In vitro depressant effects of U-54494A, an anticonvulsant related to kappa opioids, in the hippocampus

Abstract

The effects of cis-3,4 dichloro-N-2-(1-pyrrolidinyl)cyclo-hexyl-benzamide (U-54494A), an anticonvulsant related to kappa opioids, were studied in vitro on the extracellular electrical activity of the CA1 region of slices of hippocampus in the rat. The effects of U-54494A were compared to those of the kappa opioid agonist trans-3,4 dichloro-N-2-(1-pyrrolidinyl)cyclo-hexyl benzeneacetamide methane sulphonate (U-50488H). Both U-54494A and U-50488H, in concentrations of 50 and 100 microM, respectively, reduced the magnitude of the orthodromically evoked CA1 population spikes after electrical stimulation of the stratum radiatum (100-200 microA, 70 microseconds, 0.1 Hz). Naltrexone (25 microM), or the selective kappa opiate receptor antagonist, 1-cyclopenthyl-5-(1,2,3,4,5,6-hexahydroxy-3,6,11-trimethyl-2 -6-methano-3- benzazocin)-3-pentatone methane sulphonate (WIN 44441-3) (25 microM), prevented the depressant activity of U-54494A (200 microM) on the CA1 population spikes. High calcium (+3mM) solutions prevented the depressant activity of increasing concentrations of both U-54494A and U-50488H on the amplitude of CA1 population spikes. Up to 200 microM, both drugs were ineffective in depressing the epileptiform bursting in CA1, due to 1 mM penicillin or to perfusion of the slice in absence of magnesium ions. The results demonstrate: (1) the inability of U-54494A to show antagonistic activity in two in vitro models of interictal epilepsy; (2) a depressant effect of U-54494A on basal synaptic transmission in the CA1 region of the hippocampus, which may be related to an influence on transneuronal calcium currents and which may be involved in the reported antagonism of ictal epileptic seizures by drugs.