Abscissa: cumulative dose, log scale. Subjects were maintained in accordance with guidelines provided by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animals Resources, National Institutes of Health. Apparatus. During experimental sessions, subjects sat in customized Plexiglas chairs (based on Kelleher and Morse, 1968) in ventilated chambers that were provided with white noise to mask extraneous sounds. While seated, monkeys faced a panel made up of colored Ro 28-1675 stimulus lights that could be illuminated to serve as visual stimuli and a response lever that protruded through the front panel of the chair and was easily accessible to the subject. Each lever-press with a pressure 0.2 N produced an audible click and was recorded as Ro 28-1675 a response. A shaved portion of the seated monkeys tail was comfortably secured under brass electrodes by a small stock and was coated with electrode paste to ensure a low-resistance electrical contact between electrodes and tail. Brief, low-intensity current (200 ms; 3 mA) could be programmed for delivery Ro 28-1675 to the tail from a 50-Hz transformer. Stimulus events were programmed and data were recorded using a commercially available interface and computer program (MED-PC, MedState Notation; Med Associates Inc., St. Albans, VT). Behavioral Procedure. Subjects responded under a 30-response fixed ratio (FR30) schedule of stimulus-shock termination (Morse and Kelleher, 1966; Bergman et al., 1995). Under terminal contingencies, daily sessions began with illumination of the visual stimuli on the front panel of the chair; current was scheduled for delivery to the monkeys tail every 20-seconds during the time that stimulus lights were illuminated. Under this schedule, the completion of 30 consecutive responses within the 20-s interval extinguished stimulus lights and the associated program of current delivery, and initiated a 10-second timeout (TO10) period during which all lights in the chamber were off and lever-presses had no scheduled consequences. After the TO10, the visual stimuli were re-illuminated and the schedule contingencies were again in effect. Daily sessions comprised five successive components. Each component Ro 28-1675 consisted of a 10-minute timeout period during which no stimuli were presented and lever-press responses had no scheduled consequences followed by a 3-minute response period during which the FR30, 10 schedule of stimulus-shock termination was in effect. Under these conditions, each component terminated after the 3-minute response period or the fourth delivery of current to the monkeys tail, whichever occurred first. Drugs. CB1 ligands, except 9-THC and rimonabant, were synthesized at the Center for Drug Discovery (Northeastern University, Boston, MA). These included the novel CB1 agonists Ro 28-1675 AM411 (Lu et al., 2005) and AM4054 (Delatte et al., 2008; G. A. Thakur and A. Makriyannis, manuscript in preparation), the stable analog of the endocannabinoid anandamide, methanandamide, and the CB1 neutral antagonist AM4113 (Bergman et al., 2008; Sink et al., 2008). The CB1 agonist 9-THC and the inverse agonist/antagonist rimonabant (SR141716A) were obtained from the National Institute of Drug Abuse (Bethesda, MD). WIN55,212.2, methamphetamine, “type”:”entrez-protein”,”attrs”:”text”:”SKF82958″,”term_id”:”1156217255″,”term_text”:”SKF82958″SKF82958, SCH23390, test for post hoc analysis. In all cases, significance was defined at the 95% level of confidence ( 0.05). Open in a separate windows Fig. 1. Effects of the cannabinoid CB1 agonist AM411 in squirrel monkeys responding under a FR30 schedule of stimulus-shock termination before and during chronic treatment with AM411 (1.0 mg/kg per day, i.m.). Abscissa: prechronic vehicle, 0.32, and 1.0 mg/kg AM411, and days of chronic treatment with Cd24a AM411 (0.32 mg/kg: filled circles; 1.0 mg/kg: open triangles); ordinates: rate of responding as a percentage of control rates. Points are means ( S.E.M.) based on data from three or four monkeys. Open circle above prechronic V represents mean control values (100% average S.D.) over the five sequential components of the session. Dotted line represents mean 100% averaged across session components. Capped solid lines indicate treatment dose of AM411 in mg/kg per day. Between days 40.
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