Drosophila metabolize 1,4-butanediol into γ-hydroxybutyric acid in vivo

doi:10.1016/S0014-2999(03)01993-9

European Journal of Pharmacology

Volume 473, Issues 2–3, 25 July 2003, Pages 149-152

https://doi.org/10.1016/S0014-2999(03)01993-9 Get rights and content

Abstract

A solvent, 1,4-butanediol, is also abused as a recreational drug. In mammals, 1,4-butanediol is metabolized into γ-hydroxybutyric acid (GHB), which stimulates metabotropic γ-aminobutyric acid (GABA) GABA_B and putative GHB receptors. Here we show that in vivo injection of 1,4-butanediol into adult Drosophila leads to GHB synthesis (GHB was detectable 5 min after 1,4-butanediol injection and increased dramatically 1–2 h later). This synthesis of GHB was accompanied by an impairment of locomotor activity that was mimicked by a direct injection of GHB into flies. We propose Drosophila as a model to study the molecular actions of 1,4-butanediol and GHB.

Introduction

Novel invertebrate models of drug abuse are being developed (Wolf and Heberlein, 2003), including the use of Drosophila melanogaster (fruit fly) in neuropharmacological research (Manev et al., 2003). Drosophila are remarkable in that they respond to drugs of abuse (e.g., cocaine and ethanol) with molecular and behavioral patterns similar to those in mammals. Compared to mammals, Drosophila are more amenable to gene manipulations; for example, mutations or gene silencing via RNA interference (Dzitoyeva et al., 2001), which can be combined with pharmacological tools (Dzitoyeva et al., 2003).

1,4-Butanediol is a naturally occurring alcohol used as an industrial solvent that is also abused as a recreational drug; prolonged human consumption of this substance leads to severe withdrawal symptoms (Mycyk et al., 2001). It appears that 1,4-butanediol produces central nervous system effects after it is metabolized into γ-hydroxybutyric acid (GHB), which acts as an agonist at metabotropic receptors for the neurotransmitter γ-aminobutyric acid (GABA), GABA_B receptors (Carai et al., 2002), and also at putative GHB receptors Castelli et al., 2002, Wu et al., 2003. Since Drosophila expresses GABA_B receptors Mezler et al., 2001, Dzitoyeva et al., 2003, fruit flies could be used to further characterize the interaction of 1,4-butanediol with this receptor system. As a first step in this research, we investigated whether in vivo administration of 1,4-butanediol leads to its conversion into GHB in flies.

Section snippets

Drosophila and injections

Flies (male Canton S, 4–5 days old) were cultured at 25 °C, 50–60% humidity, 12 h/12 h light/dark cycle, on yeast, dark corn syrup, and agar food. For injections, flies were anesthetized by CO₂ (maximally for 5 min). Using custom-beveled glass pipettes coupled to a cell injector (Narashige) and a micromanipulator, under a stereo microscope, we injected a volume of 0.2 μl/fly by a pulse pressure of 300 kPa (Dzitoyeva et al., 2003). The drugs, that is, 3% 1,4-butanediol (Aldrich) and GHB (Sigma),

Results

The GC/MC method we used in this study did not detect GHB in samples prepared from control flies. However, 5 min after 1,4-butanediol injection, GHB was already detectable, and the concentration of GHB increased significantly in samples obtained 1 and 2 h post-injection (Table 1).

Behaviorally, injection of 1,4-butanediol into the flies did not produce any significant effect on the time of their recovery from anesthesia, and the extent of locomotor activity in the immediate post-injection period

Discussion

Our results demonstrate for the first time that Drosophila metabolize 1,4-butanediol into GHB in vivo. In mammals, the conversion of 1,4-butanediol into GHB may involve alcohol dehydrogenase, aldehyde dehydrogenase, and possibly some other enzymes Carai et al., 2002, Snead et al., 1989, Quang et al., 2002, whereas endogenous GHB is primarily synthesized from GABA (Maitre et al., 2000). These pathways may be operative in Drosophila. Although we did not detect endogenous GHB in control flies

Acknowledgments

This work was supported by the National Institute on Drug Abuse grant RO3DA14811 to H. Manev.

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Short communicationDrosophila metabolize 1,4-butanediol into γ-hydroxybutyric acid in vivo

Abstract

Introduction

Section snippets

Drosophila and injections

Results

Discussion

Acknowledgments

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Alcohol

Trends Pharmacol. Sci.

Ann. Emerg. Med.

Biochem. Pharmacol.

Short communication
Drosophila metabolize 1,4-butanediol into γ-hydroxybutyric acid in vivo