Dopamine D4 receptor stimulation in GABAergic projections of the globus pallidus to the reticular thalamic nucleus and the substantia nigra reticulata of the rat decreases locomotor activity

Dopamine D4 receptors are localized in the GABAergic projections that globus pallidus (GP) neurons send to the reticular nucleus of the thalamus (RTN), the substantia nigra reticulata (SNr) and the subthalamic nucleus (STN). Deficient D4 function in this network could lead to hyperactivity and thus be important in generating some of the symptoms of ADHD (attention deficit hyperactivity disorder), a condition associated with polymorphisms of dopamine D4 receptors. It is then, unexpected that systemic injections of D4 ligands have no significant effects on the motor activity of normal rats. We further examined this issue by microinjecting D4 ligands and psychostimulant drugs in relevant structures. Interstitial dopamine overflow in the RTN was increased by reverse microdialysis of both methylphenidate and methamphetamine. Intranuclear injections in the RTN of methylphenidate, methamphetamine and the selective D4 agonist PD 168,077 reduced motor activity. Intraperitoneal injection of the D4 antagonist L 745,870 blocked the effects of these intranuclear injections. Similarly, intranuclear injections of PD 168,077 in the SNr inhibited motor activity, an effect that was also blocked by intraperitoneal L 745,870. In rats with 6-OHDA induced hemiparkinsonism, intraperitoneal PD 168,077 produced ipsilateral turning behavior that was blocked by L 745,870. Our results suggest that diminished D4 signaling in GP projections could lead to increased traffic through the relay nuclei of the thalamus and hyperactivity. Hence this basal-ganglia–thalamus network may be one of the targets of the beneficial effects that psychostimulant drugs have in disorders associated with D4 receptor abnormalities.This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

► D4 receptor activation decreases locomotor activity at pallidal projections.
► Psychostimulant drugs activate D4 receptors at pallidal targets.
► A Basal-ganglia–thalamus network with D4 receptors is proposed.
► D4 receptor ligands modulate locomotor activity by a site-specific action.