Genetic influences on drug-induced psychomotor activation in mice.
A number of processes are important in the development of substance dependence including initial sensitivity to the acute pharmacological effects of drugs/alcohol. The objectives of the present study were (1) to identify quantitative trait loci (QTLs) associated with the initial sensitivity to the effects of morphine in the A/J, C57BL/6J and AXB/BXA recombinant inbred strains of mice; (2) to identify potential commonalities in the chromosomal regions associated with morphine, cocaine and ethanol sensitivity using multiple-trait genetic analysis and (3) to determine whether there were interstrain differences in dopamine uptake and transporter binding. Initial sensitivity to morphine was determined by measuring locomotor activity in a computerized open-field apparatus following acute morphine administration (0, 10, 20 and 40 mg/kg). Significant differences in morphine-induced activation were observed across the panel of AXB/BXA mice. Genetic analysis found significant QTLs on chromosomes 5, 7, 11, 12, 15 and 17 close to loci previously mapped for cocaine-related behaviours and to parameters of dopaminergic functioning (uptake and receptor binding). Comparisons of the A/J vs. C57BL/6J progenitors found no strain differences for total dopamine uptake (V(max) or K(m)) in freshly prepared striatal synaptosomes from naive animals, and no differences in the IC(50) for the inhibition of dopamine uptake by cocaine. In addition, there were no differences in dopamine transporter density (B(max) or K(d)) measured using (3)H-GBR 12935 binding in synaptosomal membranes or via quantitative autoradiography. Multiple-trait analysis was conducted to examine the genetic interrelationships among morphine-, cocaine- and ethanol-induced activation in the AXB/BXA. Analysis yielded suggestive QTLs for the joint trait on chromosomes 5, 8, 13 and 15, as well as significant regions on chromosomes 11 (Pmv46, 11 cM, LOD = 7.39) and 12 (D12Mit110, 19 cM, LOD = 4.43) that may be common to all three drugs of abuse.
Gill
K J
KJ
Research Institute of the McGill University Health Centre, Quebec, Canada. kathryn.gill@mcgill.ca
Boyle
A E
AE
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002874:Chromosome Mapping; D003042:Cocaine / Q000494:pharmacology; D004252:DNA Mutational Analysis; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics*; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects* / Q000235:genetics*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011595:Psychomotor Agitation / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D013045:Species Specificity; D019966:Substance-Related Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D000431:Ethanol; D009020:Morphine; D003042:Cocaine; D004298:Dopamine