title: Paliperidone increases spontaneous and evoked firing of mesocortical dopaminergic neurons by activating a hyperpolarization-activated inward current.
abstract: Mesocortical dopaminergic (DA) subtype neurons specifically project to the prefrontal cortex, which is closely related with schizophrenia. Mesocortical DA neurons have unique physiological characteristics that are different from those of mesostriatal and mesolimbic DA neurons. Paliperidone, an atypical antipsychotic, is currently used to treat schizophrenia and has better therapeutic effects than typical antipsychotics. However, the underlying physiological mechanism remains unclear. To explore the effects of paliperidone on mesocortical DA neuron activity, here, we retrogradely labeled these cells with fluorescent microsphere retrobeads, and the electrophysiological changes were recorded in whole-cell recordings in rat midbrain slices with or without paliperidone. The data showed that paliperidone (20μmol/L) increased the spontaneous firing rates of labeled mesocortical neurons (P<0.05). Moreover, paliperidone also increased the frequency of evoked action potentials by current injection stimulation (P<0.05), whereas the accompanying amplitude decreased. Furthermore, to explore the mechanisms of paliperidone's effect, Ih currents were detected, and the results showed that hyperpolarizing voltage pulses evoked instantaneous Ih inward currents and paliperidone increased the maximum Ih current. In addition, paliperidone decreased the spontaneous inhibitory postsynaptic currents. Thus, paliperidone increased the spontaneous and evoked firing of mesocortical neurons, possibly by activating the Ih inward current and reducing the inhibitory synaptic transmission, which provides an underlying mechanism of paliperidone's application in schizophrenia.
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Haiman
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Dexiao
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Neurology, The Qilu Hospital of Shandong University, Jinan, Shandong, 250031,China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Bao
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Yanlai
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Zhaoxi
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong 250012, China. Electronic address: sunjinhao@gmail.com.
authors.forename: Jinhao
authors.initials: J
authors.lastname: Sun
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D009434:Neural Pathways / Q000166:cytology; D000068882:Paliperidone Palmitate / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000166:cytology; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects; D046509:Tissue Culture Techniques
chemical_list: D014150:Antipsychotic Agents; D000068882:Paliperidone Palmitate
keywords: Dopaminergic; I(h) current; Mesocortical; Paliperidone