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) D3 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 D3 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 D3-mediated mechanism and suggest that selective DA D3 receptor antagonism may be beneficial in the treatment of psychiatric diseases, such as schizophrenia, which are characterized by cognitive dysfunction.