Relationships between GABA and polyamines in developing rat brain.

3-(Aminomethyl)-2,6-difluorophenol (6) and 4-(aminomethyl)-2, 6-difluorophenol (7) were synthesized in eight and four steps, respectively, starting from 2,6-difluorophenol, to test the potential of the 2,6-difluorophenol moiety to act as a lipophilic bioisostere of a carboxylic acid. Compounds 6 and 7 are potential bioisosteric analogues of gamma-aminobutyric acid (GABA). Substrate studies and inhibition studies were carried out with pig brain gamma-aminobutyric acid aminotransferase; 6 and 7 are very poor substrates, but both inhibit the enzyme, indicating that the 2, 6-difluorophenol moiety appears to be able to substitute for a carboxylic acid to increase the lipophilicity of drug candidates.

4-Aminobutyrate Transaminase↗

PubMed1999

Septohippocampal adaptive GABAergic responses by AF64A treatment.

A cholinergically disrupted laboratory animal has been produced by administration of the cholinotoxin ethylcholine aziridinium mustard (AF64A), which produced a dysfunction in the cholinergic forebrain system. After AF64A treatment, a reduction of choline acetyl transferase (ChAT) activity was measured in the hippocampal regions. ChAT activity was preferentially reduced in tissue samples of the dorsal with respect to the ventral hippocampus, and concomitantly with this reduction, a compensatory increase in ChAT activity in the medial septum was found. Tissue gamma-aminobutyric acid (GABA) content in the hippocampal and septal brain areas was not affected by AF64A, indicating a specific effect on the cholinergic septohippocampal projection. The rate of GABA accumulation induced by aminooxyacetic acid administration was higher in the dorsal hippocampus and medial septum of AF64A-treated animals, but not in their ventral hippocampus and lateral septum, where significant changes occurred in ChAT activity. Concomitantly with the changes in GABA metabolism, a significant Bmax increase and Kd reduction of 3H-flunitrazepam binding in the hippocampus of AF64A-treated animals were associated with changes in the ChAT activity. This finding suggests an increase of GABA input on the cholinergic somas of the medial septum and an uncompensated GABAergic interneuron activity in the hippocampus. In this study, we present an adaptive mechanism of homotypic compensatory metabolism by cholinergic somas, and a heterotypic response of the GABAergic septohippocampal projection system, which was elicited by AF64A administration.

4-Aminobutyrate Transaminase↗

PubMed1998

Localization of GABA transaminase immunoreactivity in the rat substantia nigra pars reticulata.

Precise cellular localization of gamma-aminobutyric acid transaminase (GABA(T)), a degrading enzyme for the neurotransmitter GABA, was determined in the rat substantia nigra (SN) by immunocytochemical experiments using a recently developed monoclonal antibody. In order to characterize the GABA(T)-immunoreactive neurons, double immunocytochemistry was also performed using tyrosine hydroxylase (TH) as a neurochemical marker for dopaminergic neurons in the substantia nigra pars compacta (SNc). Immunoreactivity for GABA(T) was primarily localized in perikarya of the SN. There were only a few GABA(T)-immunoreactive neurons found to display TH immunoreactivity. Most of the GABA(T)-immunoreactive neurons were then identified as reticulata neurons. These results indicate that reticulata neurons are the major nigral neurons that express GABA(T) immunoreactivity and there may be functional compartmentalization of the GABA metabolism in the rat substantia nigra pars reticulata (SNr).

4-Aminobutyrate Transaminase↗