- Background: Cholecystokinin (CCK) and its analogs generates anxiety in humans and measurable anxiety-like behaviors in rats. CCK receptor blockers have had mixed results as a treatment approach for anxiety disorders. Since CCK is a peptide, we explored another strategy to reduce CCK levels in brain by antisense oligodeoxynucleotide inhibition of DNA transcription or messenger RNA (mRNA) translation for CCK precursor protein. Methods: Antisense oligodeoxynucleotide complementary to the start coding region of rat CCK-precursor was intracerebroventricularly (icv) infused into rats three times at 24-hour intervals. Control groups received infusions of either a scramble sequence oligodeoxynucleotide or vehicle. On the fourth day, rats were assessed in the elevated plus maze paradigm. Results: Compared to vehicle and scramble sequence oligodeoxynucleotide control, icv CCK-antisense exogenous administration for 3 days significantly diminished anxiety behavior in rats. Conclusions: Antisense inhibition of CCK-mediated anxiety could have therapeutic potential in human anxiety disorders.