Effect of BHT 920 on monoaminergic neurons of the rat brain: an electrophysiological in vivo and in vitro study

Abstract

BHT 920 was originally described as a dopamine autoreceptor agonist. In this study, the effect of this compound on the firing rate of noradrenergic locus coeruleus, serotonergic dorsal raphe and dopaminergic ventral tegmental area neurons was examined both in the anaesthetized rat and in rat brain slices. Extracellular recordings were performed in cells whose identity was determined by electrophysiological, pharmacological and histological criteria. In vivo, BHT 920 inhibited the firing of locus coeruleus neurons (ID 50: 14.5 ± 4.7 μg/kg, mean ± SEM) and ventral tegmental area neurons (ID50 7 ± 3 μg/kg) at very low doses. As a comparison, the ID50 of clonidine on locus coeruleus cells was 5.5 ± 0.6 μg/kg and the ID50 of apomorphine on ventral tegmental area neurons was 13 ± 3 μg/kg. BHT 920 also decreased the firing of dorsal raphe cells, but this effect was obtained at higher doses (ID50: 57 ± 11 μg/kg). The in vitro study confirmed the results obtained in vivo. BHT 920 potently inhibited the firing of locus coeruleus cells (IC50: 71 ± 28 nM) and was less potent than clonidine (IC50: 5.3 ± 0.98 nM). The compound also inhibited the firing of ventral tegmental area neurons at very low concentrations (IC50: 21 ± 3.3 nM), being more potent than apomorphine (IC50: 56 ± 29 nM). BHT 920 only slightly decreased the firing rate of dorsal raphe neurons at 50 gM, showing that the drug has little direct effect on these cells. A pharmacological analysis performed in vitro showed that the effect of BHT 920 was specifically inhibited by the D₂ antagonist sulpiride (1 μM) in the ventral tegmental area and by the alpha₂ antagonist idazoxan (1 μM) in the locus coeruleus. This electrophysiological study shows that BHT 920 is a potent D₂ and alpha₂ agonist in the rat brain.