Involvement of pallidothalamic circuitry in working memory

This study evaluated the capacity of mu-opioid and glutamate receptor agoni sts to differentially regulate the involvement of the GABAergic projection from the ventral pallidum to the mediodorsal thalamus in working memory and locomotor activity. Microinjection of either the ionotropic glutamate rece ptor agonist alpha -amino-3-hydroxqy-5-methyl-4-isoxazolepropionate (AMPA) or the mu agonist [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]enkephalin into the ventr al pallidum of male Sprague-Dawley rats produced a dose-dependent impairmen t in working memory, estimated using a forced delayed alternation task in a T-maze. Performance in a spatial discrimination task without delay was als o impaired by glutamate. but not by mu receptor, stimulation. Involvement o f the GABAergic projection from the ventral pallidum to the mediodorsal tha lamus in mu-opioid-induced impairment of working memory was verified by sho wing that inhibiting GABAB receptors in the mediodorsal thalamus blocked th e effect of [(D)-Ala(2),N-Me-Phe(4),Gly-ol(5)]enkephalin in the ventral pal lidum. Similarly, either glutamate or mu-opioid receptor stimulation in the ventral pallidum elicited motor activity, and the motor stimulant effect o f the mu agonist was blocked, while that of AMPA is not affected by GABAB r eceptor blockade in the mediodorsal thalamus. Distinction between mu and gl utamate receptor stimulation was further revealed by the fact that stimulat ing mu receptors in the ventral pallidum caused a dose-dependent reduction in extracellular GABA levels, while AMPA was without effect on GABA in the ventral pallidum. These data indicate that stimulating mu-opioid receptors reduces GABAergic tone in the ventral pallidum. which increases activity in the GABAergic pro jection to the mediodorsal thalamus, thereby impairing working memory. More over, it is hypothesized that mu receptors in the ventral pallidum gate the recruitment of working memory into ongoing behavioral activity. (C) 2001 I BRO. Published by Elsevier Science Ltd. All rights reserved.