Pharmacological Activation Of Dopamine D 4 Receptor Modulates Morphine-Induced Changes In The Expression Of Gad 65/67 And Gaba b Receptors In The Basal Ganglia.

Dopamine D4 receptor (D4 R) stimulation, in a putative D4 R/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 D4 R 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 D4 R agonist together with morphine leads to a restoration of GABA signaling by preventing drug-induced changes in GAD65/67 expression in the caudate putamen, globus palidus and substantia nigra. Results from GABAB R1 and GABAB R2 expression suggest a role of D4 R in modulation of the GABAB 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 D4 R 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.