Description:
<jats:p>Midbrain dopamine neurons play physiological roles in many processes including reward learning and motivated behavior. Conversely, dysfunction of these neurons is implicated in disorders such as schizophrenia and drug abuse. Midbrain dopamine neurons are tonically inhibited by γ‐Aminobutyric acid (GABA)ergic inputs from multiple brain regions. Neurotensin (NT) is a neuropeptide which modulates midbrain dopamine neuron excitability through multiple mechanisms, including a decrease of GABA mediated inhibition of dopamine neurons. However, it is not known if NT acts post‐synaptically on GABA type‐B receptor signaling, pre‐synaptically at GABA terminals to alter GABA release, or through a combination of synaptic mechanisms. Here we utilize whole cell patch‐clamp electrophysiology of dopamine neurons in brain slices to show that neurotensin acts both pre‐ and post synaptically to decreases GABA type‐B receptor‐mediated currents in the substantia nigra in mice. Bath perfusion of neurotensin produced a sustained depression of GABA type‐B receptor‐mediated currents that was more pronounced when GABA was released endogenously (due to electrical stimulation) compared to when GABA was directly applied to the cell (via iontophoresis). GABA type‐B receptor mediated currents exhibited paired pulse depression when currents were elicited with electrical stimulation, but not GABA iontophoresis. Bath application of neurotensin increased the paired pulse ratio with electrical stimulation but had no effect on paired pulse currents elicited by GABA iontophoresis, providing further evidence neurotensin modulates GABA release. As NT is an endogenous peptide present at high levels in the midbrain, determining the mechanism of action by which NT alters midbrain dopamine neuron excitability is a crucial step in understanding the importance of NT in dopamine mediated behavior and related disorders.</jats:p><jats:p><jats:bold>Support or Funding Information</jats:bold></jats:p><jats:p>Support provided by NIH R01 DA 32701</jats:p>