PHARMACOGENETICS OF COCAINE .2. MESOCORTICOLIMBIC AND STRIATAL DOPAMINE AND COCAINE RECEPTORS IN C57BL AND DBA MICE

Studies were conducted to determine whether genetic differences in behavioural effects of cocaine in C57BL/6 and DBA/2 mice might be mediated by strain differences in dopamine and serotonin transporters and dopamine D1 and D2 receptors in specific brain regions. Binding characteristics of [H-3]CFT, a cocaine analogue, in the presence of either GBR12909, a dopamine uptake blocker or fluoxetine, a serotonin uptake blocker and binding of [H-3]-paroxetine, a specific serotonin uptake receptor antagonist, were evaluated. We observed regional differences in [H-3]CFT binding parameters in the presence of GBR12909 or fluoxetine, but no strain differences by brain region were observed. There were no differences in [H-3]paroxetine binding characteristics between corresponding brain regions from C57BL and DBA/2 mice. The D1 antagonist, [H-3]SCH23390 and the D2 ligands [H-3]sulpiride or [I-125]epiderpride were used to determine dopamine receptor characteristics. Regional differences were found in [H-3]SCH23390 and [H-3]sulpiride, with higher affinities and lower densities in frontal cortex compared to striatum; with no differences in [H-3]SCH23390 binding in corresponding tissues from C57BL and DBA/2 brains. There were strain-related differences in [H-3]sulpiride and in [H-3]epidepride binding in striatal membranes with higher densities in C57BL than in DBA/2. Our findings suggest striatal D2 receptor differences are possibly involved in genetic differences in cocaine-related behaviours.