Pharmacology Biochemist~ & Behavior, Vol. 9, pp. 249-253. Printed in the U.S.A. Role of Peripheral Mechanisms in the Behavioral Effects of 5-Hydroxytryptophan RICHARD B. CARTER, LINDA A. DYKSTRA, J. DAVID LEANDER Departments of Psychology and Pharmacology, University of North Carolina Chapel Hill, NC 27514 AND JAMES B. APPEL Behavioral Pharmacology Laboratory, Department of Psychology, University of South Carolina Columbia, SC 29208 (Received 22 February 1978) CARTER, R. B., L. A. DYKSTRA, J. D. LEANDER AND J. B. APPEL. Role of peripheral mechanisms in the behav- ioral effects of 5-hydroxytryptophan. PHARMAC. BIOCHEM. BEHAV. 9(2) 249-253, 1978.--The effects of 5-hydroxytryptophan (5-HTP) were studied in rats trained to press a lever under a fixed-ratio (FR-32) schedule of water presentation, d-, l- and d,/-5-HTP all decreased responding in a dose-related manner. The levo isomer (12.5-25 mg/kg) was twice as potent as the racemic form (25-50 mg/kg) in this respect. Moderate doses of d-5-HTP (< 100 mg/kg) did not affect responding, whereas 200 mg/kg produced almost complete suppression. The response decrement produced by 25 mg/kg I-5-HTP was completely antagonized by pretreatment with either 50 mg/kg or 400 mg/kg of the decarboxylase inhibitor, benserazide (Ro4-4602). The specific peripheral decarboxylase inhibitor, carbidopa (MK-486) (50 mg/kg) and the peripheral serotonergic antagonist, xylamidine tosylate (1 mg/kg) also antagonized the effects of 25 mg/kg I-5-HTP. These results suggest that at least some of the behavioral effects of 5-HTP are due to increases in levels or turnover of 5-HTP in peripheral serotonergic neuronal systems. 5-HTP Serotonin (5-HT) Benserazide (Ro4-4602) Carbidopa (MK-486) Xylamidine tosylate Decarboxylase inhibitors Peripheral serotonergic antagonists Schedule-controlled responding RESEARCHERS investigating behavioral changes resulting from alterations in the functional activity of the neuro- transmitter, serotonin (5-HT), have often utilized its im- mediate amino acid precursor, d,l-5-hydroxytryptophan (d,I-5-HTP) to increase the concentration of 5-HT in brain. Aprison and Ferster were the first to observe a quantitative relationship between the dose of d, I-5-HTP and the extent of disruption of responding maintained under a multiple FR 50, FI 10 min schedule of food presentation in pigeons [1,2]. In subsequent studies, this disruption was found to be corre- lated most closely with changes in 5-HT concentrations in the brain, more specifically the telencephalon and di- encephalon [5], and was not correlated with changes in norepinephrine or dopamine [3]. Similar results were ob- tained in studies with rats [4]. Thus, it was hypothesized that the behavioral effects of d,/-5-HTP were the result of changes in concentrations of 5-HT in central neuronal sys- tems [1-6]. Furthermore, it was assumed that since only the l isomer of d,I-5-HTP readily crosses the blood-brain barrier, it alone was responsible for the behavioral changes observed and that the d isomer, isolated outside the blood-brain bar- rier, was not behaviorally active [5]. Recent data, however, have suggested that serotonergic mechanisms which lie outside the blood-brain barrier (hereafter referred to as peripheral systems) may play an important role in the mediation of the behavioral effects of d,I-5-HTP. It has been found that xylamidine tosylate, a peripheral serotonergic antagonist [9], partially blocks the disruption in responding produced by d,I-5-HTP in rats under a FR 20 schedule of milk presentation, whereas cinanserin, a potent serotonergic antagonist both centrally and peripherally, almost entirely blocks such effects [16]. Similarly, it has been shown that d,/-5-HTP-induced disrup- tion of responding is antagonized when rats are pretreated with both low and high doses of the decarboxylase inhibitor, benserazide (Ro4-4602) [8]. Low doses (e.g. 50 mg/kg) of benserazide inhibit peripheral but not central /-aromatic amino decarboxylase, whereas high doses (e.g. 400 mg/kg) inhibit both central and peripheral decarboxylase [7,13]. These f'mdings suggest that peripheral mechanisms may be involved in the behavioral effects of d,/-5-HTP. For example, the d isomer might be behaviorally active or the ! isomer might be exerting effects in the periphery as well as in central neuronal systems. If peripheral mechanisms are in- ~A preliminary account of this work was presented at the 62nd Annual Meeting of the Federation of American Societies for Experimental Biology held in Atlantic City, NJ, April 9-14, 1978. ZSend reprint requests to: Richard B. Carter, Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27514. Copyright © 1978 ANKHO International Inc.--0091-3057/78/080249-05501.00/0