Selegiline) in Monkeys*

Intravenous self-administration studies with /-deprenyl (selegiline) in monkeys* /-Deprenyl and its stereoisomer d-deprenyl did not maintain intravenous self-administration behavior in rhesus monkeys. In contrast, /-methamphetamine, the major metabolite of /-deprenyl, as well as the baseline drug, cocaine, maintained high rates of intravenous self-administration behavior. Treatment with /-deprenyl doses up to 1.0 mg/kg before self-administration sessions failed to alter self-administration of either cocaine or /-methamphetamine. Thus /-deprenyl did not appear to have cocaine- or methamphetamine-like reinforcing properties in monkeys and was ineffective in altering established patterns of psychomotor-stimulant self-administration behavior. These results support clinical findings that de- spite long-term use of /-deprenyl for the treatment of Parkinson's disease by large numbers of patients, no instances of abuse have been documented. /-Deprenyl has recently been suggested as a potential med- ication for the treatment of various types of drug abuse, including cocaine abuse, but its failure to produce selective effects in decreasing cocaine or methamphetamine self-administration behavior in the present experiments makes such an application seem unlikely. (CLIN PHARMACOL THER 1994;56:774-80.) Gail D. Winger, PhD,a Sevil Yasar, MD,b'd'e S. Steven Negus, PhD,a and Steven R. Goldberg, pIli/i d'e Ann Arbor, Mich., and Baltimore, Md. From the 'Department of Pharmacology, University of Michigan /-Deprenyl (selegiline) has been known for several Medical School, Ann Arbor, the bDepartment of Anesthesiology years to increase and prolong the effectiveness of and Critical Care Medicine, Johns Hopkins University Medical /-dihydroxyphenylalanine (L-dopa) in the treatment of School, Baltimore, thee Department of Pharmacology and Exper- the itmental Therapeutics, University of Maryland School of Medi- symptoms of Parkinson's disease." More re- cine, Baltimore, thed Department of Pharmacology, Georgetown cently, /-deprenyl alone has been found to slow the University Medical School, Washington, D.C., and thee Preclin- progression of Parkinson's disease and to delay the ical Pharmacology Laboratory, National Institute on Drug Abuse, need for L-dopa therapy.5'6 However, the mechanism Institutes of Health, Intramural Research Program, Bal- National by which it produces these therapeutic benefits is not timore. This research was supported in part by U.S. Public Health Service clearly understood.7 grants DA 04403 and DA 05951. A preliminary report of por- /-Deprenyl is a selective and irreversible antago- tions of this research appeared in ref. 1. Animals used in this nist of monoamine oxidase B (MAO-B),8'9 an enzyme study were maintained in facilities fully accredited by the Ameri- that primarily has an extraneuronal location in the can Association for the Accreditation of Laboratory Animal Care human brain10" and that deaminates synaptic accu- (AAALAC), and all experimentation was conducted in accor- mulations of cathecolamines and 13-phenylethylamine dance with the guidelines of the University Committee on the Use and Care of Animals, University of Michigan School of Medi- (13_pEA).12,13 /-Deprenyl inhibits deamination of do- cine, and the Institutional Care and Use Committee of the Addic- pamine in vitro, and its mechanism of therapeutic action Research Center, National Institute on Drug Abuse, National tion was thought to be by increasing brain levels of Institutes of Health, and the Guide for Care and Use of Labora- dopamine in vivo. However, MAO-B is not present tory Animals of the Institute of Laboratory Animal Resources, within dopaminergic nerve terminals in human National Research Council, Department of Health and Human brain Services, publication (NIH) 85-23, revised 1985. and does not appear to be a primary contributor to do- Reprint requests: Gail D. Winger, PhD, Department of Pharmacol- pamine's inactivation in vivo in humans. However, ogy, 1301 MSRB III, 1150 W. Medical Center Dr., University of the administration of /-deprenyl to intact rats, which Michigan, Ann Arbor, MI 48109-0632. show a greater distribution of MAO-B in brain than in *The drug names d- and /-methamphetamine used in this article have humans, can produce increased dopamine levels.14 been commonly employed in the experimental literature and are used herein. It should be noted, however, that methamphetamine Recent studies in rats have suggested that /-depre- does not exist in racemic form but d-methamphetamine instead re- nyl's mechanism of therapeutic effect might be from fers to the d-isomer of N-methylamphetamine and that 1-metham- its metabolic conversion to /-methamphetamine15.16 or phetamine is more correctly named /-N-methylamphetamine. that its inhibition of MAO-B might lead to increases 13/0/60528 774 CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUME 56, NUMBER 6, PART 2 Winger et al. 775 in striatal levels of 13-PEA, which in turn might poten- METHODS tiate the responses of striatal neurons to dopamine.17 The reinforcing effects of /-deprenyl, d-deprenyl, Both of these mechanisms of action of /-deprenyl sug- and /-methamphetamine were evaluated with operant gest the possibility that this drug might be abused by procedures in rhesus monkeys (Macaca mulaua) by susceptible individuals. d-Methamphetamine has ac- making specified doses of each drug available for in- knowledged abuse potential in humans, and 1-metham- travenous self-administration. Results with /-deprenyl phetamine is an effective reinforcer of intravenous have been reported previously.' Using apparatus first self-administration behavior in the rat.18 Phenylethy- described by Deneau et al.29 and modified as de- lamine is a naturally occurring amine that is structur- scribed by Winger et al.,3° each monkey was surgi- ally similar to amphetamine. The administration of cally prepared with a long-term venous catheter and large doses of 13-PEA to rhesus monkeys can produce individually housed 24 hours a day in a stainless-steel an amphetamine-like stereotypy.19 This compound has cage containing a side panel with two response levers been shown to maintain intravenous self-administra- and three stimulus lights. Each monkey wore a har- tion behavior in dogs.20'21 Thus medications that in- ness that was connected to a flexible steel spring arm, crease levels of 13-PEA may have potential for abuse which was designed to allow the animal free move- by humans. ment within the cage but to protect the venous cathe- Indications that /-deprenyl itself might have abuse ter. The catheter was led through the arm to an injec- liability come primarily from preclinical studies in tion pump (model MHRK 55 Watson and Marlow which it has been found to have effects in common Co.) that was located behind the cage. with amphetamine or cocaine. Several investigators A procedure for rapidly evaluating the reinforcing have reported that /-deprenyl has cocaine-like discrim- effects of intravenously delivered drugs in rhesus inative stimulus properties in rats22,23 and pigeons.24 monkeys was used.3° Silicone rubber catheters (Max- The racemic form of deprenyl but not other MAO-B Med. Inc., Portage, Wis.) were surgically implanted inhibitors have discriminative stimulus effects in com- in a jugular, femoral, or brachial vein with ketamine mon with d-amphetamine.25 Yasar et al.26 and Yasar (10 mg/kg) and xylamine (2 mg/kg) anesthetic. Dur- and Bergman27 found that in animals trained to dis- ing twice-daily experimental sessions, one of the stim- criminate the stimulus effects of d-amphetamine or ulus lights was illuminated red, which signaled drug d-methamphetamine from saline solution, large doses availability. In the presence of the red light, 30 re- of /-deprenyl had discriminative stimulus effects in sponses (fixed ratio 30) on the lever beneath the light common with the d - and /-isomers of amphetamine in resulted in the intravenous delivery of drug or saline rats and the d - and /-isomers of methamphetamine in solution. A center, green, stimulus light was on dur- squirrel monkeys. ing pump activation. Each injection was followed by a The abuse liability of /-deprenyl can be assessed more 45-second blackout period, when all lights were extin- directly by evaluation of its ability to maintain drug- guished and lever presses had no programmed conse- seeking and drug-taking behavior, that is, its effective- quences. Experimental sessions were limited to 130 ness as a reinforcer of self-administration behavior.28 minutes, and two sessions were scheduled each day, Studies in which intravenous drug injection is contin- separated by at least 4 hours. Each session was di- gent on behavioral responses made by experithental an- vided into four components; each component was sig- imals have shown that many of the drugs that are sub- naled by illumination of the red stimulus light and was ject to abuse by humans are self-administered by separated from the following component by a 10- experimental animals 29 In the current study the rein- minute intercomponent interval. During the intercom- forcing effects of both the 1- and the d-stereoisomers of ponent interval, no lights were illuminated, and re- deprenyl were evaluated in rhesus monkeys that were sponses on the lever had no programmed conse- experienced with self-administration of cocaine. In ad- quences. dition, the reinforcing effects of /-methamphetamine, With this rapid-evaluation procedure, a unique dose the major metabolite of /-deprenyl, were evaluated in per injection of drug was available during each of the these monkeys, and the ability of /-deprenyl to modify four components of a session. A component ended af- responding maintained by either cocaine or /-metham- ter 20 injections of that particular dose were earned or phetamine was determined Finally, the effects of 1- 25 minutes had elapsed, whichever occurred first. deprenyl on food-maintained behavior were evaluated Drug concentration was kept constant throughout a in an additional group of monkeys. session and doses were altered by adjusting the dura- CLINICAL PHARMACOLOGY & THERAPEUTICS 776 Winger et al.

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