The Journal of Neurophysiology Vol. 83 No. 2 February 2000, pp. 723-734
Copyright ©2000 by the American Physiological Society

Neuropeptide Y₅ Receptors Reduce Synaptic Excitation in Proximal Subiculum, But Not Epileptiform Activity in Rat Hippocampal Slices

 ¹Department of Pharmacology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada; and  ²Department of Pharmazie, Swiss Federal Institute, CH 8057 Zurich, Switzerland

Ho, Melisa W. Y., Annette G. Beck-Sickinger, and William F. Colmers. Neuropeptide Y₅ Receptors Reduce Synaptic Excitation in Proximal Subiculum, But Not Epileptiform Activity in Rat Hippocampal Slices. J. Neurophysiol. 83: 723-734, 2000. Neuropeptide Y (NPY) potently inhibits excitatory synaptic transmission in the hippocampus, acting predominantly via a presynaptic Y₂ receptor. Recent reports that the Y₅ receptor may mediate the anticonvulsant actions of NPY in vivo prompted us to test the hypothesis that Y₅ receptors inhibit synaptic excitation in the hippocampal slice and, furthermore, that they are effective in an in vitro model of anticonvulsant action. Two putative Y₅ receptor-preferring agonists inhibited excitatory postsynaptic currents (EPSCs) evoked by stimulation of stratum radiatum in pyramidal cells. We recorded initially from area CA1 pyramidal cells, but subsequently switched to cells from the subiculum, where a much greater frequency of response was observed to Y₅ agonist application. Both D-Trp³²NPY (1 µM) and [ahx^8-20]Pro³⁴NPY (3 µM), a centrally truncated, Y₁/Y₅ agonist we synthesized, inhibited stimulus-evoked EPSCs in subicular pyramidal cells by 44.0 ± 5.7% and 51.3 ± 3.5% (mean ± SE), in 37 and 58% of cells, respectively. By contrast, the less selective centrally truncated agonist, [ahx^8-20] NPY (1 µM), was more potent (66.4 ± 4.1% inhibition) and more widely effective, suppressing the EPSC in 86% of subicular neurons. The site of action of all NPY agonists tested was most probably presynaptic, because agonist application caused no changes in postsynaptic membrane properties. The selective Y₁ antagonist, BIBP3226 (1 µM), did not reduce the effect of either more selective agonist, indicating that they activated presynaptic Y₅ receptors. Y₅ receptor-mediated synaptic inhibition was more frequently observed in slices from younger animals, whereas the nonselective agonist appeared equally effective at all ages tested. Because of the similarity with the previously reported actions of Y₂ receptors, we tested the ability of Y₅ receptor agonists to suppress stimulus train-induced bursting (STIB), an in vitro model of ictaform activity, in both area CA3 and the subiculum. Neither [ahx^8-20]Pro³⁴NPY nor D-Trp³²NPY were significantly effective in suppressing or shortening STIB-induced afterdischarge, with <20% of slices responding to these agonists in recordings from CA3 and none in subiculum. By contrast, 1 µM each of [ahx^8-20]NPY, the Y₂ agonist, [ahx^5-24]NPY, and particularly NPY itself suppressed the afterdischarge in area CA3 and the subiculum, as reported earlier. We conclude that Y₅ receptors appear to regulate excitability to some degree in the subiculum of young rats, but their contribution is relatively small compared with those of Y₂ receptors, declines with age, and is insufficient to block or significantly attenuate STIB-induced afterdischarges.