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

Abstract

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.

Gammahydroxybutyrate (GHB) receptor ligand effects on evoked synaptic field potentials in CA1 of the rat hippocampal slice

“…However, effects on hippocampal acetylcholine were attributed to GBL whereas GHB was found to be ineffective (Ladinsky et al, 1983). In addition to demonstrating that GBL is neither active nor converted, the fact that high concentrations were markedly less effective than sucrose are consistent with the notion that GBL partitions freely across cell membranes, and exhibits little or no osmotic effect.…”

“…It is well documented that pharmacologic concentrations of GHB increase dopamine synthesis, turnover, and release (Vargiu et al, 1966;Spano et al, 1971;Cheramy et al, 1977;Hutchins et al, 1972;Morgenroth et al, 1976;Walters and Roth, 1972). There may be similar effects on serotonin (Waldmeier and Fehr, 1978;Hedner and Lundborg, 1983) and acetylcholine (Giarman and Schmidt, 1963;Ladinsky et al, 1983), although fewer studies address effects on these neurotransmitters. GHB administration does appear to stimulate dramatically the release of growth hormone and prolactin (Takahara et al, 1977).…”

Chronic intragastric administration of gamma-butyrolactone produces physical dependence in baboons

“…Moreover, one study found that when GBL and GHB were administered in equimolar doses, GBL produced prolonged effects and higher plasma drug concentrations of GHB than did GHB itself (Lettieri and Fung 1978). GBL and GHB also produce differential effects in the central cholinergic system (Ladinsky et al 1983). When investigating the time course of GHB and GBL, it has been reported that the discriminative stimulus effects had similar time courses in rats (Baker et al 2005), whereas EEG changes produced by GBL were more rapid and consistent than changes after GHB administration in monkeys (Snead 1991).…”

Behavioral effects and pharmacokinetics of gamma-hydroxybutyrate (GHB) precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in baboons

“…Rodent studies also suggest that GHB, GBL, and 1,4-BD may differentially effect locomotor behavior (Davies 1978; de Fiebre et al 2004) and the onset and duration of action of the three compounds in rodents differ (Carter et al 2003). In addition, GBL significantly increased acetylcholine in rat striatum, hippocampus, and cortex while GHB did not (Ladinsky et al 1983). When tested in a food-maintained operant procedure, GBL decreased response rate 90 min after administration while 1,4-BD did not suppress responding until 150 min after administration (McMahon et al 2003).…”