title: Chronic cocaine exposure induces noradrenergic modulation of inhibitory synaptic transmission to cholinergic neurons of the laterodorsal tegmental nucleus.
abstract: The laterodorsal tegmental nucleus (LDT), which sends cholinergic efferent connections to dopaminergic (DA) neurons in the ventral tegmental area (VTA), plays a critical role in the development of addictive behavior and the reinstatement of cocaine-seeking behavior. Although repeated cocaine exposure elicits plastic changes in excitatory synaptic transmission and intrinsic membrane excitability in LDT cholinergic neurons, it remains unclear whether inhibitory synaptic transmission is modulated by cocaine exposure. The LDT receives fibers containing noradrenaline (NA), a neurotransmitter whose extracellular levels increase with cocaine exposure. Therefore, it is hypothesized that repeated cocaine exposure induces plastic changes in LDT cholinergic neurons via NA. Ex vivo electrophysiological recordings in LDT cholinergic neurons were obtained from rats repeatedly exposed to cocaine. Bath-application of NA induced similar levels of hyperpolarization in both saline- and cocaine-treated neurons. However, NA attenuated the amplitude of inhibitory postsynaptic currents (IPSCs) in cocaine- but not saline-treated neurons through α2 adrenoceptors. This NA-induced IPSC attenuation was observed in the presence of strychnine, but not gabazine, indicating that NA modulated GABAergic but not glycinergic neurotransmission. NA increased the paired-pulse ratios of evoked IPSCs and decreased the frequencies of miniature IPSCs (mIPSCs) without affecting their amplitudes, suggesting a presynaptic mechanism. These findings suggest that repeated cocaine exposure induces neuroplasticity in GABAergic synaptic transmission onto LDT cholinergic neurons by probably modulating presynaptic α2 adrenoceptors. This potentially increases the activity of LDT cholinergic neurons, which might contribute to the development of addictive behavior by enhancing VTA DA neuronal activity.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Taoka
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Kamiizawa
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Wada
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Masabumi
authors.initials: M
authors.lastname: Minami
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.|Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kaneda
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage; D000818:Animals; D059329:Cholinergic Neurons / Q000187:drug effects* / Q000502:physiology*; D003042:Cocaine / Q000008:administration & dosage*; D005260:Female; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology; D005998:Glycine / Q000502:physiology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects*; D008297:Male; D009638:Norepinephrine / Q000008:administration & dosage / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D013681:Tegmentum Mesencephali / Q000187:drug effects* / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D000316:Adrenergic alpha-Agonists; D018341:Receptors, Adrenergic, alpha-2; D005680:gamma-Aminobutyric Acid; D003042:Cocaine; D005998:Glycine; D009638:Norepinephrine
keywords: acetylcholine; addiction; mesocorticolimbic system; noradrenaline; ventral tegmental area