Effect of cocaine administration on mice over-expressing corticotrophin releasing factor (CRF)

M. Kasahara1, M. E. Breuer2, J. S. W. Chan2, F. S. van den Bergh2, L. Groenink2, A. Dirks2, B. Olivier2, Z. Sarnyai1 (P. A. McNaughton1). 1Department of Pharmacology, University of Cambridge, Cambridge, U.K.; 2Department of Psychopharmacology, University of Utrecht, Utrecht, The Netherlands.

Pharmacological and behavioural studies have shown that CRF plays a key role in the mediation of the effects of stress on drug addiction and it mediates some of the neuroendocrine and behavioural effects of psychostimulants (Koob et al., 1999; Sarnyai et al., 2001). To better understand the relationship between stress and cocaine addiction, and the role of CRF in particular, we studied effects of acute and repeated cocaine administration and cocaine sensitization in the animal model of chronic stress, using transgenic mice over-expressing CRF in their brains (CRF-OE mice), primarily in limbic-cortical regions.

The locomotor activity (total distance traveled, distance traveled in the centre circle, frequency of entry to the centre circle, time spent in the centre circle, velocity in the whole arena and velocity within the center circle) of 14 wildtype (WT) (weight ranged between 29.8g-36.9g at the start of experiment) and 14 CRF-OE (25.6g-38.5g) male C57BL/6J mice, which were individually placed and were allowed to freely explore in a circular open field (diameter 42cm, height 29.5cm) was recorded and measured using Ethovision® automated tracking programme (Noldus Information Technology, U.S.). After 30 minutes of pre-treatment period in the open field arena, the half of each genotype groups were treated with cocaine (15mg/kg body weight) and the rest were treated with saline (0.9% NaCl) intraperitoneally and then were allowed to freely explore in the same arena for 60 minutes. This procedure was repeated over the period of 7 days and after the 7 day drug-free period followed, on day 15, a final drug treatment was given. Repeated measure ANOVA, where between-subject measures were the genotype (WT/CRF-OE) and the treatment (Saline/Cocaine) and Post-hoc analysis showed that there was a significant difference between WT and CRF-OE mice in number of entries to the supposedly centre circle before (n=28, F=16.944, p<0.01) and after the acute (n=28, F=36.471, p<0.0001) and repeated (n=28, F=36.471, p<0.0001) cocaine treatment. The behaviorual profile of CRF-OE mice changed profoundly as a result of cocaine administration. CRF-OE mice show significantly more activity in the centre of the open field and the development of a very profound behavioural sensitization to this effect, as compared to WT animals.

These results suggest that overproduction of CRF in limbic-cortical regions, as it may happen in response to chronic stress, leads to increased sensitivity to some of the behavioural effects of cocaine.

Koob et al. (1999) Brain Res. 848: 141-152.
Sarnyai et al. (2001) Pharmacol Rev. 53(2):209-43.