Repeated administration of HA-966 and haloperidol to rats: similar tolerance to striatal dopamine accumulation after HA-966 challenge, but dissimilar effects on striatal [3H]spiperone binding.
Repeated administration of 1-hydroxy-3-amino-pyrrolidone-2 (HA-966) to rats induces tolerance, as shown by a decreased, drug-stimulated accumulation of dopamine (DA) in the striatum. In the present study we compared the adaptive response of the striatal dopaminergic system to repeated administration of HA-966 with the adaptive response observed after repeated haloperidol. These treatments deprive dopamine (DA) receptors from their agonist and cause a blockade of DA receptors, respectively. Tolerance to HA-966 was not accompanied by a change in the specific binding of [3H]spiperone to striatal membranes. This is in contrast to the well-documented up-regulation of DA receptors that occurs with tolerance to haloperidol. Repeated haloperidol pretreatment also diminished DA accumulation following a challenge dose of HA-966, to a similar extent as that caused by repeated pretreatment with HA-966. These similar effects of pretreatment with HA-966 or haloperidol on the response to the HA-966 challenge are in line with, and strengthen, the idea that an increased sensitivity of presynaptic DA receptors is responsible for the decreasing effect of HA-966 after its repeated administration. Haloperidol and HA-966 clearly have different effects on postsynaptic DA receptors, as is shown by their differential effects on striatal [3H]spiperone binding.
Van der Krogt
J A
JA
Department of Pharmacology, Medical Faculty, University of Leiden, The Netherlands.
Van Valkenburg
C F
CF
Belfroid
R D
RD
Heerkens
C B
CB
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004361:Drug Tolerance; D006220:Haloperidol / Q000008:administration & dosage*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D011760:Pyrrolidinones / Q000008:administration & dosage*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism
D011760:Pyrrolidinones; D011954:Receptors, Dopamine; D015102:3,4-Dihydroxyphenylacetic Acid; D013134:Spiperone; C001369:1-hydroxy-3-amino-2-pyrrolidone; D006220:Haloperidol; D004298:Dopamine; D006719:Homovanillic Acid