Short-term, D2 receptor blockade induces synaptic degeneration, reduces levels of tyrosine hydroxylase and brain-derived neurotrophic factor, and enhances D2-mediated firing in the ventral pallidum

Repeated treatments with neuroleptics are associated with biochemical and morphological alterations in forebrain neurons as well as an upregulation of D2-mediated changes in neuronal function. The present study evaluated the histological and physiological effects of three once-daily treatments with...

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Bibliographic Details
Published in:Brain research 2004-01, Vol.995 (1), p.14-22
Main Authors: Meredith, G.E., Switzer, R.C., Napier, T.C.
Format: Article
Language:English
Subjects:
Animals
Antipsychotic Agents - toxicity
BDNF
Biological and medical sciences
Brain-derived neurotrophic factor
Brain-Derived Neurotrophic Factor - drug effects
Brain-Derived Neurotrophic Factor - metabolism
Cell Survival - drug effects
Cell Survival - physiology
Disease Models, Animal
Dopamine - biosynthesis
Dopamine Agonists - pharmacology
Dopamine Antagonists - toxicity
Dopamine D2 Receptor Antagonists
Drug Administration Schedule
Dyskinesia, Drug-Induced - metabolism
Dyskinesia, Drug-Induced - pathology
Eticlopride
Haloperidol
Haloperidol - toxicity
Immunohistochemistry
Male
Medical sciences
Microscopy, Electron
Nerve Degeneration - chemically induced
Nerve Degeneration - metabolism
Nerve Degeneration - pathology
Neuroleptic
Neuropharmacology
Pharmacology. Drug treatments
Plasticity
Presynaptic Terminals - drug effects
Presynaptic Terminals - pathology
Presynaptic Terminals - ultrastructure
Prosencephalon - drug effects
Prosencephalon - metabolism
Prosencephalon - ultrastructure
Psycholeptics: tranquillizer, neuroleptic
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Quinpirole
Quinpirole - pharmacology
Rats
Rats, Sprague-Dawley
Receptors, Dopamine D2 - metabolism
Salicylamides - toxicity
Synaptic Transmission - drug effects
Synaptic Transmission - physiology
Tyrosine 3-Monooxygenase - metabolism
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Description
Summary:Repeated treatments with neuroleptics are associated with biochemical and morphological alterations in forebrain neurons as well as an upregulation of D2-mediated changes in neuronal function. The present study evaluated the histological and physiological effects of three once-daily treatments with two chemically divergent neuroleptics, haloperidol (1 mg/kg i.p./day) and eticlopride (3 mg/kg i.p./day), measured in rats 24 h after the last injection. It was determined that this short-term antagonism of D2-like receptors induced fiber and terminal degeneration and significantly decreased tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF) immunoreactivity in the ventral pallidum (VP), as determined by optical density measurements. While other forebrain regions demonstrated changes in TH and BDNF, the neurodegeneration profile was unique to the VP. This was accompanied by an enhancement in the efficacy of the D2 agonist quinpirole to increase spiking rate of VP neurons recorded in chloral hydrate-anesthetized rats. These data indicate that short-term treatments with D2 antagonists are sufficient to induce changes in the biochemical and morphological profiles uniquely within the VP. Moreover, the functional ramifications of these changes appear to include profound alterations in the way dopamine regulates neuronal activity in this region.
ISSN:0006-8993
1872-6240
DOI:10.1016/j.brainres.2003.09.040