Stereoselective antagonism by enantiomers of alanine and serine of phencyclidine-induced hyperactivity, stereotypy and ataxia in the rat.
Intracerebroventricular injection of the D-forms of alanine (Ala; 2-200 micrograms/rat) and serine (Ser; 20-2000 micrograms/rat) caused a dose-dependent inhibition of the ability of 10 mg/kg of phencyclidine (PCP; given i.p.) to increase automatically quantitated locomotor counts and cumulated scores of locomotion, stereotypy and ataxia for 90 min after PCP administration. D-Ala and D-Ser were found to be more potent than the corresponding L-isomers in attenuating the PCP-induction of these behavioral abnormalities. Although L-, but not D-Ser, at moderate doses (400 micrograms/rat) produced a slight decrease in cumulative ataxia scores after a 10-mg/kg PCP administration, D-, but not L-Ser, reduced the behavioral scores at large doses (more than 1000 micrograms/rat). Similarly, bilateral i.c.v. infusion of D-Ala (140 micrograms/rat) reduced the increasing effects of a lower dose of PCP (5 mg/kg i.p.) on locomotion, stereotypy and ataxia scores, whereas the L-form of Ala (140 micrograms/rat) lacked the inhibitory influence. The stereo-selectivity of the antagonism by Ala and Ser of PCP-induced abnormal behavior parallels that of the potencies of these amino acids as agonists for the strychnine-insensitive glycine site linked to the N-methyl-D-aspartate type excitatory amino acid receptor. Furthermore, the decreasing effects of D-Ala (200 micrograms/rat i.c.v.) and D-Ser (2000 micrograms/rat i.c.v.) on PCP-induced hyperactivity were antagonized by i.c.v. application of 5,7-dichlorokynurenate and 7-chlorokynurenate which are selective antagonists of the glycine modulatory site.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Mental Disorder Research, National Institute of Neuroscience, Tokyo, Japan.
Y
Y
Tanii
T
T
Nishikawa
A
A
Hashimoto
K
K
Takahashi
D000409:Alanine / Q000494:pharmacology*; D000818:Animals; D001259:Ataxia / Q000517:prevention & control*; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010622:Phencyclidine / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D012694:Serine / Q000494:pharmacology*; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects*
D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D010622:Phencyclidine; D000409:Alanine