- Cholecystokinin (CCK) and its analogs generate anxiety in humans and measurable anxiety-like behaviors in rats. CCK receptor blockers have been reported to have variable effects in the treatment of anxiety disorders. In a prior study, intracerebroventricular administration of CCK-antisense oligodeoxynucleotides (ASODN) for 3 days significantly diminished anxiety-like behavior in rats. Counter to our expectations, intraperitoneal (i.p.) administration of CCK-ASODN significantly increased anxiety-like behavior and impaired retention performance in the Morris water maze. The aim of the present study was to manipulate CCK-mediated anxiety-like behavior and spatial memory in rats by peripheral (i.p.) administration of ASODN to preproCCK in the presence of antagonists to CCK1 and CCK2 receptor subtypes to further elucidate the roles of these two receptors and better understand the effects of i.p. CCK-ASODN. CCK-ASODN was injected i.p. to rats five times at 24-hr intervals with and without administration of CCK1R antagonist PD135158 or CCK2 antagonist benzotrip. Control groups received injections of either a scrambled oligodeoxynucleotide (ScrODN) or vehicle. On Day 6, the rats were assessed in the elevated plus maze paradigm and in the Morris water maze. The rats were sacrificed and their blood was assessed for corticosterone, ACTH, and prolactin levels. The results show that i.p. CCK-ASODN significantly increased anxiety-like behavior and impaired retention performance in the Morris water maze, compared to both control groups, accompanied by increased plasma corticosterone and plasma ACTH concentrations. In contrast, administration of CCK-ASODN together with CCK2R antagonist, but not with CCK1R antagonist, significantly decreased anxiety-like behavior in rats, but still impaired retention performance in the Morris water maze paradigm. Lower levels of plasma corticosterone and ACTH in CCK-ASODN+CCK2R antagonist-treated rats accompanied the reduced anxiety-like behavior. The present study showed an anxiolytic effect of i.p. CCK-ASODN in the presence of CCK2R, but not CCK1R. Depression and Anxiety 00:000–000, 2004. © 2004 Wiley-Liss, Inc.