title: Dopamine D2 receptor-dependent modulation of striatal NO synthase activity.
abstract: BACKGROUND
  Striatal nitric oxide (NO)-producing interneurons receive synaptic contacts from midbrain dopamine (DA) neurons and are regulated by phasic DA transmission. Classic antipsychotic drugs elevate neuronal NO synthase (NOS) expression in the rat striatum. Given that NO signaling potently modulates the membrane excitability of striatal projection neurons, it is plausible that up-regulation of NOS activity after DA D2 receptor blockade contributes to the therapeutic efficacy and/or motor side effects associated with antipsychotic drugs.
  
  
  OBJECTIVE
  This study assessed the impact of DA D(2) receptor activation on striatal NOS activity in vivo. Characterization of the dopaminergic regulation of striatal NO signaling will be relevant for understanding the mechanism(s) of action of antipsychotic drugs.
  
  
  METHODS
  Striatal NO efflux, evoked via electrical stimulation of the substantia nigra (SN) or systemic administration of the DA D(1) receptor agonist SKF 81297, was assessed in anesthetized rats using an NO-selective amperometric microsensor.
  
  
  RESULTS
  The facilitatory effect of SN stimulation on striatal NO efflux was attenuated by systemic administration of the DA D(2) receptor agonist quinpirole. Conversely, administration of the DA D(2) receptor antagonist eticlopride augmented evoked NO efflux. NO efflux induced by systemic administration of SKF 81297 was attenuated by quinpirole and restored by co-administration of quinpirole and eticlopride. The facilitatory effect of SKF 81297 on NO efflux was also significantly attenuated after pretreatment with the non-specific NOS inhibitor methylene blue.
  
  
  CONCLUSIONS
  Activation of NO synthesis by phasic DA transmission is down-regulated via a DA D2 receptor-dependent mechanism. DA D(2) receptor activation opposes DA D(1) receptor activation of NO synthesis at a site postsynaptic to the DA terminal. Further studies examining NO-DA dynamics may have potential to reveal novel therapeutic strategies to treat various brain disorders.
authors.affiliation: Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Sammut
authors.forename: Kristina E
authors.initials: KE
authors.lastname: Bray
authors.forename: Anthony R
authors.initials: AR
authors.lastname: West
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001479:Basal Ganglia / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D001552:Benzazepines / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D012457:Salicylamides / Q000494:pharmacology; D013378:Substantia Nigra / Q000378:metabolism; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D019257:Quinpirole; D009569:Nitric Oxide; C067113:SK&F 81297; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; C045989:eticlopride; D008751:Methylene Blue; D004298:Dopamine