Rats were treated for 21 d with the selective D1
dopamine receptor antagonist SCH23390, the selective D2
dopamine receptor antagonist spiperone, the nonselective
dopamine receptor antagonist cis-
flupentixol, or a combination of
SCH23390 and
spiperone. In addition, a group of rats received L-prolyl-L-leucyl-
glycinamide (PLG) for 5 d after the 21 d chronic
spiperone treatment. Chronic treatment with
SCH23390 resulted in a significant increase in D1
dopamine receptor density with no change in the D2
dopamine receptor density. Conversely,
spiperone treatment resulted in a significant increase in D2
dopamine receptors and no change in D1
dopamine receptor density. PLG treatment had no effect.
SCH23390 plus
spiperone treatment resulted in a significant increase in both D1 and D2
dopamine receptor densities. However, although in vitro cis-
flupentixol has an equal affinity for D1 and D2
dopamine receptors, only the D2
dopamine receptor density increased after chronic treatment with cis-
flupentixol. In vivo treatment with the
protein-modifying
reagent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (
EEDQ), which irreversibly inactivates D1 and D2
dopamine receptors, was used to investigate the paradoxical, selective D2
dopamine receptor up-regulation induced by cis-
flupentixol treatment. In vivo treatment with cis-
flupentixol before
EEDQ administration prevented the D1 and D2
dopamine receptor reductions induced by
EEDQ. However, cis-
flupentixol protected, in a dose-dependent manner, a greater percentage of D2
dopamine receptors than of D1
dopamine receptors from
EEDQ-induced modification. These data indicate that, in vivo, cis-
flupentixol preferentially interacts with D2
dopamine receptors and could explain why only D2
dopamine receptors were up-regulated following chronic treatment with cis-
flupentixol. Rats were tested for their cataleptic response to the administered
drug over the course of the chronic
drug treatment.
Catalepsy scores of rats receiving
spiperone decreased over the course of treatment, with a significant reduction in
catalepsy occurring by treatment day 5. The profound
catalepsy observed in rats receiving
SCH23390 did not change over the 21 d of treatment. Rats receiving cis-
flupentixol demonstrated tolerance to its cataleptogenic effects, with a significant reduction in
catalepsy observed by treatment day 7. During the 3 week treatment, the time between
drug injection and a full cataleptic response to cis-
flupentixol increased from 20 to 60 min, suggesting a tolerance to the D2, but not D1,
dopamine receptor antagonism by cis-
flupentixol.(ABSTRACT TRUNCATED AT 400 WORDS)