As 2-AG undergoes isomerization to 1-AG arising from acyl group migration during sample workup 56 , the peak areas of both isomers were combined for 2-AG quantitation. Keeping this limitation in consideration, however, this basic study using mice is still informative as there are similarities in many aspects between mice and humans 48 , and information generated from animal studies will doubtlessly shed light on mechanism of synthetic cannabinoids.
JWH is a potent non-selective cannabinoid receptor agonist that was found in the first generation of spice products 1 , 2. For these reasons, coupled with the rapidly growing use and dangerous adverse effect profile of K2 products, it is critical that clinicians and basic scientists obtain a strong mechanistic understanding of the cannabinoid constituents in K2, so these drugs can be identified, regulated and therapies designed to address the adverse effects. Temperature and locomotor activity data were collected at regular 5-min intervals and processed simultaneously by the Vital View data acquisition system Mini Mitter Co. Despite the continued misuse of synthetic cannabinoids by humans, little is known about the functional consequences of repeated administration of JWH or related substances found in spice products. The apparently contradictory findings between our results and those of Tai et al.
Fatty acid amide hydrolase FAAH is an intracellular membrane-bound enzyme that degrades fatty acid amides and it is responsible for inactivation of AEA by catalyzing its breakdown to arachidonic acid AA and ethanolamine 36 , Typical adverse effects arising from synthetic cannabinoid use are tachycardia, agitation, and nausea; more serious adverse events include seizures, acute kidney injury, new onset psychosis, severe cardiac crisis, and death 27 , Likewise, acute JWH is reported to induce downregulation of CB1 receptors in cultured neurons by a mechanism involving rapid receptor internalization Vehicle administration did not significantly alter summed catalepsy scores on day 1 of treatment, and there was no change in scores for vehicle-treated rats over the 7-day treatment regimen. A recent report, employing crude human liver microsomes, suggests that specific isoforms of the cytochromes P system are essential for metabolism of JWH to various mono- and dihydroxylated metabolites  , including the metabolites examined in the present study. Cannabinoids have therapeutic potential in several diseases including cancer, pain, and stress
We also administered a submaximal dose of 0. However, further studies are necessary to elucidate more details of the underlying molecular mechanisms. Synthetic cannabinoid tolerance in humans could potentially lead to dose escalation, which could be more dangerous with synthetic cannabinoids when compared to marijuana. In the present study, we aimed to investigate the effect of acute administration of JWH, a synthetic cannabinoid, on the hippocampal metabolome to assess biochemical changes in vivo.
Total binding was defined as the amount of radioactivity observed when 0. Therefore, this study also provides invaluable information to develop safer therapeutics against several brain disorders. After acute serotonergic drug challenge, body temperatures were measured using the handheld reader at 0. To the best of our knowledge, this is the first report to evaluate the metabolomic changes in mice after JWH exposure.
Since vehicle administration did not change catalepsy scores over the course of treatment, we compared the effects of JWH treatment across days to the effects of vehicle treatment on day 1. Higher immobile time usually reflects a depressive-like status, but has also been demonstrated to indicate some types of memory impairment Discussion The psychiatric literature supports a strong relationship between heavy cannabis use and risk for subsequent psychosis and schizophrenia The test trial was performed 1 h after the training trial. Temperature and locomotor activity data were collected at regular 5-min intervals and processed simultaneously by the Vital View data acquisition system Mini Mitter Co.
The right panel of Figure 3 depicts the effects of 1. Metabolomics, the comprehensive study of global metabolites, is a highly sensitive and powerful tool for systemic toxicological approach 14 , 15 , and may provide comprehensive information on the dynamic changes induced by JWH
The time spent exploring each object and the total amount of time spent exploring both objects were recorded. Our results indicate that memory impairment following JWH administration may be explained by the elevation of endocannabinoids and the suppression of BDNF in the hippocampus.
Rats were assigned a catalepsy score based on three behaviors: immobility absence of movement , flattened body posture, and splayed limbs limbs spread out away from the center of the body. When administered to mice, JWH produces effects consistent with other CB1 receptor agonists, including hypothermia, analgesia, reduced motor activity, and catalepsy 5 , 6. Therefore, we aimed to investigate the effects of JWH on the hippocampal metabolome of mice to elucidate the potential mechanism of the impairment in learning and memory. Therefore, the impairment on learning and memory elicited by JWH has so far been attributed to effects on this specific brain region. Altogether, the presence of parent synthetic cannabinoid molecules within a single dose of K2, combined with the respective active metabolites produced, could conceivably act in concert to produce the dynamic range of effects observed following use of various K2 preparations.
Additionally, we showed that JWH causes a reduction in the levels of brain-derived neurotrophic factor BDNF , which is known to modulate synaptic plasticity and adaptive processes underlying learning and memory. Body temperature and catalepsy scores were determined at 1, 2, and 4 h post-injection each day.