Differential behavioral responses to cocaine are associated with dynamics of mesolimbic dopamine proteins in Lewis and Fischer 344 rats

Differential behavioral and biochemical responses to drugs of abuse may ref lect genetic makeup as suggested by studies of inbred Lewis (LEW) and Fisch er 344 (F344) rats. We investigated locomotor activity, stereotypy signs, a nd levels of specific proteins in the nucleus accumbens (NAc) and ventral t egmental area (VTA) in these strains at baseline and following chronic admi nistration of cocaine (30 mg/kg/day for 14 days). Using Western blot analys is, we replicated our previous findings of baseline strain differences and found lower levels of Delta FosB immunoreactivity in NAc of F344 vs. LEW ra ts. F344 rats showed greater baseline locomotor activity, sniffing, and gro oming compared to LEW rats. Chronic cocaine increased Delta FosB 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) immunore activity in VTA. Chronic cocaine led to greater increases in overall stereo typy in F344 vs. LEW rats and decreased exploratory behaviors in LEW rats. Opposing effects by strain were seen in locomotor activity. Whereas F344 ra ts showed higher initial activity levels that decreased with cocaine exposu re (tolerance), LEW rats showed increased activity over days (sensitization ) with no strain differences seen at 14 days. Further, conditioned locomoto r 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. Synapse 41:179 -190, 2001. (C) 2001 Wiley-Liss, Inc.