Betel nut constituents as inhibitors of γ-aminobutyric acid uptake

Abstract

THE pharmacological properties of betel nut, the dried seed of Areca catechu which is consumed in immense quantities in the East as a masticatory, are usually interpreted in terms of the cholinomimetic effects of the major alkaloid component, arecoline. Betel nut contains lesser amounts of the related alkaloid guvacoline and the amino acids arecaidine and guvacine. According to popular tradition, a mixture of crushed betel nut and lime is enveloped in leaves of Piper betle before chewing. This treatment with lime has been shown to hydrolyse almost quantitatively arecoline to arecaidine¹, a well tolerated substance which lacks the typical parasympathomimetic effects of arecoline, including tremor and salivation^1,2. Studies on the effects of arecaidine on the behaviour of mice indicate that this substance participates in producing some of the psychic changes ascribed to the betel mixture^1,2. These betel constituents are tetrahydronicotinic acid derivatives (Fig. 1) and we have shown that nipecotic acid, ‘hexahydronicotinic acid’, is a potent inhibitor of the uptake of the central inhibitory transmitter γ-aminobutyric acid (GABA) in rat brain slices³. Nipecotic acid potentiates the depressant action of microelectrophoretically administered GABA on the firing of feline spinal neurones⁴. As the uptake of GABA is likely to be concerned with the inactivation of this transmitter, interference with GABA uptake could result in behavioural changes. The structural similarities between nipecotic acid and the betel nut constituents together with the above mentioned findings prompted us to examine the influence of these compounds on GABA uptake. We have found that arecaidine and guvacine are competitive inhibitors of GABA uptake in rat brain slices and we propose that some of the psychic effects of betel nut consumption may be the result of inhibition of GABA uptake.