Triazolam blocks the initial rotational effects of quinpirole but permits the later developing reduction of dopamine D2-mediated rotational behavior and dopamine D2 receptors.
Continuous infusion of the dopamine D2 receptor agonist quinpirole into mice with unilateral striatal 6-hydroxydopamine lesions initially produces a supersensitive rotational behavior. This is followed by reductions of dopamine D2-mediated behavior and dopamine D2 receptors. In this study we attempted to determine if it is possible to inhibit the acute increase in D2-mediated behavior while still allowing the reduction of D2-mediated behavioral responses and dopamine D2 receptors to occur. Mice were implanted with Alzet minipumps containing either quinpirole alone or quinpirole combined with the GABA receptor modulator triazolam or the dopamine D2 receptor antagonist sulpiride, and rotational behavior was monitored for the 6 days of infusion. The pumps were then removed, and D2 receptors in striatal membranes were determined. Triazolam completely blocked the initial rotational behavior normally induced by implanting quinpirole. However, the quinpirole-induced reduction of D2-mediated behavioral responses and D2 receptors still occurred. Continuous infusion of sulpiride also inhibited the rotational behavior produced by quinpirole, but it prevented the reduction of dopamine D2 receptors. We conclude that up-regulated dopamine receptors and dopaminergic behaviors can be reversed by the continuous administration of a dopamine receptor agonist and that this reversal can occur without producing an initial exacerbation of dopaminergic responses. These results suggest that this type of treatment regimen might be useful for treating clinical conditions associated with dopaminergic supersensitivity.
Department of Pharmacology, Medical College of Pennsylvania/EPPI, Philadelphia 19129.
L W
LW
Zhou
S P
SP
Zhang
S
S
Welsh
T A
TA
Connell
B
B
Weiss
D000704:Analysis of Variance; D000818:Animals; D015259:Dopamine Agents / Q000037:antagonists & inhibitors*; D015536:Down-Regulation / Q000187:drug effects; D004873:Ergolines / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D019257:Quinpirole; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D013469:Sulpiride / Q000494:pharmacology; D014229:Triazolam / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D015259:Dopamine Agents; D004873:Ergolines; D017448:Receptors, Dopamine D2; D014229:Triazolam; D019257:Quinpirole; D005680:gamma-Aminobutyric Acid; D013469:Sulpiride