Modeling tardive dyskinesia: predictive 5-HT2C receptor antagonist treatment.
Tardive dyskinesia (TD), a movement disorder produced by long-term treatment with a classical antipsychotic drug, is generally considered to be a disorder of dopamine (DA) systems, since classical antipsychotics are potent DA D(2) receptor blockers. Also, acute DA D(1) agonist treatment of rats is known to produce vacuous chewing movements (VCMs), a behavioral feature resembling the oral dyskinesia that is so prominent in most instances of TD. In this paper we outline a series of studies in a new animal model of TD in which DA D(1) receptor supersensitivity was produced by neonatal 6-hydroxydopamine (6-OHDA) -induced destruction of nigrostriatal DA fibers. In rats so-lesioned 5-HT receptor supersensitivity is additionally produced, and in fact 5-HT receptor antagonists attenuate enhanced DA D(1) induction of VCMs. Moreover, in 6-OHDA-lesioned rats treated with haloperidol for one year, there a 2-fold increase in numbers of VCMs (vs intact rats treated with haloperidol); and this high frequency of VCMs persists for more than 6 months after discontinuing haloperidol treatment. During this stage, 5-HT(2) receptor antagonists, but not DA D(1) receptor antagonists, attenuate the incidence of VCMs. This series of findings implicates the 5-HT neuronal phenotype in TD, and promotes 5-HT(2) receptor antagonists, more specifically 5-HT(2C) receptor antagonists, as a rational treatment approach for TD in humans.
Kostrzewa
Richard M
RM
Department of Pharmacology, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. kostrzew@etsu.edu
Huang
Nuo-Yu
NY
Kostrzewa
John P
JP
Nowak
Przemyslaw
P
Brus
Ryszard
R
D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D006801:Humans; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D017447:Receptors, Dopamine D1 / Q000502:physiology; D012702:Serotonin Antagonists / Q000627:therapeutic use*
D044405:Receptor, Serotonin, 5-HT2C; D017447:Receptors, Dopamine D1; D012702:Serotonin Antagonists; D004298:Dopamine