Abstract: DESCRIPTION (provided by applicant): Marijuana dependence and withdrawal are increasingly reported, yet adequate treatment options have not been identified. This R01 will expand upon a compelling line of investigation demonstrating that drug discrimination can be used to quantify the behavioral effects of the cannabinoid antagonist SR 141716A in monkeys receiving delta9-THC. Dependence will be established with delta9-THC and withdrawal characterized by directly observable signs, drug discrimination, and neuroendocrine response. Aim 1 will examine a role for cannabinoid and monoamines in the discriminative stimulus effects of delta9-THC withdrawal, induced both by SR 141716A and by temporary discontinuation of A9-THC treatment. Studies will examine a role for cannabinoids and monoamines in the directly observable signs of withdrawal induced by SR 141716A. Collectively, studies in Aim 1 will examine the relative contribution of cannabinoids and monoamines across different indices of withdrawal and will test the hypothesis that monoamines attenuate discriminative measures and not other indices of withdrawal. Aim 2 will examine a role for hypothalamic pituitary adrenal activity (indexed by cortisol and ACTH) in the acute and chronic effects of delta9-THC and will examine a role for CRH antagonists in modifying delta9-THC withdrawal. Drug discrimination will be used in Aim 3 to characterize the subjective effects of inhaled marijuana smoke which represents the predominant route of administration in humans. Studies will examine modification of the discriminative stimulus effects of inhaled marijuana smoke by cannabidiol and cannabinol and blockade of these discriminative stimulus effects by cannabinoid antagonists. A likely future direction will be to characterize dependence that occurs to inhaled marijuana smoke. This application will address a need for understanding the behavioral, pharmacologic, and neuroendocrine determinants of cannabinoid dependence and will examine test compounds for modification of cannabinoid withdrawal and acute marijuana action.

Thesaurus Terms:
Cannabis, amine, behavioral medicine, cannabinoid, drug abuse chemotherapy, drug addiction antagonist, drug withdrawal, psychopharmacology
adrenocorticotropic hormone, corticotropin releasing factor, cortisol, drug administration rate /duration, hormone inhibitor, hypothalamic pituitary adrenal axis, inhalation drug abuse, inhalation drug administration, placebo, substance abuse related behavior
Macaca mulatta, behavioral /social science research tag

Institution: UNIVERSITY OF TEXAS HLTH SCI CTR SAN ANT
SAN ANTONIO, TX 78229
Fiscal Year: 2006
Department: PHARMACOLOGY
Project Start: 30-SEP-2004
Project End: 31-AUG-2009
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
IRG: ZDA1

Characterization of Cannabinoid Agonists and Apparent pA2 Analysis of Cannabinoid Antagonists in Rhesus Monkeys Discriminating 9-Tetrahydrocannabinol

Lance R. McMahon

Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas

Received May 8, 2006; accepted August 28, 2006.
JPET 319:1211-1218, 2006

Subjects. Two female and two male rhesus monkeys (Macaca mulatta), housed individually on a 14-/10-h light/dark schedule, were maintained at 95% free-feeding weight (range, 5.7–7.9 kg) with a diet comprising primate chow (High Protein Monkey Diet; Harlan Teklad, Madison, WI), fresh fruit, and peanuts, and were provided water in the home cage. All monkeys were pharmacologically and experimentally naive before being trained to discriminate 0.1 mg/kg i.v. 9-THC (McMahon et al., 2005 ). Monkeys were maintained in accordance with the Institutional Animal Care and Use Committee, The University of Texas Health Science Center at San Antonio, and the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996 ).

Surgery. Monkeys were prepared with chronic in-dwelling catheters (heparin-coated polyurethane; o.d., 1.68 mm; i.d., 1.02 mm; Instech Solomon, Plymouth Meeting, PA). Upon anesthesia with ketamine (10 mg/kg i.m.) and isoflurane (1.5–3.0%, inhaled via face mask), a catheter was inserted and advanced 5 cm into a subclavian vein to the level of the vena cava or into a femoral vein. Suture silk (coated Vicryl; Ethicon Inc., Somerville, NJ) was used to anchor the catheter to the vessel and to ligate the section of the vessel proximal to the catheter insertion. The other end of the catheter passed s.c. to the midscapular region of the back, where it was attached to a vascular access port (Mida-cbas-c50; Instech Solomon).

Apparatus. During experimental sessions, monkeys were seated in chairs (model R001; Primate Products, Miami, FL) that provided restraint and were placed in ventilated, sound-attenuating chambers equipped with two response levers and stimulus lights. Feet were placed in shoes containing brass electrodes through which a brief electric stimulus (3 mA, 250 ms) could be delivered from an A/C generator. An interface (MedAssociates, St. Albans, VT) connected the chambers to a computer, which controlled and recorded experimental events.

Discrimination Procedure. Three monkeys had been trained to discriminate 9-THC (0.1 mg/kg i.v.) from vehicle (McMahon et al., 2005 ), and a fourth monkey was trained for the current study. Monkeys responded under a fixed ratio 5 (FR5) schedule of stimulus-shock termination in a multiple-cycle procedure. Each cycle began with a 15-min timeout, during which responses had no programmed consequence, followed by a 5-min response period, during which illumination of red lights (one positioned above each of the two levers) signaled a pending electric stimulus (every 40 s). The correct lever was determined by an infusion of vehicle or 9-THC before the session; determination of correct levers (e.g., left, vehicle; right, 9-THC) varied among monkeys and remained the same for an individual throughout the study. Five consecutive responses on the correct lever extinguished the red lights and postponed the schedule for 30 s. Responding on the incorrect lever reset the response requirement on the correct lever. Response periods ended after 5 min or the delivery of four electric stimuli, whichever occurred first.