The Journal of Neuroscience, September 1, 2002, 22(17):7687-7694

Metabolic Mapping of the Effects of Cocaine during the Initial Phases of Self-Administration in the Nonhuman Primate

Linda J. Porrino, David Lyons, Mack D. Miller, Hilary R. Smith, David P. Friedman, James B. Daunais, and Michael A. Nader

Center for the Neurobiological Investigation of Drug Abuse, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Subjects.
Twelve experimentally naive adult male rhesus monkeys (Macaca mulatta) weighing between 7.6 and 11.5 kg (mean ± SD; 9.5 ± 1.04) at the start of the study served as subjects. Monkeys were individually housed in stainless steel cages with water available ad libitum; animals had physical and visual contact with each other. Their body weights were maintained at ~90-95% of free-feeding weights by banana-flavored pellets earned during the experimental sessions and by supplemental feeding of Lab Diet Monkey Chow (PMI Nutrition International, Brentwood, MO), provided no sooner than 30 min after the session. All procedures were performed in accordance with established practices as described in the National Institutes of Health Guide for Care and Use of Laboratory Animals. In addition, all procedures were reviewed and approved by the Animal Care and Use Committee of Wake Forest University.

Behavioral apparatus.
Cocaine self-administration and food-reinforced responding occurred in ventilated and sound-attenuated operant chambers (1.5 × 0.74 × 0.76 m; MedAssociates, East Fairfield, VT) designed to accommodate a primate chair (model R001; Primate Products, Redwood City, CA). The chamber contained an intelligence panel (48 × 69 cm), located on the right side and consisted of two retractable levers (5-cm-wide) and three stimulus lights. The levers were positioned within easy reach of the monkey sitting in the primate chair. One gram food pellets were delivered from a feeder located on the top of the chamber. For cocaine self-administering animals, a peristaltic infusion pump (7531-10; Cole-Parmer Co., Chicago, IL) delivered drug injections at a rate of ~1 ml/10 sec. Operation of the chambers and data acquisition were accomplished with a Power Macintosh computer system with an interface (MedAssociates).

Surgical procedures.
All monkeys, including controls, were surgically prepared, under sterile conditions, with an indwelling intravenous catheter and vascular access port (model GPV; Access Technologies, Skokie, IL). Monkeys were anesthetized with a combination of ketamine (15 mg/kg, i.m.) and butorphanol (0.03 mg/kg, i.m.), and an incision was made near the femoral vein. After blunt dissection and isolation of the vein, the proximal end of the catheter was inserted into the vein for a distance calculated to terminate in the vena cava. The distal end of the catheter was threaded subcutaneously to an incision made slightly off the midline of the back. The vascular access port was placed within a pocket formed by blunt dissection near the incision. Before each experimental session, the back of the animal was cleaned with 95% ethanol and betadine scrub, and a 22 gauge Huber Point Needle (model PG20-125) was inserted into the port leading to the venous catheter, connecting an infusion pump, containing the cocaine solution, to the catheter. Before the start of the session, the pump was operated for ~3 sec, filling the port with the dose of cocaine that was available during the experimental session. At the end of each session, the port was filled with heparinized saline (100 U/ml) to help prevent clotting. In addition at the time of the venous catheterization, each monkey was implanted with a chronic indwelling catheter into the adjacent femoral artery for collection of timed arterial blood samples during the 2-DG procedure. The surgical procedures were identical to those described for the venous catheters.

Self-administration procedures.
Monkeys were initially trained to respond on one of two levers by reinforcing each response on the correct lever with a 1 gm banana-flavored pellet. Over approximately a 3 week period the interval between availability of food pellets was gradually increased until a 3 min interval was achieved (i.e., fixed interval, 3 min schedule; FI 3 min). Under the final schedule conditions, the first response on the lever after 3 min resulted in the delivery of a food pellet; sessions ended after 30 food presentations. At the end of each session, the response levers were retracted, house lights and stimulus lights were extinguished, and animals remained in the darkened chamber for 30 min before they were returned to their home cages. All monkeys responded under the FI 3 min schedule of food presentation for at least 20 sessions and until stable performance was obtained (±20% of the mean for three consecutive sessions, with no trends in response rates). When food-maintained responding was stable, the feeder was unplugged, and the effects of extinction on responding were examined for 5 consecutive sessions, after which responding was re-established and maintained by food presentation.