5-HYDROXYTRYPTAMINE-INDUCED EXCITATORY POSTSYNAPTIC CURRENTS IN NEOCORTICAL LAYER-V PYRAMIDAL CELLS - SUPPRESSION BY MU-OPIATE RECEPTOR ACTIVATION

Activation of 5-hydroxytryptamine-2A receptors increases the frequency of excitatory postsynaptic currents through a focal action at apical, but not basilar, dendrites of neocortical layer V pyramidal cells. Si nce mu-, delta- and kappa-opiate receptors are known to inhibit depola rization-induced glutamate release in cerebrocortical slices, we exami ned the opiate receptor subtype(s) that suppress(es) 5-hydroxytryptami ne-induced excitatory postsynaptic currents in the medial prefrontal c ortex and whether this suppression was occurring through a presynaptic or a postsynaptic mechanism. Only opioid agonists that act upon mu-re ceptors (i.e. [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]enkephalin, the endogeno us mu-selective agonist endomorphin-1 and the nea-selective opioid ago nist [Met]enkephalin) suppressed 5-hydroxytryptamine-induced excitator y postsynaptic currents. The delta-agonist [D-phen(2,5)]enkephalin and the kappa-agonist U50,488 were ineffective. Only the selective mu-ant agonist CTOP blocked the suppressant effect of enkephalin, while the s elective delta-antagonist naltrindole and the selective kappa-antagoni st norbinaltorphimine were ineffective. Since the 5-hydroxtryptamine-i nduced excitatory postsynaptic currents are mediated by pha-amino-3-hy droxy-5-methylisoxazole-4-propionate (AMPA)-type excitatory amino acid receptors, the failure of mu-agonists to either block postsynaptic AM PA responses or induce outward currents in layer V pyramidal cells sug gest that mu-agonists are acting at a presynaptic site to block 5-hydr oxytryptamine-induced excitatory postsynaptic currents. Strikingly, a regional selectivity in the suppressant effect of mu-receptor activati on on 5-hydroxytryptamine-induced excitatory postsynaptic currents exi sts, as 300 nM [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]enkephalin suppressed 5 -hydroxytryptamine-induced excitatory postsynaptic currents in the med ial prefrontal cortex by nearly 100%, while in the frontoparietal cort ex 1 mu M [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]enkephalin suppressed 5-hydr oxytryptamine induced excitatory postsynaptic currents by only 58%. Th is is the first demonstration of a previously unsuspected physiologica l interaction between 5-hydroxytryptamine-2A and mu-opiate receptors a nd may be relevant to the relationship between these receptors and bot h mood and psychotic disorders. (C) 1998 IBRO. Published by Elsevier S cience Ltd.