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Generally, neurotoxicity of a substance is evaluated by animal behavioral aspects, i. However, because of their subjective properties, it is necessary to set up a more objective automated measurement to determine their neurotoxicity. We also examined their neurotoxicity using brain samples through histopathological diagnose, especially in the nucleus accumbens core region. The animals received solid diet and tap water ad libitum.
We performed all experiments between and The FOB test was performed using published procedures Moser et al. Briefly, the FOB test was comprised of several behavioral changes including catalepsy, traction, tremor, convulsion, exopthalmos, piloerection, salivation, lacrimation, diarrhea, skin coloration, pinna reflex, righting reflex, and death.
Two different observers checked each items described above simultaneously to prevent arbitrariness. The observational check lists and measurements are summarized in Table 1. The motor function changes were evaluated through two test methods: locomotor activity and rota-rod test. The test apparatus for the locomotor activity test was designed to measure locomotor activity automatically using UV system AM , Benwick Electronics, Benwick, UK when experimental animals moved in the chamber.
The locomotor activity of the mice was measured 30 min and 2 hrs after the last substance administration. To evaluate whether the changes of coordinative functions by CNS damages were due to test substances, rota-rod test was performed using Rota-rod apparatus Daejong, Seoul, Korea.
Mice that remained their position on the running apparatus at 10 rpm for at least 2 min were selected for further evaluation. It was considered as coordination disturbance when mice fell from the test apparatus within 2 min. Morris water maze test was performed to evaluate the changes of learning and memory function through administration of the test substances.
Two sets of experiment were performed. In test 1, the substances including vehicle and methamphetamine were injected through i. After the last administration, the first trial was performed.
The same procedure was then applied to the mice once every day for 5 days. Test 2 was performed everyday for 5 days after consecutive administration of the substances, including negative vehicle and positive methamphetamine controls. A platform 20 cm height, 10 cm diameter was placed at NW section. The movement of experimental mice was measured using Smart version 2. Memory acquisition and memory retention was evaluated separately. Memory acquisition was measured through escape latency.
Memory retention was measured after the memory acquisition was tested as a probe trial. Brain samples were prepared from the mice after the last administration of test substances. All tested groups consisted of 12 mice each. Some mice showed abnormal behaviors catalepsy, loss of traction, convulsion right after the administration of the tested substances.
Most of the abnormalities were normalized in synthetic cannabinoid treated mice although those abnormal behaviors remained in methamphetamine treated animals after 2 hr of administration. One mouse treated with 0. However, the death seemed to due to causes other than the effect of the substance Table 2. All groups treated with tested synthetic cannabinoids showed decreased weight gain rate in a dose-dependent manner. Neuroscience 91 2 — Biol Psychiatry 64 2 — Drug Alcohol Depend 60 2 Neuropsychopharmacology 32 10 — Addiction 10 — Article Google Scholar.
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The Lancet Hall W, Solowij N Adverse effects of cannabis. Lancet — Prog Neuropsychopharmacol Biol Psychiatry 35 1 — Drug testing and analysis 8 7 — Addiction 96 7 — Schizophr Bull 31 3 — Proceedings of the national Academy of sciences 87 5 — Drug Test Anal 5 — Addiction 3 — Clin Toxicol 56 6 — J Pharmacol Exp Ther 2 — Soc Psychiatry Psychiatr Epidemiol 39 1 :9— Schizophr Res — Johns A Psychiatric effects of cannabis.
The British Journal of Psychiatry 2 — J Clin Psychopharmacol 31 1 — Prostaglandins Leukot Essent Fatty Acids 66 — Schizophr Bull 46 5 — Lundqvist T Cognitive consequences of cannabis use: comparison with abuse of stimulants and heroin with regard to attention, memory and executive functions.
Pharmacology, biochemistry, and behavior 81 2 — Mackie K Distribution of cannabinoid receptors in the central and peripheral nervous system. In: Cannabinoids. Springer, pp Am J Psychiatry 6 — Medical Cannabis and Cannabinoids 3 1 — Fortschr Neurol Psychiatr 84 3 — Schizophr Res 1 — Rapid Commun Mass Spectrom 26 19 — Forensic Sci Int Human Psychopharmacology: Clinical and Experimental 28 4 — The American journal on addictions 21 3 — Front Psychiatry ARTN Neuropsychopharmacology 31 10 — Psychopharmacology Berl 4 — The World Journal of Biological Psychiatry 11 — Eur Neuropsychopharmacol 24 1 — Prog Neuropsychopharmacol Biol Psychiatry 39 2 — Finally, our data show that rats receiving daily injections of JWH develop profound tolerance to its hypothermic and cataleptic effects, such that these effects are nearly absent after 7 days of treatment.
Typical behavioral responses to DOI administration in rats are wet dog shakes analogous to the head twitch response in mice and back muscle contractions, also known as skin jerks 21 — These responses are accepted as specific indicators of 5-HT 2A receptor activation since the effects are blocked by selective 5-HT 2A receptor antagonists.
We found no significant difference in the number of wet dog shakes or skin jerks induced by DOI between the cannabinoid-treated and vehicle-treated groups at either time point. Our findings differ from those of Hill et al. It is noteworthy that we observed trends for augmented wet dog shakes and attenuated skin jerks in rats exposed to JWH, but these effects did not reach significance, perhaps due to variability in the behavioral data.
We also administered a submaximal dose of 0. Hill et al. This hypothesis was later supported by the work of Franklin et al. It is well known that HU displays a much longer time course of action when compared to other synthetic cannabinoids, including JWH, and may bind pseudo-irreversibly to the CB 1 receptor.
Hruba and McMahon found that rhesus monkeys trained to discriminate THC from vehicle continued to emit drug-appropriate responses for 48 h after administration of HU, while such responses to THC and CP 55, ceased after 5 h. Thus, the discrepancies between our results and those of Hill et al. Our study used a repeated cannabinoid administration paradigm followed by the administration of DOI after 1 and 7 days of withdrawal, so this may help to explain the differences between our results and those of Darmani.
The present findings in rats show that administration of CB 1 agonists causes considerable catalepsy see Figures 1 — 3 , so it seems possible that suppression of motor activity caused by acute cannabinoids could influence subsequent behavioral effects of 5-HT 2A receptor agonists. We purposefully designed our experiments to examine the responsiveness to 5-HT agonists at 1 and 7 days after the acute effects of cannabinoid administration had subsided.
We found a modest yet significant increase in the behavioral and hypothermic effects induced by 8-OH-DPAT in rats receiving repeated JWH treatments when compared to those receiving repeated vehicle treatments.
In a previous study, Hill et al. Both hypothermia and corticosterone release are presumably mediated by 5-HT 1A receptors in the brain 31 , thus Hill et al.
It seems possible that discrepancies between our results and those of Hill et al. On the other hand, Zavitsanou et al. Our data demonstrating an increase in 5-HT 1A receptor sensitivity after exposure to JWH is a unique finding, and its relationship to the development of psychiatric symptoms following cannabinoid exposure warrants further study.
Future research should determine whether 5-HT 1A upregulation occurs after repeated exposure to other synthetic cannabinoids.
Importantly, and in contrast to existing findings using other cannabinoid compounds, our data show that repeated exposure to JWH does not induce robust alterations in 5-HT 2A receptor responsiveness, but increases 5-HT 1A responsiveness. In addition to assessing changes in serotonergic activity after cannabinoid exposure, one of the secondary aims of our study was to examine pharmacological responses to repeated JWH injections. Rats in our study had implantable temperature transponders to facilitate the non-invasive measurement of body temperature.
JWH was shown to dose-dependently cause hypothermia and catalepsy, both of which were reversed by rimonabant see Figure 2. The present data showing acute decreases in body temperature after JWH administration in rats are consistent with previous findings from our laboratory and others, which show dose-related hypothermic effects of JWH as assessed by radiotelemetry or rectal probes to measure core temperatures 33 — As the repeated injection procedure progressed in our study, rats began to develop tolerance to both the hypothermic and cataleptic effects produced by JWH By day 5 of repeated treatments, the effects of JWH became submaximal at all time points, and continued to decrease in the two remaining days.
By day 7 of repeated treatments, the temperature and cataleptic effects JWH were not significantly different from vehicle-treated animals. Previous studies in mice have shown that repeated daily injections of THC or synthetic cannabinoids produce behavioral tolerance due to downregulation and desensitization of CB 1 receptors Likewise, acute JWH is reported to induce downregulation of CB 1 receptors in cultured neurons by a mechanism involving rapid receptor internalization The experiments of Tai et al.
The apparently contradictory findings between our results and those of Tai et al. Tai et al. The development of tolerance to cannabis is well documented, and the demonstration of tolerance to JWH could have important clinical implications 40 , Dose escalation in human THC users is often observed as a means to overcome cannabis tolerance, but this phenomenon likely will not cause acute bodily harm.
By contrast, dose escalation with JWH or other potent synthetic cannabinoids could be more dangerous. 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 , Further research is required to determine if such dose escalation occurs in humans who use synthetic cannabinoids.
To summarize, we found that repeated treatment with the synthetic cannabinoid JWH does not lead to significant changes in 5-HT 2A receptor responsiveness in rats, but produces transient increases in 5-HT 1A receptor responsiveness.
These findings, unlike data generated using other synthetic cannabinoids, do not support the contention that exposure to cannabinoid receptor agonists universally leads to an increase in 5-HT 2A receptor responsiveness, suggesting that alteration of 5-HT 2A neurotransmission may not be responsible for the link between cannabinoid exposure and the subsequent development of psychotic symptoms.
On the other hand, rats in our experiments developed tolerance to both hypothermia and catalepsy produced by JWH after several consecutive days of treatment, findings which differ from prior work in mice suggesting that tolerance only develops to hypothermic effects. Synthetic cannabinoid tolerance in humans could potentially lead to dose escalation, which could be more dangerous with synthetic cannabinoids when compared to marijuana.
JE and MB were responsible for experiment design, statistical analysis, and manuscript writing. JE collected the data. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. J Mass Spectrom —7. Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds.
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