Effects of Short Chain Fatty Acids on the Perfused Cat Brain

This study was aimed to elucidate the effects of short chain fatty acids such as N-sodium butyric acid, N-sodium valeric acid, N sodium caproic acid and gamma-hydroxybutyrate (OBA), on the cerebral blood flow, oxygen consumption, glucose uptake, lactic acid output and EEG of the perfused brain. The brain perfusion was conducted by a modified method of Geiger and Magnes with non-anesthetized cats made immobile with d-tubocurarine. During the brain perfusion, 1 ml of artificial blood containing the aqueous solution (pH 7.4) of 0.1 or 1.0 m mole each of N-sodium butyric acid, N-sodium valerie acid, N-sodium caproic acid, or 0.09 m mole of OBA was injected intracarotidly. The results are briefly summarized as follows. 1) In the rapid administration of these short chain fatty acids EEG in all the cases tended to show slow waves 30-40 seconds after the start of the injection, indicating a marked inhibitory effect on the EEG. As for the degree of this inhibition it was most marked with N-caproic acid followed by N-valeric acid, OBA and N-butyric acid in that descending order. Among them, especially in the cases administered with 1.0 m mole of N-caproic acid and N-valeric acid, there appeared slow wave followed by its flattening on EEG, indicating an irreversible strong inhibitory effect on EEG, and also a marked inhibitory effect on the vital signs of the cat. In the cases given 0.1 m mole of N-butyric acid or N-valeric acid, slow wave on EEG was transient, lasting on for 20-30 seconds, which was reversible without flattening and tended to recover rapidly. The tendency was especially marked with the administration of 0.1 m mole of N-butyric acid. In the cases administered with 0.09 m mole of OBA, marked slow waves lasted for a long time, but 10 minutes after the commencement of the administration, the fast wave component increased and there was observed a recovery of the response to sound stimuli. 2) In the cases administered with 0.1 m mole of N-butyric acid, N-valeric acid, N-caproic acid and with 0.09 m mole of OBA, every case showed an increase in the cerebral blood flow along with the appearance of slow wave on the EEG with the time difference of about 10 seconds. Especially marked was the accelerating effect of N-butyric acid at the dose of 0.1 m mole on the cerebral blood flow, and it lasted for a fairly long time and this increased blood flow persisted even when the slow wave had disappeared and the EEG had returned to the normal level. On the contrary, in the cases administered with a high dose (1.0 m mole) of N-caproic acid or N-valeric acid, the enhancing effect on the cerebral blood flow was extremely slight, indicating that the inhibitory effect of these short chain fatty acids on the central nervous system does not necessarily coincide with their accelerating effect on the cerebral blood flow. 3) All these short chain fatty acids showed an accelerating effect on the glucose uptake in the brain, and this effect was most marked in the case administered with 0.1 m mole of N-butyric acid. As for the other fatty acids they showed only 1/2-1/3 the accelerating effect of N-butyric acid, of them OBA showing the lowest effect. 4) The rapid administration of these short chain fatty acids hardly has any effect on the oxygen consumption and the lactic acid output in the perfused brain. In other words, although these short chain fatty acids possess an inhibitory effect on the EEG of the neocortex of the perfused cat brain, they act acceleratingly on the glucose uptake. This fact seems to indicate that the mechanism of the inhibitory action on the central nervous system by these short chain fatty acids differs from that of other hypnotics and anesthetics

Effects of Nucleic Acid Derivatives on the Perfpsed Cat Brain

For the purpose to study the effect of various nucleic acid derivatives on the blood flow, oxygen consumption, glucose uptake, output of lactic acid, and EEG of the perfused brain, perfusion experiments were conducted by a modified method of Geiger & Magnes with non-anesthetized cats made immobile with d-tubocurarine. Nucleic acid derivatives used in the experiments were Adenosine, ATP, AMP, Guanosine, GMP, Cytidine, CMP and UMP. Each of these was injected rapidly into the carotid artery of the perfusing brain. In addition, for the continuous effects of ATP, UMP and CMP, artifcial blood containing these nucleotides was perfused. The results of the study are briefly presented as followed. 1) As for the accelerating effect of these nucleic acid derivatives on the blood flow, Adenosine and Guanosine, nucleosides of the purine derivatives and ATP, AMP and GMP (nucleosides of the san e derivatives) all showed the accelerating effect, but ATP had the strongest effect and AMP as well as Adenosine showed about an equal but slightly weaker effect than that of ATP. GMP and Guanosine did not show much accelerating effect on the cerebral blood flow. 2) The accelerating effect of ATP on the cerebral blood flow was transient lasting only for a short time. This seems to be due to the lowered vascular resistance by direct dilatating action of this substance on the blood vessels. In contrast, the accelerating effect of Adenosine, while it was somewhat weaker than that of ATP, was rapid and lasted several times longer than that of ATP. 3) In the case of perfused brain given rapid ATP injection, irrespective of the dose of ATP, simultaneous with the increase of the cerebral blood flow there occurred an increase in oxygen consumption, glucose uptake and lactic acid output of the brain, while such an increase was not so marked in the cases injected with AMP, Adenosine, GMP and Guanosine. 4) Cytidine (nucleoside of the pyrimidine derivatives) and CMP, UMP (nucleotides of the same derivatives) had hardly any effect on the blood flow and oxygen consumption of the brain, but these substances increased glucose uptake and decreased lactic acid output. 5) A rapid injection of these nucleic acid derivatives hardly affected EEG of the perfused cat brain, but when the brain perfusion was carried out continuously with artificial blood containing CMP and UMP, the glucose uptake was increased and lactic acid output decreased also the fuctional level of the perfused brain was well maintained throughout the perfusion experiment for more than one hour

Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia

Previously the NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (ERP) mismatch negativity (MMN) and the performance of an 'AX'-type continuous performance test (AX-CPT)--measures of auditory and visual context-dependent information processing--in a similar manner as observed in schizophrenia. This placebo-controlled study investigated effects of the 5-HT(2A) receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin administration induced significant performance deficits in the AX-CPT, but failed to reduce MMN generation significantly. These results indirectly support evidence that deficient MMN generation in schizophrenia may be a relatively distinct manifestation of deficient NMDAR functioning. In contrast, secondary pharmacological effects shared by NMDAR antagonists and the 5-HT(2A) agonist (ie disruption of glutamatergic neurotransmission) may be the mechanism underlying impairments in AX-CPT performance observed during both psilocybin and ketamine administration. Comparable deficits in schizophrenia may result from independent dysfunctions of 5-HT(2A) and NMDAR-related neurotransmission