herein, we investigated the metabolic profile of 25CN-NBOMe in vivo in rats and in vitro in Cunninghamella elegans (C. elegans) mycelium and human liver microsomes. Phase I and phase II metabolites were first detected in an untargeted screening, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) identification of the most abundant metabolites by comparison with in-house synthesized reference materials. The major metabolic pathways described within this study (mono- and bis-O-demethylation, hydroxylation at different positions, and combinations thereof, followed by the glucuronidation, sulfation, and/or N-acetylation of primary metabolites) generally correspond to the results of previously reported metabolism of several other NBOMes. The cyano functional group was either hydrolyzed to the respective amide or carboxylic acid or remained untouched. Differences between species should be taken into account in studies of the metabolism of novel substances

2C-B-Fly-NBOMe Metabolites in Rat Urine, Human Liver Microsomes and C. elegans: Confirmation with Synthesized Analytical Standards

Compounds from the N-benzylphenethylamine (NBPEA) class of novel psychoactive substances are being increasingly utilized in neurobiological and clinical research, as diagnostic tools, or for recreational purposes. To understand the pharmacology, safety, or potential toxicity of these substances, elucidating their metabolic fate is therefore of the utmost interest. Several studies on NBPEA metabolism have emerged, but scarce information about substances with a tetrahydrobenzodifuran (“Fly”) moiety is available. Here, we investigated the metabolism of 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran-4-yl)-N-(2-methoxybenzyl)ethan-1-amine (2C-B-Fly-NBOMe) in three different systems: isolated human liver microsomes, Cunninghamella elegans mycelium, and in rats in vivo. Phase I and II metabolites of 2C-B-Fly-NBOMe were first detected in an untargeted screening and identified by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Several hypothesized metabolites were then synthesized as reference standards; knowledge of their fragmentation patterns was utilized for confirmation or tentative identification of isomers. Altogether, thirty-five phase I and nine phase II 2C-B-Fly-NBOMe metabolites were detected. Major detected metabolic pathways were mono- and poly-hydroxylation, O-demethylation, oxidative debromination, and to a lesser extent also N-demethoxybenzylation, followed by glucuronidation and/or N-acetylation. Differences were observed for the three used media. The highest number of metabolites and at highest concentration were found in human liver microsomes. In vivo metabolites detected from rat urine included two poly-hydroxylated metabolites found only in this media. Mycelium matrix contained several dehydrogenated, N-oxygenated, and dibrominated metabolites