Pharmacological activation of dopamine D4 receptor modulates morphine-induced changes in the expression of GAD65/67 and GABAB receptors in the basal ganglia

Abstract

Dopamine D₄ receptor (D₄R) stimulation, in a putative D₄R/μ opioid heteroreceptor (MOR) complex, counteracts the molecular, cellular and behavioural actions of morphine which are associated with morphine addiction, without any effect on its analgesic properties. In the present work, we have evaluated the role of D₄R in modulating the effects of a continuous treatment with morphine on the GABAergic system in the basal ganglia. It has been demonstrated that the co-administration of a D₄R agonist together with morphine leads to a restoration of GABA signaling by preventing drug-induced changes in GAD_65/67 expression in the caudate putamen, globus palidus and substantia nigra. Results from GABA_BR1 and GABA_BR2 expression suggest a role of D₄R in modulation of the GABA_B heteroreceptor complexes along the basal ganglia, especially in the functional divisions of the caudate putamen. These results provide a new proof of the functional interaction between D₄R and MOR and we postulate this putative heteroreceptor complex as a key target for the development of a new strategy to prevent the addictive effects of morphine in the treatment of pain. This article is part of the Special Issue entitled 'Receptor heteromers and their allosteric receptor-receptor interactions'.

Keywords: Dopamine D(4) receptor; GABA; Morphine; Receptor-receptor interaction; Striatum.