Pharmacogenetics of cocaine: II. 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 [3H]CFT, a cocaine analogue, in the presence of either GBR12909, a dopamine uptake blocker or fluoxetine, a serotonin uptake blocker and binding of [3H]-paroxetine, a specific serotonin uptake receptor antagonist, were evaluated. We observed regional differences in [3H]CFT binding parameters in the presence of GBR12909 or fluoxetine, but no strain differences by brain region were observed. There were no differences in [3H]paroxetine binding characteristics between corresponding brain regions from C57BL and DBA/2 mice. The D1 antagonist, [3H]SCH23390 and the D2 ligands [3H]sulpiride or [125I]epidepride were used to determine dopamine receptor characteristics. Regional differences were found in [3H]SCH23390 and [3H]sulpiride, with higher affinities and lower densities in frontal cortex compared to striatum; with no differences in [3H]SCH23390 binding in corresponding tissues from C57BL and DBA/2 brains. There were strain-related differences in [3H]sulpiride and in [3H]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.
Erwin
V G
VG
Alcohol Research Center, School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262.
Womer
D E
DE
Campbell
A D
AD
Jones
B C
BC
D000818:Animals; D001549:Benzamides / Q000378:metabolism; D001552:Benzazepines / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D008032:Limbic System / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009419:Nerve Tissue Proteins; D017374:Paroxetine / Q000378:metabolism; D010597:Pharmacogenetics; D011759:Pyrrolidines / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D013045:Species Specificity; D013469:Sulpiride / Q000378:metabolism
D001549:Benzamides; D001552:Benzazepines; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011759:Pyrrolidines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011955:Receptors, Drug; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C061445:cocaine receptor; C063525:epidepride; D017374:Paroxetine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D013469:Sulpiride; D003042:Cocaine