Progressive degeneration of dopamine system functions after transient cerebral oligemia in rats

A reduction in cerebral blood flow to oligemic levels was achieved in pento barbital-anesthetized adult rats by clamping both carotid arteries (BCCA) f or 60 min. To assess the extent to which the animals' dopaminergic system w as affected over an increasing time span, their spontaneous locomotor activ ity in an unfamiliar environment and in response to the subcutaneous admini stration of apomorphine was tested at various times after either BCCA or sh am operation. Eight to 14 days after the operation, it was possible to obse rve a diminished locomotor activity in response to apomorphine injection in BCCA as compared with sham-operated animals, while oral stereotypical beha vior such as Licking was increased. At 3 months, there was only a subtle de crease in apomorphine-induced locomotor activity, and stereotypical behavio r was similar in both groups. At 7 months, the BCCA rats covered shorter di stances than sham-operated controls during the habituation phase; after apo morphine injection, more stereotypic movements, such as, e.g., sniffing, we re observed, and less running. Twelve months after surgery, no further diff erences could be observed between the two groups during the habituation pha se, but the injection of apomorphine led to increased stereotypic sniffing movements, rearing and locomotor activity in BCCA animals to a greater exte nt than in the controls. At 12 months, sensorimotor disturbances elicited b y the rota rod test, which were only transiently observed at 11 weeks and 7 months, did not appear any different from the normal age-related motor dec line of the sham-operated controls. The animals' motor co-ordination in the chimney test was not significantly disturbed during the time between 7 and 12 months after surgery, At 15 months, nocturnal locomotor activities in B CCA rats were significantly decreased. In situ hybridization (ISH) histoche mistry revealed decreased D1 receptor mRNA (D1RmRNA) in striatal neurons 19 months after surgery, while D2 receptor mRNA (D2RmRNA) and the neuronal nu mber remained the same. The present results show that just as is already kn own for the immature rat brain, the adult rat brain, too, reacts to a trans ient decrease in its blood supply by appearance of long-lasting alterations in function, and that even a single oligemic episode is capable of inducin g progressive dopaminergic dysfunctions and ultimately the partial loss of striatal D1RmRNA. (C) 1999 Elsevier Science B.V. All rights reserved.