Selective dopamine D3 receptor antagonists enhance cortical acetylcholine levels measured with high-performance liquid chromatography/tandem mass spectrometry without anti-cholinesterases.
The present study compared the effects of two selective dopamine (DA) D(3) receptor antagonists, SB-277011A (3, 10 and 30 mg/kg i.p.) and SB-414796A (3, 10 and 30 mg/kg i.p.) on extracellular levels of acetylcholine (ACh) in the rat medial prefrontal cortex (mPFC) by using a LC/MS-MS analytical method that permitted the detection of ACh without the necessity of adding acetylcholinesterase inhibitors to the perfusate. Furthermore, the present LC/MS-MS method permitted the simultaneous measurement of the respective concentrations of SB-277011A and SB-414796A in the same extracellular samples from the mPFC. The systemic administration of both selective DA D(3) receptor antagonists produced a significant increase in extracellular levels of Ach compared to vehicle-treated animals, which was associated with increases in extracellular concentrations of SB-277011A and SB-414796. Overall, the present findings further strengthen the likelihood of a modulation of cortical cholinergic function through a DA D(3)-mediated mechanism and suggest that selective DA D(3) receptor antagonism may be beneficial in the treatment of psychiatric diseases, such as schizophrenia, which are characterized by cognitive dysfunction.
Lacroix
Laurent P
LP
Department of Neuropsychopharmacology, Centre of Excellence for Drug Discovery in Psychiatry, GlaxoSmithKline S.p.A., Via A. Fleming 4, 37135 Verona, Italy.
Ceolin
Laura
L
Zocchi
Alessandro
A
Varnier
Giorgia
G
Garzotti
Marco
M
Curcuruto
Ornella
O
Heidbreder
Christian A
CA
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005110:Extracellular Space / Q000187:drug effects; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D017551:Microdialysis / Q000379:methods; D010069:Oxadiazoles / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000924:Anticholesteremic Agents; D018492:Dopamine Antagonists; D006574:Heterocyclic Compounds, 2-Ring; D010069:Oxadiazoles; C515455:SB-414796A; D000109:Acetylcholine