Effect of long-term blockade of CRF(1) receptors on exploratory behaviour, monoamines and transcription factor AP-2.

Corticotropin-releasing factor (CRF) holds a central role in reactions to various environmental stimuli. In the present study, the administration of a selective nonpeptide CRF(1) receptor antagonist, CP-154,526, for 6 days, exerted an anxiolytic effect in the elevated zero-maze (EZM) test. CP-154,526 did not affect behaviour in the exploration box when administered acutely, but increased exploration when administered for 5 days, contingently with daily behavioural testing. This effect, although of lesser magnitude, was also present in animals with neurotoxin DSP-4-induced selective denervation of locus coeruleus (LC) projections. When drug administration and behavioural testing were noncontingent in a 2-week administration schedule, CP-154,526 blocked the habituation-induced increase in exploration. This suggests that drug-environment interaction is an important component in the manifestation of the anxiolytic-like effects of CRF(1) receptor blockade. Long-term administration of CP-154,526 had a decreasing effect on noradrenaline (NA) metabolism in the frontal cortex. No manipulation influenced the levels of the transcription factor AP-2 isoforms in the LC area. AP-2 levels correlated positively with 3-methoxy-4-hydroxyphenylglycol (MHPG) in the frontal cortex of vehicle-treated animals. There was a negative correlation between the NA levels in the hippocampus and AP-2 isoforms in the LC area of naive animals. In contrast, in vehicle-treated animals, this correlation was positive. Treatment with CP-154,526, however, made the associations between LC AP-2 levels and hippocampal NA content negative, as was the case in the naive animals. This suggests that CRF(1) receptor blockade counteracts certain mechanisms of habituation, possibly by reducing the LC activity.