0022-3565/86/2373-0926$00.00/0 THE JOURNAL OF PHARMACOLOGY AND ExPERIMENTAL THERAPEUTICS ..._ .._ Vol. 237, No.3 Copyright © 1986 by The American Society for Pharmacology and ExperimeiiUifTllerapeutics -- - ------- -- Printed in U.S.A. Behavioral and Neurochemical Evaluation of Phenylpropanolamine 1 WILLIAM L WOOLVERTON, CHRIS E. JOHANSON, RENE DE LA GARZA, SUSAN ELLIS, LEWIS S_ SEIDEN and CHARLES R. SCHUSTER Department of Pharmacological and Physiological Sciences (W.L. W., L.S.S.), Department of Psychiatry (C.E.J., S.E., C.R.S.) and Committee on Biopsychology, Department of Behavioral Sciences (R.D.LG.), University of Chicago and Drug Abuse Research Center, Pritzker School of Medicine, University of Chicago, Chicago, Illinois AcceptedforpublicationMarch10, 1986 ABSTRACT (±)-Phenylpropanolamine (PPA), a widely available anorectic and mine in the frontal cortex but failed to deplete dopamine, nor- decongestant, was evaluated in several behavioral paradigms in epinephrine or serotonin in any other brain region studied. Thus, rhesus monkeys and for central nervous system neurotoxicity in PPA is an effective anorectic in rhesus monkeys that, based rats. PPA (1-30 mgjkg intragastric) reduced food intake in rhesus upon drug discrimination results, would be expected to have monkeys but was not self-administered i.v, (0_3-10 mgjkgj limited amphetamine-like subjective effects and only at doses injection) by monkeys experienced in drug self-administration_ well in excess of effective anorectic doses. However, based PPA (30-100 mgjkg intragastric) resulted in amphetamine-like upon self-administration results, PPA would not be predicted to responding in two of four monkeys trained in a drug discrimina- have amphetamine-like dependence potential. Moreover, re- tion paradigm to discriminate d-amphetamine from saline. In rats, peated administration of PPA did not produce the severe central a 4-day injection regimen of high doses of PPA (200 and 400 nervous system neurotoxicity associated with many other am- mgjkgjday) resulted in approximately a 20% depletion of dopa- phetamine congeners. PP A is a phenylethylamine that has been available for over differences between PP A and amphetamine in CNS actions, 40 years for use as an anorectic and nasal decongestant (Sil- For instance, PP A and amphetamine have different profiles of verman et al, 1980)_ In spite of its high availability, little is effects on electrical stimulation of the brain and on stimulation known about the compound behaviorally. In rodents, PPA has escape responding (Kornblith and Hoebel, 1976). Thus, the been: reported to have some effects in common with its close research that has been conducted with rats has found both chemical analog d-amphetamine, a well-studied psychomotor similarities and differences between PP A and amphetamine, stimulant, Like d-amphetamine, PP A increases locomotor ac- A limited amount of systematic data are available concerning tivity (Schulte et al., 1941; Warren and Werner, 1945), induces PP A effects in humans. Fazekas et al. (1959) reported that stereotyped behavior (Davis and Pinkerton, 1972) and reduces PP A was relatively ineffective as an anorectic when compared food intake (Cairns et al., 1984; Epstein, 1959; Tainter, 1944). to d-amphetamine. More recently, however, Hoebel et al. However, PPA is substantially less potent than d-amphetamine (1975a,b) have reported decreased food intake and body weight in these effects. The central mechanism(s) involved in these loss in humans taking PP A over several days. In addition to effects is poorly understood. Like d-amphetamine, PP A is therapeutic use, recreational use of PP A has been reported, sympathomimetic and similarities in overt behavioral effects often in conjunction with caffeine (Mueller, 1983). PPA has suggest similarities to d-amphetamine in central mechanisms also been implicated in the production of psychosis (Kane and of action. Moreover, atropine has been reported to enhance Green, 1966), an effect that is well known with amphetamines many of the effects of both compounds (Davis and Pinkerton, (Jaffe, 1985) and may be related to their eNS neurotoxicity. 1972). On the other hand, other behavioral studies suggest Clearly, additional research is needed to elucidate the CNS effects of PP A, Received for publication October 31, 1985. An effective anorectic with no dependence potential, no 1 This work was supported by National Institute on Drug Abuse Grants DA- amphetamine-like subjective effects or neurotoxicity would 00250, DA-00085 and Research Scientist Award DA-00024, C. R. Schuster Prin- cipal Investigator; Research Scientist Award MH -10562, L. S. Seiden Principal clearly be preferred to d-amphetamine. In the absence of that Investigator; and MH-14651 (S. Ellis). ideal compound, preferred anorectics should reduce food intake ABBREVIATIONS: PPA, (±)-phenylpropanolamine;CNS, central nervous system; i.q., intragastric; DA, dopamine; NE, norepinephrine; 5-HT, serotonin. 926 Effects of PPA 927 at doses well below those necessary to produce other amphet- over the last three sessions of a PP A substitution period was used in amine-like side effects. The present experiment is part of an data analysis. These values were compared to the same values for the ongoing research program designed to assess the anorectic last three sessions of the corresponding saline substitution period. A efficacy, dependence potential and eNS toxicity of available dose of PP A was considered to be a positive reinforcer in a particular anorectics (Schuster and Johanson, 1985). The reinforcing monkey if the mean number of injections for the last three sessions of a test period exceeded the mean value for saline substitution, and the properties of PP A were assessed in rhesus monkeys, a species ranges did not overlap. that has proven quite useful for predicting dependence potential Drug discrimination. The animals were four male rhesus monkeys in humans (Johanson and Balster, 1978). To allow systematic that weighed between 8.0 and 10 kg. All monkeys had participated in potency comparisons, anorectic efficacy and discriminative studies of i.v. drug self-administration and drug effects on schedule- stimulus properties were determined in this same species. The controlled responding. They were housed individually in stainless-steel discriminative stimulus properties of drugs in animals are cages in which water was available continuously. They were fed 150 to thought to be a measure of their subjective effects in humans 200 g of monkey chow after each session and were given a chewable (Woolverton and Schuster, 1983). Neurotoxicity studies were vitamin tablet 3 days/week. During experimental sessions the monkeys done in rats using procedures similar to studies with other were seated in a Plas- Lab restraining chair and placed in a wooden cubicle (175 em high x 85 em wide X 65 em deep) containing two phenylethylamines (Ricaurte et al., 1985;Wagner et al., 1980b). response levers mounted 110 ern above the floor. A 34 w white house- The results suggest that PP A is an effective anorectic with light was mounted on the ceiling. A wooden barrier was attached to the little or no dependence potential and limited amphetamine-like chair in such a way as to prevent a monkey from reaching either lever discriminative stimulus properties even at doses 10 to 20 times with both hands or both levers simultaneously. The monkey's feet were the effective anorectic dose. Moreover, upon repeated admin- placed into shoes, the bottoms of which were fitted with brass plates istration PPA does not result in amphetamine-like neurotox- for the delivery of electric shocks. icity in rats. The drug discrimination procedure has been described in detail previously (de la Garza and Johanson, 1986). Briefly, they were trained Methods in a two lever, trial procedure to avoid electric shock. One hour after an i.g. infusion of d-amphetamine (0.56 or LO rug/kg, based upon Self-administration. The animals were two male and two female individual sensitivity) or saline the houselights and lever lights were (4.1-8.2 kg) rhesus monkeys (Macaca mulatta). Two monkeys (2035 illuminated (trial) and responding on one lever (the correct lever) and 2039) were experimentally naive at the beginning of the experi- avoided electric shock and extinguished the lights. Responding on the ment. The other two (2029 and 3013) had experience with self-admin- incorrect lever started a 2-sec change over delay during which correct istration of other anorectic compounds (rnazindol, 2029; benzpheta- lever responding had no consequence. If a correct response was not mine, chlorphentermine and clortermine, 3013). Each monkey was made within 5 see of onset of the lights, shock (250 msec duration, 10 fitted with a stainless-steel restraint harness and spring arm which mA intensity) was delivered every 2 see until a correct response was attached to the rear of the experimental cubicle (70 em wide x 84 em made. After a correct response, there was a 55-sec intertrial interval. deep x 80 em high) in which the monkey lived for the duration of the The session lasted for 30 trials or 40 min, whichever came first, after experiment. Two response levers (BRS/LVE, PRL-OOl, Beltsville, MD) which a new trial began. The correct lever was determined by the were mounted on the inside front of each experimental cubicle 10 em infusion that was administered before the session. For two monkeys above the floor and a food dish was mounted between them. Four the right lever was correct after d-amphetamine infusions and the left jewelled stimulus lights, two red and two white, were mounted directly lever was correct after saline infusions. This condition was reversed for above each lever. In addition, two houselights, one white (34 w) and the other two monkeys. one red (15 w), were mounted on the ceiling of the cubicle and covered Monkeys were considered to have acquired the discrimination when with translucent Plexiglas. Drug injections were delivered by a peris- more than 90% of the trials were completed on the correct lever for six taltic infusion pump (Cole-Parker Co., Chicago, IL).