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A separate cohort of rats was given 0. Figure 5. Summed scores for serotonin syndrome behaviors and mean temperature recordings induced by a subcutaneous challenge injection of 0. Behavioral scores and core temperatures were recorded at 0, 0. Post hoc tests revealed that temperature was significantly decreased in the JWH group compared to the vehicle group at 1.

Figure 6. Time-course of core body temperature changes induced by a subcutaneous challenge injection of 0. Temperatures were recorded at 0, 0. The psychiatric literature supports a strong relationship between heavy cannabis use and risk for subsequent psychosis and schizophrenia In addition, misuse of synthetic cannabinoids such as JWH and its analogs is associated with induction of more severe psychotic symptoms when compared to the effects of marijuana 26 , The aim of the present study was to use the popular synthetic cannabinoid JWH to further explore the relationship between repeated cannabinoid exposure and serotonergic dysregulation.

JWH is a potent non-selective cannabinoid receptor agonist that was found in the first generation of spice products 1 , 2.

The present experiments yielded three primary findings. First, in contrast to the results of others [e. Second, we found a modest and significant enhancement of sensitivity to behavioral and hypothermic effects induced by 8-OH-DPAT in rats exposed to repeated injections of JWH 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.

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