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Novel synthetic cannabinoids are appearing in recreational drug markets worldwide. Clinicians, toxicologists, and policymakers who monitor public health need to be informed about the pharmacological characterization of these upcoming drugs. The synthetic cannabinoid (1-(5-Fluoropentyl)-1H-indol-3-yl)(1-naphthyl)methanone (AM-2201) was initially developed to study the endocannabinoid system.
Here we measured the pharmacodynamic effects of AM-2201 in rats, and simultaneously determined plasma pharmacokinetics for the parent drug and its metabolites. Male Sprague-Dawley rats were fitted with surgically implanted temperature transponders and indwelling jugular catheters under pentobarbital anesthesia. One week later, rats received subcutaneous injection of AM-2201 (0.1, 0.3, and 1.0 mg/kg) or its vehicle, and serial blood specimens were withdrawn via catheters.
Materials and Methods
Cayman Chemical (Ann Arbor, MI) provided analytical standards that were stored at −20°C until use. The NIDA (Rockville, MD) Drug Supply Program provided AM-2201 for administration to rats. Water, methanol, and formic acid (Optima LC/MS) were obtained from Thermo Fisher Scientific (Waltham, MA). Tween 80, dimethyl sulfoxide, sodium metabisulfite, and tert-butyl methyl ether were provided by Sigma-Aldrich (St. Louis, MO), and sterile 0.9% NaCl (saline) by Hospira, Inc (Lake Forest, IL). Thomas Scientific provided heparin saline (1000 IU/ml) and sodium pentobarbital to the NIDA Intramural Research Program Pharmacy (Baltimore, MD).
The time-course effects for body temperature and catalepsy after subcutaneous AM-2201 administration (0.1, 0.3, and 1.0 mg/kg) are depicted in Fig. 2. Temperature was significantly affected by AM-2201 dose (F3,16 = 13.96, P < 0.0001) and time (F7,112 = 65.00, P < 0.0001), with a significant dose × time interaction (F21,112 = 14.18, P < 0.0001).
The rats were anesthetized with sodium pentobarbital (60 mg/kg, i.p.),and catheters were constructed from Silastic (Dow Corning, Midland, MI). As previously described (Concheiro et al., 2014), vinyl tubing was surgically implanted into the right jugular vein. Once the catheter had reached the atrium, the distal vinyl end was plugged with a metal stylet. While still under anesthesia, a temperature transponder (model IPTT-300; Bio Medic Data Systems, Seaford, DE) was inserted after catheter implantation (Elmore and Baumann, 2018). Temperature transponders transmit radio frequency signals via a handheld reader system (DAS-7006/7r; Bio Medic Data Systems). A transponder is cylindrical in shape, measuring 14 mm by 2 mm. A prepackaged sterile guide needle delivery system delivered them along the back to the shoulder blades. After surgery, rats were housed in single rooms for at least 1 week to recover.
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