ELECTROPHYSIOLOGICAL AND BEHAVIORAL-EFFECTS OF TYR-D-ARG-PHE-SAR ON LOCUS-COERULEUS NEURONS OF THE RAT

The effect of Tyr-D-Arg-Phe-Sar (TAPS), a mu-selective tetrapeptide an alog of dermorphin, was studied in the rat both in vitro, using slices of the locus coeruleus, and in vivo, after microinjection into the lo cus coeruleus. In electrophysiological studies, TAPS (1-100 nM) was ab le to inhibit spontaneous firing, cause hyperpolarization of the membr ane potential and reduce the input resistance of neurons of the locus coeruleus, suggesting that there was an effect on the potassium channe ls. Based on the inhibition of the spontaneous firing rate, the averag e IC50 for TAPS was calculated to be 1.9 nM, a value lower than that r eported for dermorphin or morphine. The TAPS-induced effects were anta gonized by naloxone, with a dissociation equilibrium constant of 1.96 +/- 0.14 nM, The results indicate that TAPS binds to mu-opioid recepto rs on the cell membrane of neurons of the locus coeruleus to cause its inhibitory actions. In behavioral study, TAPS was microinjected bilat erally via chronically implanted cannulae into the locus coeruleus of non-anesthetized rats and its effects on locomotor activity determined . TAPS, at concentrations of 1 mu M and 10 mu M, but not of 0.1 mu M, induced hypolocomotion/sedation and the effect was significantly rever sed by naloxone (5 mg/kg i.p.). Taken together, these data suggest tha t TAPS has an inhibitory effect on neurons of the locus coeruleus and produces hypolocomotive/sedative effects in vivo. (C) 1998 Elsevier Sc ience B.V. All rights reserved.