title: Novel δ1-receptor agonist KNT-127 increases the release of dopamine and L-glutamate in the striatum, nucleus accumbens and median pre-frontal cortex.
abstract: The effects of systemic δ1-agonist on neurotransmission remains obscure, since no selective δ1-agonist exists that can penetrate the blood-brain barrier. Recently, we succeeded in synthesizing a putative δ1-receptor agonist, KNT-127, which has been demonstrated the effectiveness of systemic administration against anxiety and depressive-like behavior. To clarify the functional selectivity of KNT-127 and neurotransmission regulating system of δ1-receptor, the present study investigated the interaction between KNT-127 and δ-receptor antagonists on the release of dopamine, L-glutamate and GABA in nucleus accumbens (NAc), striatum and median pre-frontal cortex (mPFC) using multi-probe microdialysis. Intraperitoneal administration of KNT-127 increased the release of dopamine and L-glutamate in three regions, but decreased and increased GABA releases in respective NAc and mPFC without affecting that in striatum. The effects of KNT-127 in the three regions were abrogated by δ1-antagonist but not by δ2-antagonist. MK801 inhibited KNT-127-induced dopamine release in striatum and NAc, but enhanced that in mPFC, inhibited KNT-127-induced mPFC GABA release without affecting KNT-127-induced GABA reduction in NAc. Muscimol enhanced KNT-127-induced dopamine release in mPFC. Sulpiride inhibited KNT-127-induced reduction of GABA release in NAc. The results indicated that KNT-127 is a selective δ1-agonist, and suggested that δ1-receptor directly activates the release of dopamine and L-glutamate in the striatum, NAc and mPFC, but not that of GABA in the three regions. δ1-receptor indirectly inhibited GABA release in NAc via activated dopaminergic transmission, while δ1-receptor indirectly enhanced GABA release in mPFC via activated glutamatergic transmission.
authors.affiliation: Department of Psychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Tanahashi
authors.forename: Yuto
authors.initials: Y
authors.lastname: Ueda
authors.forename: Akira
authors.initials: A
authors.lastname: Nakajima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
authors.forename: Motohiro
authors.initials: M
authors.lastname: Okada
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009019:Morphinans / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C555233:KNT 127; D009019:Morphinans; D017465:Receptors, Opioid, delta; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D004298:Dopamine