Chronic stress changes prepulse inhibition after amphetamine challenge: the role of the dopaminergic system.

The goal of this research was to examine the influence of chronic mild stress (CMS) on prepulse inhibition (PPI). We used an amphetamine challenge to study the role of the dopaminergic system in limbic structures. Chronic stress caused a reduction in both sucrose preference and body weight. It was found that the initially strong response to amphetamine in the control rats was weakened after stress on both the behavioural and biochemical levels: improved PPI, decreased dopamine D2 receptor expression in the central nucleus of amygdala (CeA) and nucleus accumbens (NAC), and decreased dopamine and 3-MT (3-methoxytyramine) levels in NAC. We observed that the stress-evoked attenuation of amphetamine-induced stimulation was also paralleled by changes in corticosterone level. These effects were accompanied by a decrease in both glutamate and the glutamate/gamma-aminobutric acid (GABA) ratio in the NAC. The interpretation of these results is that prolonged stress induces compensatory mechanisms in the mesolimbic system which are responsible for psychostimulant (amphetamine) effects.

Is the interaction between fatty acids and tryptophan responsible for the efficacy of a ketogenic diet in epilepsy? The new hypothesis of action.

The effects of a ketogenic diet in controlling seizure activity have been proven in many studies, although its mechanism of action remains elusive in many regards. We hypothesize that the ketogenic diet may exert its antiepileptic effects by influencing tryptophan (TRP) metabolism. The aim of this study was to investigate the influence of octanoic and decanoic fatty acids (FAs), the main components in the MCT diet (medium-chain triglyceride diet, a subtype of the ketogenic diet), on the metabolism of TRP, the activity of the kynurenic pathway and the concentrations of monoamines and amino acids, including branched-chain amino acids (BCAA) and aromatic amino acids (AAA) in rats. The acute effects of FA on the sedation index and hippocampal electrical after-discharge threshold were also assessed. We observed that intragastric administration of FA increased the brain levels of TRP and the central and peripheral concentrations of kynurenic acid (KYNA), as well as caused significant changes in the brain and plasma concentrations of BCAA and AAA. We found that the administration of FA clearly increased the seizure threshold and induced sedation. Furthermore, we have demonstrated that blocking TRP passage into the brain abolished these effects of FA but had no similar effect on the formation of ketone bodies. Given that FAs are major components of a ketogenic diet, it is suggested that the anticonvulsant effects of a ketogenic diet may be at least partly dependent on changes in TRP metabolism. We also propose a more general hypothesis concerning the intracellular mechanism of the ketogenic diet.

The kynurenine pathway: a missing piece in the puzzle of valproate action?

The present study was designed to determine the role of the kynurenine pathway (KP) in the mechanism of action of valproate (VPA). Therefore, we investigated changes in the concentrations of tryptophan (TRP), kynurenic acid (KYNA), and kynurenine (KYN) in the brain and plasma following VPA administration (50, 250 and 500mg/kg i.p.). The most important findings of our study were that VPA administration produced a progressive and strong increase in the central concentrations of KYNA, KYN and TRP. Simultaneously, the TRP level in plasma declined, while the peripheral increase of KYNA in plasma was weaker and occurred earlier than in the hippocampus. Bearing in mind that the observed effect may be a result of a strong VPA-induced displacement of TRP from its binding sites to plasma albumin, we checked the effect of ibuprofen (IBU) administration (a prototypic drug used to study drug binding to serum albumin) on the KP. We found that IBU evoked a similar pattern of change in the KP activity as VPA. These new findings indicate the existence of a mechanism that could stimulate the production of KYNA in the brain after VPA administration, and may partially contribute to the mechanisms of VPA action. The results of our experiment indicate that an increase in the brain's KYNA level may be achieved by TRP displacement from its binding site on plasma albumin with the administration of different drugs, including VPA, IBU, or short-chain fatty acids, with important clinical consequences.