Antidepressant-like effects of CCK B receptor antagonists: involvement of the opioid system

Abstract

RB 101 ( N-[( R,S)-2-benzyl-3-[( S)-2-amino-4-methylthiobutyldithio]-1-oxopropyl]- l-phenylalaninebenzyl ester), a systemically active inhibitor of enkephalin catabolism, has been shown to elicit antidepressant-like effects in mice, both in the forced-swimming and in the conditioned suppression of the mobility tests. The same type of response has been also observed following administration of the cholecystokinin CCK B receptor antagonist L-365,260 ((3 R)-(+)- N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1 H-1,4-benzodiazepin-3-yl)-3-methylphenylurea). Interestingly, the δ-opioid receptor antagonist naltrindole (17-cyclopropylmethyl-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-6,7,2′-3′-indolomorphinan) blocks the effect of both RB 101 and L-365,260 in the conditioned suppression of the motility test. In this work we have investigated the involvement of the opioid system in the antidepressant response to the CCK B receptor antagonist L-365,260 in the forced-swimming test in mice. The effect of L-365,260 was decreased by the δ-opioid receptor antagonist naltrindole. Furthermore, the CCK B receptor agonist, BC 264 (Boc-Tyr(OSO 3H)-gNle-mGly-Trp-(NMe)Nle-Asp-Phe-NH 2), blocked the antidepressant-like effect of RB 101 while CCK-8 (H-Asp-Tyr(OSO 3H)-Met-Gly-Trp-Met-Asp-Phe-NH 2) enhanced the effect of this drug, probably through stimulation of central CCK A receptors, since the CCK A receptor antagonist devazepide ((3 S)-(−)-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1 H-1,4-benzodiazepin-3-yl)-1 H-indole-2-carboxamide) abolished the CCK-8-induced potentiation of the RB 101 effect. In addition, RB 101 enhanced the effect of L-365,260. Such an effect was blocked by the δ-opioid receptor antagonist naltrindole. These data further support the involvement of opioid receptors in the antidepressant-type effect induced by CCK B receptor blockers and support the hypothesis of a regulatory role of CCK in the activity of the endogenous opioid system. As in other experimental paradigms, CCK A and CCK B receptor stimulation appears to have opposite effects in modulating opioidergic activity.