Long-term D1-dopamine receptor sensitization in neonatal 6-OHDA-lesioned rats is blocked by an NMDA antagonist.
Repeated administration of the D1-dopamine agonist SKF-38393 to adult rats having had dopaminergic neurons destroyed early in development results in an increasing enhancement of the behavioral response to SKF-38393 with each dose until a maximum is reached. This increased sensitivity lasts for at least 6 months. In the present study, this long-lasting change in behavioral responsiveness to repeated treatment with SKF-38393, referred to as D1-dopamine receptor priming, was shown to be dose dependent with smaller doses requiring an increased number of administrations to produce a maximal response when compared to higher doses. In addition, priming occurred equally well when treatment intervals ranged from 1 day to 14 days. These latter data reinforced the view that activation of D1-dopamine receptors results in a prolonged change in neural function. In subsequent experiments, D1-dopamine receptor priming was blocked by pretreatment with the NMDA-receptor antagonist MK-801. This antagonism of priming could not be attributed to a blockade of D1-dopamine receptors by MK-801 or to the induction of interfering behaviors. Because an NMDA antagonist interfered with D1-receptor priming as it does with other long-term neural messages, a common requirement for these diverse forms of neuronal plasticity appears to involve activation of the NMDA receptor. This functional link between NMDA receptors and dopaminergic function and its relationship to neuronal plasticity could have relevance to the biochemical mechanisms involved in learning and to symptoms in central disorders during development that worsen over time, particularly those proposed to involve malfunctioning dopaminergic mechanisms.
Criswell
H E
HE
Biological Sciences Research Center, University of North Carolina School of Medicine, Chapel Hill 27599.
Mueller
R A
RA
Breese
G R
GR
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D016291:Dizocilpine Maleate; D004305:Dose-Response Relationship, Drug; D006892:Hydroxydopamines; D009043:Motor Activity / Q000187:drug effects*; D016627:Oxidopamine; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors / Q000502:physiology*
D003986:Dibenzocycloheptenes; D006892:Hydroxydopamines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016291:Dizocilpine Maleate; D016627:Oxidopamine