title: Intrinsic membrane plasticity via increased persistent sodium conductance of cholinergic neurons in the rat laterodorsal tegmental nucleus contributes to cocaine-induced addictive behavior.
abstract: The laterodorsal tegmental nucleus (LDT) is a brainstem nucleus implicated in reward processing and is one of the main sources of cholinergic afferents to the ventral tegmental area (VTA). Neuroplasticity in this structure may affect the excitability of VTA dopamine neurons and mesocorticolimbic circuitry. Here, we provide evidence that cocaine-induced intrinsic membrane plasticity in LDT cholinergic neurons is involved in addictive behaviors. After repeated experimenter-delivered cocaine exposure, ex vivo whole-cell recordings obtained from LDT cholinergic neurons revealed an induction of intrinsic membrane plasticity in regular- but not burst-type neurons, resulting in increased firing activity. Pharmacological examinations showed that increased riluzole-sensitive persistent sodium currents, but not changes in Ca(2+) -activated BK, SK or voltage-dependent A-type potassium conductance, mediated this plasticity. In addition, bilateral microinjection of riluzole into the LDT immediately before the test session in a cocaine-induced conditioned place preference (CPP) paradigm inhibited the expression of cocaine-induced CPP. These findings suggest that intrinsic membrane plasticity in LDT cholinergic neurons is causally involved in the development of cocaine-induced addictive behaviors.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Kamii
authors.forename: Ryo
authors.initials: R
authors.lastname: Kurosawa
authors.forename: Naofumi
authors.initials: N
authors.lastname: Taoka
authors.forename: Fumiya
authors.initials: F
authors.lastname: Shinohara
authors.forename: Masabumi
authors.initials: M
authors.lastname: Minami
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kaneda
mesh_terms: D000818:Animals; D059329:Cholinergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D003042:Cocaine / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008297:Male; D009473:Neuronal Plasticity; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019782:Riluzole / Q000494:pharmacology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000378:metabolism; D013681:Tegmentum Mesencephali / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051640:Small-Conductance Calcium-Activated Potassium Channels; D026941:Sodium Channel Blockers; D019782:Riluzole; D012964:Sodium; D003042:Cocaine
keywords: addiction; conditioned place preference; mesocorticolimbic circuitry; neuroplasticity; persistent sodium channel