TACHYKININS MAY MODIFY SPONTANEOUS EPILEPTIFORM ACTIVITY IN THE RAT ENTORHINAL CORTEX IN-VITRO BY ACTIVATING GABAERGIC INHIBITION

The effects of substance P and related tachykinins on intrinsic membra ne properties and synaptic responses of neurons in cortical slices wer e determined. Substance P had no detectable effect on membrane propert ies of principal neurons in layer II or V of the rat medial entorhinal cortex or on neurons in either layer of the anterior cingulate cortex . Specific agonists at the neurokinin(1)-receptor were also without ef fect as were agonists at both neurokinin(2)- and neurokinin(3)-recepto rs. Substance P hyperpolarized a small number of principal neurons. Th ese responses were weak and desensitized with repeated applications. S imilar effects were seen with other neurokinin(1)-receptor agonists. E xcitatory synaptic potentials mediated by either alpha-amino-3-hydroxy -5-methyl-4-isoxazolepionate- or N-methyl-D-aspartate-receptors in pri ncipal neurons of the entorhinal cortex were unaffected by substance P . Responses of entorhinal neurons to iontophoretically applied glutama te and N-methyl-D-aspartate were also unaffected. Inhibitory synaptic potentials mediated by either GABA(A)- or GABA(B)-receptors in entorhi nal neurons were slightly but consistently enhanced by substance P. Ne urons identified as interneurons on the basis of their firing characte ristics were consistently depolarized by substance P. These responses also desensitized with repeated applications. Spontaneous epileptiform discharges evoked in entorhinal cortex by perfusion with a GABA(A)-re ceptor antagonist (bicuculline), were reduced in frequency and, someti mes, in duration by substance P. This effect was mimicked by other neu rokinin, receptor agonists and blocked by neurokinin(1)-receptor antag onists. It was also mimicked by neurokinin A but not by a specific neu rokinin(2)-receptor agonist. The reduction in frequency of discharges was also mimicked by a GABA(B)-receptor agonist, L-baclofen, and block ed by the GABA(B)-receptor antagonist, CGP55845A, Neurokinin B, and a specific neurokinin(3)-receptor agonist (senktide), increased the freq uency and (sometimes) duration of epileptiform discharges. Substance P could also increase frequency but this usually succeeded or preceded a decrease in frequency. The effect of neurokinin B was reduced by a m etabotropic glutamate receptor antagonist. Substance P appears to have little direct effect on principal neurons of the entorhinal cortex bu t may hyperpolarize them indirectly by activating interneurons and rel easing GABA. This indirect inhibition may be responsible for the abili ty of substance P to reduce the frequency of epileptiform discharges i n the entorhinal cortex and may suggest that neurokinin(1)-receptor ag onists have potential as anticonvulsant drugs. (C) 1998 IBRO. Publishe d by Elsevier Science Ltd.