INHIBITION OF ANXIETY IN RATS BY ANTISENSE TO CHOLECYSTOKININ PRECURSOR PROTEIN

Background: Cholecystokinin (CCK) and its analogs generates anxiety in humans and measurable anxiety-like behaviors in rats. CCK receptor bl ockers have had mixed results as a treatment approach for anxiety diso rders. Since CCK is a peptide, we explored another strategy to reduce CCK levels in brain by antisense oligodeoxynucleotide inhibition of DN A 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 gro ups received infusions of either a scramble sequence oligodeoxynucleot ide or vehicle. On the fourth day, rats were assessed in the elevated plus maze paradigm. Results: Compared to vehicle and scramble sequence oligodeoxynucleotide central, icy CCK-antisense exogenous administrat ion for 3 days significantly diminished anxiety behavior in rats. Conc lusions: Antisense inhibition of CCK-mediated anxiety could have thera peutic potential in human anxiety disorders. (C) 1998 Society of Biolo gical Psychiatry.