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. Since mu-, delta- and kappa-opiate receptors are known to inhibit depolarization-induced glutamate release in cerebrocortical slices, we examined the opiate receptor subtype(s) that suppress(es) 5-hydroxytryptamine-induced excitatory postsynaptic currents in the medial prefrontal cortex and whether this suppression was occurring through a presynaptic or a postsynaptic mechanism. Only opioid agonists that act upon mu-receptors (i.e. [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin, the endogenous mu-selective agonist endomorphin-1 and the non-selective opioid agonist [Met]enkephalin) suppressed 5-hydroxytryptamine-induced excitatory postsynaptic currents. The delta-agonist [D-phen(2,5)]enkephalin and the kappa-agonist U50,488 were ineffective. Only the selective mu-antagonist CTOP blocked the suppressant effect of enkephalin, while the selective delta-antagonist naltrindole and the selective kappa-antagonist norbinaltorphimine were ineffective. Since the 5-hydroxytryptamine-induced excitatory postsynaptic currents are mediated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-type excitatory amino acid receptors, the failure of mu-agonists to either block postsynaptic AMPA responses or induce outward currents in layer V pyramidal cells suggest that mu-agonists are acting at a presynaptic site to block 5-hydroxytryptamine-induced excitatory postsynaptic currents. Strikingly, a regional selectivity in the suppressant effect of mu-receptor activation on 5-hydroxytryptamine-induced excitatory postsynaptic currents exists, as 300 nM [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin suppressed 5-hydroxytryptamine-induced excitatory postsynaptic currents in the medial prefrontal cortex by nearly 100%, while in the frontoparietal cortex 1 microM [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin suppressed 5-hydroxytryptamine-induced excitatory postsynaptic currents by only 58%. This is the first demonstration of a previously unsuspected physiological interaction between 5-hydroxytryptamine-2A and mu-opiate receptors and may be relevant to the relationship between these receptors and both mood and psychotic disorders.
Marek
G J
GJ
Department of Psychiatry, Yale School of Medicine and the Connecticut Mental Health Center, New Haven 06508, USA.
Aghajanian
G K
GK
D000818:Animals; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004744:Enkephalin, Methionine / Q000494:pharmacology; D004745:Enkephalins / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008959:Models, Neurological; D019579:Neocortex / Q000502:physiology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time; D044402:Receptor, Serotonin, 5-HT2A; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D004745:Enkephalins; D044402:Receptor, Serotonin, 5-HT2A; D017450:Receptors, Opioid, mu; D011985:Receptors, Serotonin; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D012701:Serotonin; D013004:Somatostatin; D004744:Enkephalin, Methionine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D020881:Enkephalin, D-Penicillamine (2,5)-