Intracerebroventricular Injection of L-Pipecolic Acid Exerts Hypnotic Effects Without Activating NMDA Receptors in Neonatal Chicks under Social Isolation-induced Stress.

L-Pipecolic acid is an intermediate of L-lysine catabolism. Its central injection exerted a hypnotic effect on the brain, which was partially mediated by the activation of γ-aminobutyric acid-A and γ-aminobutyric acid-B receptors. L-Proline has also been shown to exert a similar effect on N-methyl-D-aspartate receptors. Furthermore, L-pipecolic acid is known as L-homoproline, and both L-pipecolic acid and L-proline belong to the imino acid group; therefore, it is plausible that they share certain commonalities, including similar functions. However, the role of N-methyl-D-aspartate receptors with respect to the effects of L-pipecolic acid has not been examined yet. In the present study, the relationship between N-methyl-D-aspartate receptors and the central function of L-pipecolic acid was investigated in neonatal chicks. The behavioral postures for active wakefulness and standing/sitting motionless with eyes opened were significantly affected after intracerebroventricular injection of L-pipecolic acid; whereas, sitting motionless with head drooped (sleeping posture) was significantly enhanced. However, the N-methyl-D-aspartate receptor antagonist, MK-801, did not affect these changes. In conclusion, the central administration of L-pipecolic acid did not exert hypnotic effects through the activation of N-methyl-D-aspartate receptors in neonatal chicks. These results suggest that the imino group is not a determinant for activating N-methyl-D-aspartate receptors.

Central Injection of Glucose Modifies Behavior, Amino Acid and Monoamine Metabolism in Neonatal Chicks under Acute Stressful Conditions.

The effect of intracerebroventricular (i.c.v.) injection of a wide range of glucose concentrations on the behavioral response, central amino acid and monoamine contents was investigated in chicks exposed to a social isolation stressful condition. The chicks were given an i.c.v. injection of 0.21, 0.42, 0.84, and 1.68 µmol of D-glucose, and then behavioral changes were observed over 10 min. The behavioral stress response was dose-dependently decreased and calm behavior was increased by i.c.v. administration of glucose. In the diencephalon, glutamine was positively correlated, whereas glycine was negatively correlated with the dose of glucose. In the telencephalon, the dopamine metabolite and dopamine turnover rates were positively correlated, whereas dopamine was negatively correlated with doses of glucose. In the plasma, isoleucine and hydroxyproline were positively correlated with the dose of glucose, and several amino acids were also influenced by glucose levels. These results suggest that the possible pathways of the sedative effect of glucose include: (1) amino acids synthesized from injected glucose, which can induce the sedative and/or hypnotic effects; (2) amino acids modified by injected glucose transported in the brain from the peripheral tissues; and (3) injected glucose-induced decreases in brain dopamine levels. In conclusion, these changes induced by central glucose interact and induce the sedative effect in neonatal chicks.

Comparison of centrally injected tryptophan-related substances inducing sedation in acute isolation stress-induced neonatal chicks.

In the present study, we first focused on the function of l-tryptophan (TRP) metabolites which are synthesized in different metabolic pathways, namely, the kynurenine (KYN) pathway and serotonin (5-HT) pathway during an acute isolation stress. When l-TRP metabolites were intracerebroventricularly injected on an equimolar basis (100 nmol), 5-HT induced a sedative effect in neonatal chicks. Additionally, plasma corticosterone, dopamine, 5-HT, and its metabolite 5-hydroxyindoleacetic acid concentrations were increased in the diencephalon of the 5-HT treated group compared with other groups. Second, the two doses (400 or 800 nmol) of l- and d-TRP were compared under a corticotrophin-releasing hormone-augmented social isolation stress. When comparing the efficacy between l- and d-TRP against stress behavior, both amino acids had a similar effect and quickly suppressed distress vocalizations. Finally, d-amino acid levels in the diencephalon and telencephalon were measured but d-TRP was not found. These results indicate that l- and d-TRP induce the same effect in attenuating stress but the mode of action of TRP derivatives, namely 5-HT differs during an acute isolation stress in neonatal chick. The absence of d-TRP in the diencephalon further suggests that instead of being an endogenous factor it may play role as a pharmacological factor.