Behavioural neuropharmacology of fear and anxiety involving cholecystokinin2 receptors

Abstract

PVG hooded and Sprague-Dawley (SD) rats differ in a variety of anxiety and fear related behavioral measures. PVG hooded rats are more sensitive to the effects of cholecystokinin-2 (CCK2) receptor specific agonist and antagonist drugs as indicated by behavioral and molecular assays (Farook et al, 2001). The studies from this thesis showed that molecular differences (Farook et al, 2001; Wang et al, 2003) between PVG hooded and SD rats parallel their differences on intraperitoneal administration (I.P.) of CCK2 receptor specific agonist (CCK-4) and CCK2 receptor specific antagonist drugs (LY 225910, LY288513, and CR2945) on a variety of anxiety and fear related animal models. I.P administration of a cholecystokinin-1 (CCK1) antagonist, lorglumide (CR1409) failed to show any significant response in PVG hooded rats but showed reliable significance in SD rats. cDNA microarray and reverse transcriptase-polymerase chain reaction (RT-PCR) experiments were then carried out in collaboration to determine the CCK2 receptor expression among these 2 strains of rats. The results showed that CCK2 receptors were expressed to a greater extent in the PVG hooded rats. Anxiety habituation studies using a selective CCK2 receptor agonist (BC264) on day-8 resulted in reversal of freezing behavior in PVG hooded rats which was not observed in SD rats. These results strongly suggest that CCK2 receptors mediate the freezing behavior and the differential expression of these receptors underlie the strain difference in such behavior. Furthermore, this study also brings additional evidence for the possible existence of CCK2 receptor subsites, CCK2A and CCK2B probably corresponding to different coupling sites of the CCK2 receptor.