Novel δ1-receptor agonist KNT-127 increases the release of dopamine and L-glutamate in the striatum, nucleus accumbens and median pre-frontal cortex

Neuropharmacology. 2012 Apr;62(5-6):2057-67. doi: 10.1016/j.neuropharm.2012.01.005. Epub 2012 Jan 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism
  • Dopamine / metabolism*
  • Glutamic Acid / metabolism*
  • Male
  • Microdialysis
  • Morphinans / pharmacology*
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, delta / agonists*
  • gamma-Aminobutyric Acid / metabolism

Substances

  • KNT 127
  • Morphinans
  • Receptors, Opioid, delta
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Dopamine