Histamine H3 receptor activation inhibits dopamine synthesis but not release or uptake in rat nucleus accumbens

- The nucleus accumbens (NAcc) synaptic circuitry is modulated by dopamine.
- Dopaminergic neurons innervating the NAcc express histamine H3 receptors (H3Rs).
- H3R activation had no effect on dopamine uptake or depolarization-evoked release.
- H3R activation reduced dopamine synthesis by inhibiting cAMP formation.
- By reducing dopamine availability histamine modulates NAcc synaptic transmission.

We studied the effect of activating histamine H3 receptors (H3Rs) on rat nucleus accumbens (rNAcc) dopaminergic transmission by analyzing [3H]-dopamine uptake by synaptosomes, and dopamine synthesis and depolarization-evoked [3H]-dopamine release in slices. The uptake of [3H]-dopamine by rNAcc synaptosomes was not affected by the H3R agonist RAMH (10−10-10−6 M). In rNAcc slices perfusion with RAMH (1 μM) had no significant effect on [3H]-dopamine release evoked by depolarization with 30 mM K+ (91.4 ± 4.5% of controls). The blockade of dopamine D2 autoreceptors with sulpiride (1 μM) enhanced K+-evoked [3H]-dopamine release (168.8 ± 15.5% of controls), but under this condition RAMH (1 μM) also failed to affect [3H]-dopamine release. Dopamine synthesis was evaluated in rNAcc slices incubated with the l-dihydroxyphenylalanine (DOPA) decarboxylase inhibitor NSD-1015 (1 mM). Forskolin-induced DOPA accumulation (220.1 ± 10.4% of controls) was significantly reduced by RAMH (41.1 ± 6.5% and 43.5 ± 9.1% inhibition at 100 nM and 1 μM, respectively), and this effect was prevented by the H3R antagonist ciproxifan (10 μM). DOPA accumulation induced by preventing cAMP degradation with IBMX (iso-butyl-methylxantine, 1 mM) or by activating receptors for the vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) with PACAP-27 (1 μM) was reduced (IBMX) or prevented (PACAP-27) by RAMH (100 nM). In contrast, DOPA accumulation induced by 8-Bromo-cAMP (1 mM) was not affected by RAMH (100 nM). These results indicate that in rNAcc H3Rs do not modulate dopamine uptake or release, but regulate dopamine synthesis by inhibiting cAMP formation and thus PKA activation.This article is part of the Special Issue entitled 'Histamine Receptors'.