The methods and procedures used to evaluate self-injection of these compounds were similar to those previously described by Griffiths and colleagues (Griffiths et al. 1976; Griffiths et al. 1979). Eighteen male baboons (Papio cynocephalus) weighing between 15 and 30 kg were used as subjects. Each animal was adapted to either a standard restraint chair (Findley et al. 1971) or a harness tether restrainmg system (Lukas et al. 1982). The chaired animals were housed individually in sound-attenuated chambers. The tethered animals were housed in standard stainless steel primate cages surrounded by a sound-attenuating, double-walled plywood external enclosure.
An aluminum "intelligence panel" used in self-injection studies has been previously described (Griffiths et al. 1975). Briefly, the panel containing levers and associated stimulus lights (approximately 1 cm in diameter) was mounted on the inside of the chamber (chaired animals) or on the rear wall of the cage (tethered animals). A Lindsley lever (lower left of panel), a leaf lever (lower right of panel), and a food hopper with stimulus light (lower left of panel) were mounted on the panel. A 5x5 cm translucent Plexiglas panel that could be transilluminated was mounted on the aluminum panel in the upper left comer. A speaker for delivery of white noise and tones was mounted behind the panel. A feeder for delivering food pellets into the food pellet tray was mounted on the top of the wooden enclosure.
Baboons were surgically prepared with chronically indwelling silastic catheters implanted in either femoral or jugular veins under pentobarbital or halothane anesthesia using methods described in detail by Lukas et al. (1982). All baboons had served in studies of intravenous self-injection with a variety of drugs. They had continuous access to water via a drinking tube and to food pellets (as described below) and received two pieces of fresh fruit and a multivitamin daily.
The infusion system was similar to that described by Findley et al. (1972). The catheter was attached to a valve system that allowed slow continuous administration (55 to 60 mL in 24 hours) heparinized saline (5 units/mL) via a peristaltic pump to maintain catheter patency. Drug was injected into the valve system by means of a second pump and then flushed into the animal with 5 mL of saline from a third pump. This system necessitated a delay of approximately 20 seconds between the onset of drug delivery and actual injection into the vein. Drugs were delivered within a 2-minute period.
Food was available 24 hours per day under a fixed ratio 30 (FR 30) response schedule on the leaf lever; i.e. every thirtieth response delivered a 1 g banana-flavored food pellet and produced a brief flash of the hopper light.
Animals were trained to self-inject cocaine (0.4 or 0.32 mg/kg/injection) under an FR 160 response schedule on the Lindsley lever. Drug injections were available every 3 hours and were signaled by a 5-second tone, followed by the illumination of the jewel light over the Lindsley lever. When the jewel light was illuminated, each response on the Lindsley lever produced a brief feedback tone. Upon completion of the FR requirement, the jewel light was extinguished and the 5 mL drug injection was begun, followed by a 5 mL flush injection. Following the completion of the injections, the 5x5 cm translucent panel was illuminated for a 1-hour period, and the 3-hour timeout period was begun. There was no time limit for the completion of the response requirement.
When criterion cocaine self-injection performance (six or more injections per day for 3 consecutive days) was obtained a dose of drug or vehicle was substituted for cocaine for 12 to 15 days. Occasional equipment malfunction necessitated extending the period of substitution beyond 15 days. Cocaine self-injection performance was reestablished, and when criterion performance was obtained (typically in 3 to 5 days), another dose of drug was substituted This procedure of replacing cocaine with drug was continued through the study of a range of drug doses and their vehicles.
The order of exposure to different doses was either a mixed or an ascending sequence. The drug vehicle was generally examined immediately before or after the series of doses.
Drugs and Doses Tested. Drug solutions were prepared by dissolving the drug in physiological saline (0.9 percent sodium chloride) and were filter sterilized (Millipore). Drug doses (mg/kg/infusion) were calculated on the basis of the salt. The following drug doses were tested: d-amphetamine sulfate (0.01, 0.05, 0.1, 0.5); /-3,4-methylenedioxyamphetamine sulfate (MDA) (0.1, 0.5, 1.0, 2.0, 5.0); 4-methoxyamphetamine hydrochloride (PMA) (0.001, 0.01, 0.1, 0.1 1.0); 2,5-dimethyoxy-4-methylamphetamine hydrochloride (DOM) (0.001, 0.01, 0.1, 1.0); 2,5-dimethyoxy-4-ethylamphetamine hydrochloride (DOET) (0.001, 0.01, 0.1, 0.32. 1.0); d,/-3,4-methylenedioxy-methamphetamine HCl (MDMA) (0.1, 0.32, 1.0, 3.2); phentermine hydrochloride (0.1, 0.5, 1.0); diethylpropion hydrochloride (0.1, 0.5, 1.0, 2.0); phenmetrazine hydrochloride (0.1, 0.5, 1.0); phendimetrazine tartrate (0.1, 0.5, 1.0, 2.0); benzphetamine hydrochloride (0.1, 0.5, 1.0, 3.0); /-ephedrine hydrochloride (0.3, 1.0, 3.0, 10.0); clotermine hydrochloride (0.1, 1.0, 3.0, 5.0); chlorphentermine hydrochloride (0.1, 0.5, 2.5, 5.0); and fenfluramine hydrochloride (0.02, 0.1, 0.5, 2.5).
Chemical Structures. Figure 1 shows the chemical structures for 14 phenylethylamine compounds. Nine of these compounds are used clinically as anorectics (d-amphetamine, phentermine, diethylpropion, phenmetrazine, phendimetrazine, clotermine, chlorphentermine, benzphetamine, and fenfluramine). Four of these compounds are not approved for clinical use and are reported to have hallucinogenic properties (MDA, PMA, DOM, and DOET). The final compound (/-ephedrine) is used clinically for bronchial muscle relaxation, cardiovascular, and mydriatic effects. Figure 2 shows the chemical structure for MDMA, the methyl analog of MDA. MDMA is not approved for clinical use and has been reported to produce both LSD-like and cocaine-like effects.
Was this article helpful?