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

ABSTRACT

A reduction in cerebral blood flow to oligemic levels was achieved in pentobarbital-anesthetized adult rats by clamping both carotid arteries (BCCA) for 60 min. To assess the extent to which the animals' dopaminergic system was affected over an increasing time span, their spontaneous locomotor activity in an unfamiliar environment and in response to the subcutaneous administration of apomorphine was tested at various times after either BCCA or sham operation. Eight to 14 days after the operation, it was possible to observe a diminished locomotor activity in response to apomorphine injection in BCCA as compared with sham-operated animals, while oral stereotypical behavior such as licking was increased. At 3 months, there was only a subtle decrease in apomorphine-induced locomotor activity, and stereotypical behavior was similar in both groups. At 7 months, the BCCA rats covered shorter distances than sham-operated controls during the habituation phase; after apomorphine injection, more stereotypic movements, such as, e.g., sniffing, were observed, and less running. Twelve months after surgery, no further differences could be observed between the two groups during the habituation phase, but the injection of apomorphine led to increased stereotypic sniffing movements, rearing and locomotor activity in BCCA animals to a greater extent than in the controls. At 12 months, sensorimotor disturbances elicited by 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 decline 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 BCCA rats were significantly decreased. In situ hybridization (ISH) histochemistry revealed decreased D1 receptor mRNA (D1RmRNA) in striatal neurons 19 months after surgery, while D2 receptor mRNA (D2RmRNA) and the neuronal number remained the same. The present results show that just as is already known for the immature rat brain, the adult rat brain, too, reacts to a transient decrease in its blood supply by appearance of long-lasting alterations in function, and that even a single oligemic episode is capable of inducing progressive dopaminergic dysfunctions and ultimately the partial loss of striatal D1RmRNA.