In vivo effects of anticonvulsant drugs on nerve terminal (synaptosomal) GABA levels in 11 brain regions of the rat

Abstract

The in vivo effects of two GABA-elevating drugs with anticonvulsant properties, namely valproic acid (VPA) and aminooxyacetic acid (AOAA), on nerve terminal GABA levels in discrete rat brain regions were studied by means of a newly developed synaptosomal model. The profile of synaptosomal GABA increases obtained with AOAA was quite different from that seen with VPA. Thus, AOAA (30 mg/kg i.p., 2 hours) caused significant increases in olfactory bulb, cortex, hippocampus, thalamus and cerebellum, whereas VPA (200 mg/kg i.p., 0.5 hour) significantly increased GABA also in hypothalamus, substantia nigra and superior and inferior colliculus. In contrast to the regional selectivity of both drugs with respect to synaptosomal GABA levels, AOAA in most regions was more potent than VPA in increasing whole tissue GABA levels determined prior to subcellular fractionation. The data thus demonstrate that comparison of GABA levels in synaptosomal fractions rather than homogenates from discrete brain areas provides a more sensitive index of the action of GABA-elevating drugs administered in vivo.

The potential role of lamotrigine in schizophrenia

“…Effects of valproate on GABAergic transmission have been extensively explored (Loscher 1999;Johannessen 2000). Significant increases in whole-brain GABA levels have been observed in rats after valproate at 200 mg/kg (Loscher et al 1985). The mechanism through which valproate enhances GABA levels remains to be confirmed, although inhibition of the enzyme succinate semialdehyde dehydrogenase is considered a likely candidate (Johannessen 2000).…”

Effects of Vigabatrin on Brain GABA+/CR Signals in Patients with Epilepsy Monitored by 1H‐NMR‐Spectroscopy: Responder Characteristics

“…The nonresponders tended to take proportionally, but not significantly, more VPA and CBZ than the full responders. A possible GABA-enhancing effect by an unknown but presumably different mechanism than VGB is reported for VPA, at least at high concentrations (40)(41)(42)(43)(44)(45). In a few studies, such a GABA-modulating effect was also observed for CBZ (46,47).…”

Testing of neuroprotective compounds in a transgenic mouse model of Huntington's disease

“…Accordingly, the phenomenon can be explained in that there are regional differences in the effects of valproate on the GABA levels in certain brain areas. For example, there is a considerable elevation in midbrain regions such as the substantia nigra (Iadarola et al, 1979;Loscher et al, 1985), the reticular part of which is an important part of both direct and indirect pathways of the basal ganglia circuitry. In HD, the function of the indirect pathway deteriorates first, while the direct pathway remains intact in the early stages (reviewed by Ramaswamy et al, 2007), resulting in hyperkinetic movements in humans.…”