title: Differential behavioral responses to cocaine are associated with dynamics of mesolimbic dopamine proteins in Lewis and Fischer 344 rats.
abstract: Differential behavioral and biochemical responses to drugs of abuse may reflect genetic makeup as suggested by studies of inbred Lewis (LEW) and Fischer 344 (F344) rats. We investigated locomotor activity, stereotypy signs, and levels of specific proteins in the nucleus accumbens (NAc) and ventral tegmental area (VTA) in these strains at baseline and following chronic administration of cocaine (30 mg/kg/day for 14 days). Using Western blot analysis, we replicated our previous findings of baseline strain differences and found lower levels of DeltaFosB immunoreactivity in NAc of F344 vs. LEW rats. F344 rats showed greater baseline locomotor activity, sniffing, and grooming compared to LEW rats. Chronic cocaine increased DeltaFosB levels in NAc in both strains, whereas adaptations in other proteins were induced in F344 rats only. These included reduced levels of tyrosine hydroxylase (TH) in NAc and increased TH and glial fibrillary acidic protein (GFAP) immunoreactivity in VTA. Chronic cocaine led to greater increases in overall stereotypy in F344 vs. LEW rats and decreased exploratory behaviors in LEW rats. Opposing effects by strain were seen in locomotor activity. Whereas F344 rats showed higher initial activity levels that decreased with cocaine exposure (tolerance), LEW rats showed increased activity over days (sensitization) with no strain differences seen at 14 days. Further, conditioned locomotor activation to vehicle injections was greater in F344 vs. LEW rats. These results suggest that behavioral responsiveness to chronic cocaine exposure may reflect dynamics of mesolimbic dopamine protein levels and demonstrate the role of genetic background in responsiveness to cocaine.
authors.affiliation: Divisions of Substance Abuse and Molecular Psychiatry, Yale University School of Medicine and Connecticut Mental Health Center, New Haven, CT 06508, USA.
authors.forename: C N
authors.initials: CN
authors.lastname: Haile
authors.forename: N
authors.initials: N
authors.lastname: Hiroi
authors.forename: E J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: T A
authors.initials: TA
authors.lastname: Kosten
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000032:analysis / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013045:Species Specificity; D013239:Stereotyped Behavior / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018765:Dopamine Uptake Inhibitors; D005904:Glial Fibrillary Acidic Protein; D016760:Proto-Oncogene Proteins c-fos; D014446:Tyrosine 3-Monooxygenase; D019204:GTP-Binding Proteins; D003042:Cocaine