Nociceptin/orphanin FQ inhibits tyrosine hydroxylase phosphorylation, dopamine synthesis and dopamine D1-like receptor signaling in rat nucleus accumbens and dorsal striatum

Nociceptin/orphanin FQ (N/OFQ) has been reported to inhibit dopamine (DA) release in basal ganglia mainly by acting on NOP receptors in substantia nigra and ventral tegmental area. We investigated whether N/OFQ could affect dopamine transmission by acting at either DA nerve endings or DA-responsive post-synaptic neurons. In synaptosomes of rat nucleus accumbens and striatum, N/OFQ inhibited DA synthesis and tyrosine hydroxylase (TH) phosphorylation at Ser40 via NOP receptors coupled to inhibition of the cyclic AMP/protein kinase A pathway. Immunofluorescence studies showed that N/OFQ preferentially affected phospho-Ser40-TH in nucleus accumbens shell and that in this subregion NOP receptors partly co-localized with either TH- or DA D1 receptor-positive structures. In nucleus accumbens and striatum, N/OFQ inhibited DA D1 receptor-stimulated cyclic AMP formation, but failed to affect either adenosine A2A or DA D2 receptor regulation of cyclic AMP. In nucleus accumbens slices, N/OFQ inhibited DA D1-induced phosphorylation of NMDA and AMPA glutamate receptors, whereas in primary cultures of accumbal cells, which were found to co-express NOP and DA D1 receptors, N/OFQ curtailed DA D1 receptor-induced CREB phosphorylation. Thus, in nucleus accumbens and striatum N/OFQ exerts an inhibitory constraint on DA transmission by acting on either pre-synaptic NOP receptors inhibiting TH phosphorylation and DA synthesis or post-synaptic NOP receptors selectively down-regulating DA D1 receptor signaling. This dual regulatory mechanism may contribute to the suppressive action of N/OFQ on motor activity and rewarding effects of drugs of abuse.