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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. | LitMetric

AI Article Synopsis

  • Dopamine D4 receptors are found in GABAergic pathways from globus pallidus neurons to various brain regions, and their dysfunction may contribute to ADHD symptoms due to genetic variations in these receptors.
  • Systemic injections of D4 ligands show no effect on normal rat motor activity, but microinjections of D4 ligands and stimulants like methylphenidate increased dopamine levels in specific brain areas, resulting in reduced motor activity.
  • The study suggests that impaired D4 signaling may enhance activity in thalamic relay nuclei, indicating that this brain network could be crucial for the efficacy of psychostimulant medications in treating disorders linked to D4 receptor issues.

Article Abstract

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'.

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Source
http://dx.doi.org/10.1016/j.neuropharm.2011.11.001DOI Listing

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