Dopamine D₄ receptor activation decreases the expression of μ‐opioid receptors in the rat striatum

Abstract

The dopaminergic and opioid peptide systems interact in many nuclei of the brain. In the striatum, dopamine/opioid peptide interactions modulate locomotor and motivated behaviors as well as reward, motivational, and tolerance processes in opiate dependence. Dopamine D(4) receptors (D(4) R) and mu-opioid receptors (MOR) are highly concentrated in the striosomes (islands) of the striatum, suggesting the existence of receptor-receptor interactions between them. In the present work we studied the role of D(4) R in modulating MOR expression in the islands by using immunohistochemistry and image analysis. The activation of D(4) R by the agonist PD168,077 (1 mg/kg) decreased MOR immunoreactivity (IR) in the striosomes 6 hours after drug treatment. MOR IR levels had recovered 12 hours later. Treatment with a D(4) R antagonist (L745,870, 1mg/kg) blocked downregulation of MOR IR, showing that the D(4) R agonist effects observed were specific. Furthermore, treatment with the D(2)/D(3) receptor agonist quinpirol (1 mg/kg) and D(2)/D(3) receptor antagonist raclopride (1 mg/kg) had no effect in MOR IR, suggesting that D(4) R is the only D2-like receptor producing an MOR downregulation in the islands. The decreases of MOR IR in the striosomes suggest that D(4) R activation may reduce MOR signaling. Increasing evidence has demonstrated that the islands in the striatum play a critical role in habit acquisition during drug addiction. D(4) R/MOR interactions could be crucial in such processes.

Dopamine D4 Receptor Counteracts Morphine-Induced Changes in µ Opioid Receptor Signaling in the Striosomes of the Rat Caudate Putamen

“…While D 1 R increases MOR density in the cell surface membrane by the formation of a D 1 R-MOR heteromer [40], genetic deletion of the D 2 R down-regulates MOR density [41]. We have previously demonstrated that acute D 4 R stimulation down-regulates MOR IR in the striosomes of the CPu, suggesting that D 4 R interacts with MOR promoting its internalization and degradation [26]. The participation of other D2-like receptors, i.e.…”

“…However, contradictory results referred on MOR levels have been obtained in different regions of the CNS, including the CPu, from unchanged to increased expression [23–25], which has been related to morphine sensitization. We have previously demonstrated that the acute activation of the dopamine D 4 receptor (D 4 R) decreases MOR immunoreactivity (IR) in the striosomal compartment of the CPu [26], where a high degree of co-localization between the two receptors exists [27]. Additionally, specific agonist activation of D 4 R prevents striatal acute and chronic morphine induced increases of several transcription factors (c-Fos, ΔFosB, and P-CREB) [28,29].…”

Blockade of Dopamine D4 Receptors Attenuates Reinstatement of Extinguished Nicotine-Seeking Behavior in Rats

“…It seems unlikely that the failure of PD 168,077 to induce nicotine-seeking behavior resulted from a low selectivity for DRD4, because the agonist has been demonstrated to be highly selective for DRD4, showing low binding affinities for other dopaminergic, adrenergic, or serotoninergic receptors (eg, with 4100-fold selectivity over DRD1, 4400-fold selectivity over DRD2, and 4300-fold selectivity vs DRD3) (Glase et al, 1997). It also seems unlikely that the failure of PD 168,077 to induce nicotine-seeking behavior resulted from an insufficient dosage as a similar range of doses has been used to elucidate the specific function of DRD4 in in vivo studies (Bernaerts and Tirelli, 2003;Gago et al, 2007;Nayak and Cassaday, 2003). Previously, it was reported that the role of both DRD1 antagonists and agonists in the reinstatement of cocaine-seeking behavior is dissociable in rats: a selective DRD1 antagonist, SCH23390, attenuates, whereas a selective DRD1 agonist has no affect on, the reinstatement of cocaine-seeking behavior in rats (Self, 2004).…”

Changes in mu-opioid receptor expression and function in the mesolimbic system after long-term access to a palatable diet

“…There is some evidence for dopamine receptor and mu-opioid receptor cross-talk. Activation of D4 dopamine receptors decreases immunoreactivity for muopioid receptors in striosomes of the striatum (Gago et al, 2007). Furthermore, increasing dopamine concentration with methamphetamine decreases the mu-opioid receptor mRNA in SH-SY5Y neuroblastoma cells (Langsdorf & Chang, 2011).…”