Histaminergic neurons modulate acetylcholine release in the ventral striatum: role of H₃ histamine receptors

Abstract.

To investigate whether histaminergic neurons influence the activity of cholinergic neurons, the ventral striatum was superfused through a push-pull cannula and the release of endogenous acetylcholine was determined in the superfusate. Local inhibition of histamine synthesis by superfusion with α-fluoromethylhistidine (FMH) gradually decreased the release rate of acetylcholine. Superfusion with histamine increased the release of acetylcholine. The releasing effect of histamine was greatly inhibited when the striatum was simultaneously superfused with the D₂/D₃ agonist quinpirole and the D₁ antagonist (±)-7-bromo-1-(fluoresceinylthioureido)phenyl-8-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzapine (SKF 83566). The effect of histamine on acetylcholine release was abolished by the GABA_A receptor antagonist bicuculline. Superfusion with the H₃ receptor agonists imetit or immepip increased acetylcholine release rate in the striatum. The releasing effects of the two H₃ agonists were FMH resistant, while superfusion with quinpirole and SKF 83566 abolished the H₃ receptor agonist-induced acetylcholine release. Superfusion with the H₃ receptor antagonist thioperamide enhanced acetylcholine release rate. The releasing effect of thioperamide was abolished after inhibition of histamine synthesis by FMH. The release of acetylcholine by thioperamide was also abolished on simultaneous superfusion with quinpirole and SKF 83566.

The findings show that, in the striatum, the activity of cholinergic neurons is permanently modulated by neighbouring histaminergic nerve terminals and axons. The release of acetylcholine is also permanently inhibited by neighbouring GABAergic neurons. The enhanced release of acetylcholine by the H₃ receptor agonists imetit and immepip is due to stimulation of H₃ heteroreceptors, while the increase of acetylcholine release by the H₃ receptor antagonist thioperamide is elicited via blockade of H₃ autoreceptors. Histamine released from histaminergic nerve terminals increases the release of acetylcholine in part by inhibition of dopamine release which, in turn, decreases GABAergic transmission. A dopamine-independent way seems also to be involved in the histamine-evoked acetylcholine release.