Pharmacology Biochemistry and Behavior, Vol. 2, pp. 783--789. ANKHO International Inc., 1974. Printed in the U.S.A. p-Chloroamphetamine: Evidence Against a Serotonin Mediated Learning Deficit in PKU GERALD J. SCHAEFER, 2 ROBERT J. BARRETT, ELAINE SANDERS-BUSH AND CHARLES V. VORHEES Psychology Research Laboratories, Veterans Administration Hospital and Vanderbilt University Nashville, Tennessee 37203 and Tennessee Neuropsychiatric Institute, Department of Pharmacology Vanderbilt University School of Medicine, Nashville, Tennessee 37203 (Received 13 May 1974) SCHAEFER, G. J., R. J. BARRETT, E. SANDERS-BUSH AND C. V. VORHEES. p-Chloroamphetamine. evidence against a serotonin mediated learning deficit in PKU. PHARMAC. BIOCHEM. BEHAV. 2(6) 783-789, 1974. - Rats were injected with 5.0 mg/kg of p-chloroamphetamine (PCA) or saline from 1-28 days of age. Groups treated with PCA showed hypoactivity in the open field at 29, 50 and 75 days of age when compared to rats treated with saline and facilitated avoidance in Y-maze acquisition at 57-61 days of age. At 36 and 68 days of age, at the time of behavioral testing, brain serotonin (5HT) was reduced slightly or not at all. However, in separate groups, brain 5HT was reduced 23% and 35% in 14 and 26 day-old rats after only a single treatment with PCA, suggesting that 5HT was reduced during the treatment period. At 66-68 days of age, 5HT turnover was also unaltered. These results suggest that the behavioral effects were due to neonatal 5HT depletion during a critical period of development rather than a concurrent 5HT depletion at the time of behavioral testing. Moreover, these data are at variance with the concept that neonatal 5HT depletion impairs learning ability and is the underlying CNS defect in phenylketonuria. p-Chloroamphetamine Serotonin Phenylketonuria Shock avoidance learning Open field Behavior THE genetically determined biochemical defect in phenyl- kel:onuria (PKU) is reduced or inactive hepatic phenylal- anJne hydroxylase [17]. This biochemical lesion produces, directly, a block in the conversion of phenylalanine to tyrosine, and an accumulation of phenylalanine and its metabolites in plasma and urine. Indirectly, the accumula- tion of phenylalanine and phenylpyruvic acid produces a decrease in serotonin (5HT) in rat brain [4, 5, 10, 20, 35, 4011, apparently by impairing the uptake of 5HT precursors [22, 30, 39]. It has been proposed that this indirect effect of reduced cerebral 5HT during some critical stage of early development may be the basis of the severe mental retarda- tion associated with PKU [37,38]. Experimental attempts to induce PKU have traditionally involved chronic neonatal administration of excess phenylalanine [15] or p- chlorophenylalanine (PCPA) [14, 16, 25, 31, 36], a phenylalanine and tryptophan hydroxylase inhibitor, or combination of both [1, 6, 7, 29, 34]. Only the latter model has been consistently successful in producing a permanent behavioral change after the treatment regimen has been discontinued; however, all of these PKU models fail to adequately separate the effects of reduced 5HT from other potential behavioral effects of excess phenylalanine. This is further complicated in cases where PCPA is used, since as noted above, PCPA inhibits 5HT synthesis thereby confounding the direct effects produced by PCPA with the 1Supported in part by Training Grant MH-08107 and by MH-11468. 2 The authors wish to express their thanks to Michael J. Germain for his assistance in the conduct of these experiments. 783