Mode of action of gamma-butyrolactone on the central cholinergic system

Gamma-butylactone (GBL), a drug depressing the central nervous system, produced marked increases in acetylcholine contents in rat brain hemispheric regions (striatum, hippocampus, cortex) and in striatal choline content without modifying choline acetyltransferase or acetylcholinesterase activities. In the hippocampus GBL also strongly decreased the acetylcholine turnover rate and inhibited the high affinity uptake of choline. Its increase in acetylcholine content was prevented by an acute electrolytic lesion of the medial septum but not by a wide array of drug treatments designed to interfere with neurotransmission in various pathways. The results are taken to indicate that GBL directly depresses the cholinergic septal-hippocampal afferents by interrupting impulse flow. In the striatum, too, GBL markedly depressed the acetylcholine synthesis rate but had no effect on the high affinity choline uptake process. Such dissociation of the two phenomena had previously been observed using other drugs and may denote that acetylcholine synthesis in this region is regulated differently from that in the hippocampus. By comparison, gamma-hydroxybutyric acid (GHBA), an active metabolite which shares with GBL the capacity to produce a somnolent state and depress impulse flow in the dopaminergic nigroneostriatal pathway, had no effect on either striatal acetylcholine content or on hippocampal high affinity choline uptake. The results suggest that GBL can be distinguished from GHBA in its neuropharmacological central cholinergic effects.