Cocaine sensitisation and dopamine D2 and MU opioid receptor changes in chronic “binge” cocaine treated preprodynorphin knockout mice

a A. Bailey, aJ.H. Yoo, bI. Racz, bA. Zimmer, aI. Kitchen. a SBMS, University of Surrey, Guildford, UK bLife&Brain Center, Bonn, Germany

There is evidence showing that the k -opioid receptor (KOP-r) system plays an important role in cocaine addiction (Shippenberg et al. 1996; Kuzmin et al. 1997) . Cocaine induces endogenous KOP activity which opposes alterations in brain function resulting from repeated cocaine use.

We have now examined the influence of deletion of preprodynorphin (ppDYN) on cocaine-induced locomotion and sensitisation. In addition, we have measured μ- opioid receptor (MOP-r) agonist (DAMGO) stimulated [ 35S]GTPγS binding and dopamine D1, D2 receptor and dopamine transporter (DAT) binding labelled with [ 3H]SCH23390, [3H]Raclopride and [3H]Mazindol respectively. Male wild-type (WT) and ppDYN knockout (KO) mice (C57BL/6J, 25-30 g) were injected with saline or cocaine (45 mg/kg/day) in a “binge” administration paradigm for 14 days. ANOVA followed by LSD post hoc test was used to compare groups in all experiments described above.

WT and KO mice showed similar enhanced responses after acute cocaine administration (P<0.0001 for WT, P<0.0001 for KO, P=0.12 for WT vs KO, Figure. 1). Chronic cocaine administration produced an enhancement of locomotor sensitisation in KO (P<0.05 for WT vs KO, Figure. 1). Cocaine enhanced MOP-r activation in WT (P<0.05) but not in KO (P=0.47). There was no change in D2 receptor binding in cocaine treated WT but an overall decrease in D2 receptor binding in the brains of cocaine treated KO (P<0.01). No changes were observed in D1 and DAT binding in WT and KO groups.

Figure 1. Locomotor activity in 5 min bins in WT and KO mice after “binge” cocaine administration (mean ± S.E.M., n=6) at day 1 and day 14. **P<0.01 vs Cocaine WT, day 14; *P<0.05 vs Cocaine WT, day 14; #P<0.05 vs Saline KO, day14 (LSD test).

The data confirms that the endogenous KOP system tonically inhibits dopamine neurotransmission and that ppDYN mediates the enhancement of MOP-r activity.

Kuzmin, A. V. et al (1997) Eur J Pharmacol., 321, 265-271.
Shippenberg, T. S. et al (1996) J Pharmacol Exp Ther276, 545-554


Supported by the European Commission EC (LSHM-CT-2004-005166), Korea Science and Engineering Foundation (2005-215-E00003) and Merck, Sharp and Dohme.