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JWH-018 is a synthetic cannabinoid found in several versions of the herbal mixture “Spice.” Illicit use of this Spice cannabinoid centers on its psychoactive effects which mimic those of Δ9-THC in cannabis. While considerably more potent than similar amounts of cannabis, JWH-018 also presents significant challenges for detection by typical Δ9-THC testing assays.

In July, 2009, the US Drug Enforcement Agency (DEA) listed JWH-018 on its Drugs and Chemicals of Concern list. In addition to reported seizures of Spice in Ohio and Florida, several states have passed legislative action restricting the sale or possession of JWH-018 including Alabama, Arkansas, Georgia, Kansas, Kentucky, North Dakota, and Tennessee.

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Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) is a synthetic compound found in psychoactive “spice” products that activates cannabinoid receptors. Preclinical evidence suggests that exposure to synthetic cannabinoids increases 5-HT2A/2C receptor function in the brain, an effect which might contribute to psychotic symptoms. Here, we hypothesized that repeated exposures to JWH-018 would enhance behavioral responsiveness to the 5-HT2A/2C receptor agonist DOI. Male Sprague-Dawley rats fitted with subcutaneously (sc) temperature transponders received daily injections of JWH-018 (1.0 mg/kg, sc) or its vehicle for seven consecutive days. 

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Body temperature and catalepsy scores were determined at 1, 2, and 4 h post-injection each day. At 1 and 7 days after the final repeated treatment, rats received a challenge injection of either DOI (0.1 mg/kg, sc) or the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, sc), then temperature and behavioral responses were assessed. Behaviors induced by DOI included wet dog shakes and back muscle contractions (i.e., skin jerks), while behaviors induced by 8-OH-DPAT included ambulation, forepaw treading, and flat body posture. On the first day of repeated treatment, JWH-018 produced robust hypothermia and catalepsy which lasted up to 4 h, and these effects were significantly blunted by day 7 of treatment. Repeated exposure to JWH-018 did not affect behaviors induced by DOI, but behavioral and hypothermic responses induced by 8-OH-DPAT were significantly augmented 1 day after cessation of JWH-018 treatment. Collectively, our findings show that repeated treatment with JWH-018 produces tolerance to its hypothermic and cataleptic effects, which is accompanied by transient enhancement of 5-HT1A receptor sensitivity in vivo.

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Introduction

Synthetic cannabinoids are novel psychoactive substances with pharmacological similarity to the phytocannabinoid Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana. Over the last decade, herbal smoking blends consisting of plant material laced with synthetic cannabinoids (i.e., “spice” products) have emerged in the recreational drug marketplace. Analytical investigations of the first spice products revealed that a primary psychoactive component was naphthalen-1-yl-(1-pentylindol-3-yl)methanone, also known as JWH-018 (1, 2). JWH-018 and many of its structural analogs were found in spice products during 2010 through 2013, and JWH-018 is still present on the street today (3, 4). JWH-018 is a potent agonist at cannabinoid type-1 (CB1) and cannabinoid type-2 (CB2) receptors, which displays at least threefold higher binding affinity than THC at both receptors (5, 6). When administered to mice, JWH-018 produces effects consistent with other CB1 receptor agonists, including hypothermia, analgesia, reduced motor activity, and catalepsy (5, 6). In drug discrimination studies, JWH-018 fully substitutes for the THC stimulus cue in both mice and rats Buy jwh-018 powder online with discreet delivery

Several lines of clinical evidence support a relationship between heavy cannabis use and risk for development of psychosis and schizophrenia (10–13). Although the precise underpinnings of schizophrenia are not fully understood, dysregulation of brain serotonin (5-HT) systems has been implicated in certain psychotic symptoms, such as paranoia and hallucinations (14–16). Preclinical studies in rodents show that exposure to CB1 receptor agonists can influence 5-HT receptor responsiveness in vivo. For example, Darmani reported that acute pretreatment with various cannabinoids, including THC and the potent cannabinoid receptor agonist (6aR,10aR)-9-(hydroxymethyl)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6H,6aH,7H,10H,10aH-benzo[c]isochromen-1-ol (HU-210), inhibits behavioral effects of the 5-HT2A/2C agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) in mice (17). By contrast, Hill et al. found that repeated treatment with HU-210 for 12 days enhances wet dog shakes induced by DOI in rats (18). Franklin et al. found that 7-day exposure to the cannabinoid agonist 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP 55,940) enhances cortisoterone release induced by DOI in rats, and this effect is accompanied by upregulation of 5-HT2A receptors in the hypothalamus 

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Recent evidence suggests a direct interaction between CB1 and 5-HT2A receptors in rat brain. In particular, Viñals et al. showed that CB1 and 5-HT2A receptor heteromers are present in hippocampus and other brain regions related to memory formation, and these heteromers are necessary for the amnesic effects of THC, but not its analgesic effects (20).

Despite the continued misuse of synthetic cannabinoids by humans, little is known about the functional consequences of repeated administration of JWH-018 or related substances found in spice products. Given the emerging evidence for interactions between cannabinoid and 5-HT systems in the brain, we sought to determine the effects of repeated treatment with JWH-018 on the behavioral responsiveness to selective 5-HT receptor agonists. Specifically, male Sprague-Dawley rats were treated for seven consecutive days with JWH-018, then challenged with DOI or the 5-HT1A receptor agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) at 1 day and 7 days after the last JWH-018 treatment. Body temperatures and catalepsy scores were determined during the repeated dosing regimen of JWH-018, while body temperatures and agonist-induced behaviors were measured following challenge doses of 5-HT drugs. We hypothesized that repeated exposure to JWH-018 would enhance subsequent behavioral responsiveness to DOI in rats [e.g., see Ref. (18)]. Such increases in 5-HT2A/2C activity produced by cannabinoid exposure could contribute to adverse psychiatric symptoms associated with cannabinoid use.

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Materials and Methods

Drugs and Reagents

Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) was obtained from Cayman Chemical (Ann Arbor, MI, USA). (−)-2,5-Dimethoxy-4-iodoamphetamine HCl (DOI) and (+)-8- hydroxy-2-(dipropylamino)tetralin HBr (8-OH-DPAT) were obtained from Sigma Aldrich (St. Louis, MO, USA). 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide HCl (rimonabant) was obtained from the pharmacy at the National Institute on Drug Abuse (NIDA), Intramural Research Program (IRP). JWH-018 and rimonabant were dissolved into a 1:1:18 mix of dimethyl sulfoxide:Tween 80:sterile saline, whereas other drugs were dissolved in sterile saline. All injections were administered at a volume of 1.0 mL/kg.

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Animals and Surgery

Male Sprague-Dawley rats (Envigo, Frederick, MD, USA) weighing 250–300 g were double-housed (lights on: 7:00 a.m.–7:00 p.m.) under conditions of controlled temperature (22 ± 2°C) and humidity (45 ± 5%) with free access to food and water. Experiments were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Vivarium facilities were fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care, and study procedures were approved by the NIDA IRP Animal Care and Use Committee. After 2 weeks of acclimation to the vivarium, rats were subjected to surgical procedures and subsequently used for experiments. Rats were rapidly anesthetized with isoflurane using a drop jar which contained a raised floor above a gauze pad saturated with 5 mL of isoflurane. Once fully anesthetized, each rat received a surgically implanted IPTT-300 transponder (Bio Medic Data Systems, Seaford, DE, USA) to facilitate the non-invasive measurement of body temperature via a portable radio frequency reader system (handheld reader). The transponders were 14 mm × 2 mm cylinders implanted subcutaneously (sc) posterior to the shoulder blades via a sterile guide needle. Animals were individually housed postoperatively and allowed 7–10 days for recovery.

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Acute JWH-018 Administration and Rimonabant Antagonism

As a first step in our study, we examined the dose–response effects of acute JWH-018 administration in a cohort of 12 rats. Rats were tested once per week for three consecutive weeks. On test day, rats were moved to the testing room in their home cages and given 1 h to acclimate. Feeding trays were removed, and wire lids were placed atop the cages. Rats received sc injections of JWH-018 (0.1, 0.3, or 1.0 mg/kg) or its vehicle. Immediately before injection, and at various times thereafter (0.25, 0.5, 0.75, 1, 1.5, 2, and 4 h post-injection), body temperature was measured using the handheld reader, and animals were observed for 90 s to assess behaviors. 

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Observers were not blind to the drug treatment condition. 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). Each behavior was given a numerical score of 1 for “behavior absent,” 2 for “behavior present,” or 3 for “behavior continuous/intense”; the three scores were summed to provide a single value ranging from 3 to 9 at each time point.

Once dose–response experiments were completed, we next tested the effect of pretreatment with the CB1 receptor antagonist rimonabant on the responses induced by JWH-018 in a cohort of 12 rats. Rats were tested once per week for three consecutive weeks. Rats were pretreated with either 1.0 mg/kg of the CB1 receptor antagonist rimonabant or its vehicle 30 min before injection with either 1.0 mg/kg JWH-018 or its vehicle. Body temperature measurements and behavior scoring were carried out as described previously for acute dose–response experiments.

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Repeated Dosing with JWH-018

Results from the acute dose–response experiments demonstrated that 1.0 mg/kg JWH-018 produced robust hypothermia and catalepsy. Thus, this dose was used for the repeated injection experiments carried out in a group of 32 rats. The repeated dosing with JWH-018 or its vehicle was carried out in the vivarium. Rats fitted with surgically implanted sc temperature transponders received a single sc injection of either 1.0 mg/kg JWH-018 or its vehicle, and were returned to their home cages. Immediately before injection, and at 1, 2, and 4 h post-injection, body temperature was measured using the handheld reader, and animals were observed for 90 s. During the observation period, behaviors were scored using the catalepsy scale as detailed above in the Section “Acute JWH-018 Administration and Rimonabant Antagonism.” The JWH-018 injection procedure was repeated daily for seven consecutive days.

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Challenge Injection with Serotonergic Agonists

One day after the last repeated treatment with JWH-018 or vehicle (i.e., day 8, or day 1 of withdrawal), rats were moved to the testing room in their home cages and given 1 h to acclimate. Feeding trays were removed, and wire lids were placed atop the cages. One cohort of 16 rats received 0.1 mg/kg of DOI, whereas another cohort of 16 rats received 0.3 mg/kg of 8-OH-DPAT. The doses of DOI and 8-OH-DPAT were based on preliminary dose–response experiments, which identified drug doses evoking robust behavioral changes that were less than maximal (data not shown). The specific non-contingent behaviors induced by DOI were wet dog shakes and back muscle contractions (i.e., skin jerks). Both behaviors are known to be mediated by 5-HT2A receptors in rats (21–23). 

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The numbers of wet dog shakes and skin jerks present during the observation period were tallied. Wet dog shakes were defined as a rapid and sudden rotation of the head, neck, and shoulders from one side to the other, analogous to the way a wet dog may shake to dry itself. Skin jerks were defined as brief paraspinal muscle contractions of the back muscles in a tail to head direction. Specific non-contingent behaviors induced by 8-OH-DPAT were locomotion in the horizontal plane (i.e., ambulation), forepaw treading, and flattened body posture, components of the 5-HT behavioral syndrome known to be mediated by 5-HT1A receptors (24, 25). Possible scores for each behavior were 0 (behavior absent), 1 (behavior present), or 2 (behavior intense or continuous). At the end of the observation period, the scores for the three behaviors were summed to produce a 5-HT syndrome score for each time point.

After acute serotonergic drug challenge, body temperatures were measured using the handheld reader at 0.25, 0.5, 0.75, 1, 1.25, 1.5, and 2 h post-injection, and behavior scores were given at each time point as appropriate for the treatment received (i.e., wet dog shakes and skin jerks for DOI treatment, and serotonin syndrome scores for 8-OH-DPAT treatment). The acute challenge procedure with DOI and 8-OH-DPAT was repeated 1 week after the last repeated JWH-018 treatment.

Data Analysis and Statistics

Data were tabulated, analyzed, and graphically depicted using GraphPad Prism (version 5.02; GraphPad Software, Inc., La Jolla, CA, USA). Time-course temperature data were analyzed using a two-way analysis of variance (treatment × time), followed by a Bonferroni post hoc test to determine significance between group means at specific time points. Mean temperature data from the DOI and 8-OH-DPAT experiments were evaluated by two-tailed t-tests. 

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Catalepsy data from the acute dose–response, rimonabant antagonism and repeated treatments were analyzed by Kruskal–Wallis test (non-parametric), followed by Dunn’s multiple comparison test to determine significance between group means. Summed behavioral score data from the DOI and 8-OH-DPAT challenge experiments were analyzed using a Mann–Whitney test (non-parametric) comparing effects of repeated JWH-018 versus vehicle pretreatments. Statistical analyses were performed on data from all 7 days of the JWH-018 repeated administration experiment, however, Figure 3 only shows data from selected days to make the graphs easier to interpret. p < 0.05 was considered the minimal criterion for statistical significance.

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Results

Effects of Acute JWH-018 Administration

The left panel of Figure 1 illustrates the effect of acute JWH-018 administration on core body temperature in male rats. JWH-018 produced a dose-related change in core temperature (F3,256 = 111.1, p < 0.0001), with significant reductions compared to vehicle control after the 1.0 mg/kg dose at 0.5, 0.75, 1, 1.5, and 2 h post-injection. A maximum decrease of ~3°C was observed at 1 h after the 1.0 mg/kg dose. It is worth noting that 0.1 mg/kg JWH-018 caused a noticeable, albeit non-significant, increase in temperature for the first 2 h, suggesting biphasic dose–response effects of the drug on body temperature. As seen in the right panel of Figure 1, JWH-018 dose-dependently increased the summed catalepsy behavioral score (Kruskal–Wallis statistic 28.53, p < 0.0001). Dunn’s test revealed that significant increases from vehicle control were present following the 1.0 mg/kg dose.

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