Involvement of pallidothalamic circuitry in working memory.

Area of Science:

• Neuroscience
• Pharmacology
• Behavioral Science

Background:

• The ventral pallidum (VP) to mediodorsal thalamus (MDT) pathway modulates cognitive and motor functions.
• Mu-opioid and glutamate receptors in the VP play differential roles in these behaviors.

Purpose of the Study:

• To investigate how mu-opioid and glutamate receptor agonists differentially regulate the VP-MDT GABAergic projection.
• To determine the involvement of this pathway in working memory and locomotor activity.

Main Methods:

• Microinjections of AMPA (glutamate agonist) and [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]enkephalin (mu-opioid agonist) into the ventral pallidum of rats.
• Working memory assessed via T-maze delayed alternation and spatial discrimination tasks.
• Locomotor activity monitored, with interventions involving GABA(B) receptor blockade in the mediodorsal thalamus.
• Extracellular GABA levels measured in the ventral pallidum.

Main Results:

• Both AMPA and mu-agonist impaired working memory in a dose-dependent manner.
• Glutamate stimulation, but not mu-opioid, impaired spatial discrimination.
• Mu-opioid-induced working memory impairment was blocked by GABA(B) antagonism in the MDT.
• Both agonists increased locomotor activity; mu-agonist effect was blocked by GABA(B) antagonism, AMPA's was not.
• Mu-opioid stimulation reduced VP GABA levels; AMPA had no effect.

Conclusions:

• Mu-opioid receptor stimulation in the VP decreases GABAergic tone, enhancing VP-MDT GABAergic output, which impairs working memory.
• Glutamate and mu-opioid receptors differentially regulate VP-MDT GABAergic projection impacting cognition and motor control.
• Mu-opioid receptors in the VP may gate the recruitment of working memory into ongoing behavior.