Baseline and apomorphine-induced extracellular levels of nigral substance P are increased in an animal model of Parkinson's disease.
Parkinson's disease arises from extensive premature loss of dopamine (DA)-utilizing midbrain neurons whose axons form the nigrostriatal pathway and densely innervate the striatum (caudate-putamen). The clinical symptoms of Parkinson's disease are improved by treatment with DA receptor agonists, including apomorphine. DA agonists modulate basal ganglia outflow at multiple sites and may affect synaptic activity of multiple basal ganglia neurotransmitters, including substance-P peptide (SP). With microdialysis in the substantia nigra reticulata (s.n.r.), a major striatal projection area, we monitored the extracellular level of SP-like immunoreactivity (SP-LI) in awake rats with neurotoxin-induced destruction of nigral DA neurons, before and after treatment with apomorphine (1 mg/kg i.p.). Loss of DA neurons produced a 60% increase in baseline extracellular SP-LI levels. Apomorphine treatment increased baseline extracellular SP-LI levels up to 60% in control rats and 100% in rats with loss of nigral DA neurons. Striatonigral SP endings increase SP release in response to loss of nigral target DA neurons, and DA agonist acting on supersensitive DA receptors, perhaps on SP terminals in the nigra, further increases synaptic SP concentrations.
Orosz
D
D
Department of Neurology, University of Virginia School of Medicine, Charlottesville 22908.
Bennett
J P
JP
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D003956:Dialysis; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005728:Ganglia, Sympathetic / Q000187:drug effects; D006892:Hydroxydopamines; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013373:Substance P / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*
D006892:Hydroxydopamines; D013373:Substance P; D016627:Oxidopamine; D001058:Apomorphine; D004298:Dopamine