GABAergic neurons in the ventral tegmental area receive dual GABA/enkephalin‐mediated inhibitory inputs from the bed nucleus of the stria terminalis

Abstract

Activation of mu-opioid receptor (MOR) disinhibits dopaminergic neurons in the ventral tegmental area (VTA) through inhibition of γ-aminobutyric acid (GABA)ergic neurons. This mechanism is thought to play a pivotal role in mediating reward behaviors. Here, we characterised VTA-projecting enkephalinergic neurons in the anterior division of the bed nucleus of the stria terminalis (BST) and investigated their targets by examining MOR expression in the VTA. In the BST, neurons expressing preproenkephalin mRNA were exclusively GABAergic, and constituted 37.2% of the total GABAergic neurons. Using retrograde tracer injected into the VTA, 21.6% of VTA-projecting BST neurons were shown to express preproenkephalin mRNA. Enkephalinergic projections from the BST exclusively formed symmetrical synapses onto the dendrites of VTA neurons. In the VTA, 74.1% of MOR mRNA-expressing neurons were GABAergic, with the rest being glutamatergic neurons expressing type-2 vesicular glutamate transporter mRNA. However, MOR mRNA was below the detection threshold in dopaminergic neurons. By immunohistochemistry, MOR was highly expressed on the extrasynaptic membranes of dendrites in GABAergic VTA neurons, including dendrites innervated by BST-VTA projection terminals. MOR was also expressed weakly on GABAergic and glutamatergic terminals in the VTA. Given that GABAA α1 is expressed at GABAergic BST-VTA synapses on dendrites of GABAergic neurons [T. Kudo et al. (2012) J. Neurosci., 32, 18035-18046], our results collectively indicate that the BST sends dual inhibitory outputs targeting GABAergic VTA neurons; GABAergic inhibition via 'wired' transmission, and enkephalinergic inhibition via 'volume' transmission. This dual inhibitory system provides the neural substrate underlying the potent disinhibitory control over dopaminergic VTA neurons exerted by the BST.

Comparison of c-Fos expression in brain regions involved in maternal behavior of virgin and lactating female mice

“…Because injection of CRF into the BNST disrupts maternal behavior in lactating females [26], CRF interneurons may also be activated in virgin females presented with pups. Evidence suggests that GABAergic neurons in the BNST would be activated in lactating females presented with pups, because activation of those neurons disinhibits dopaminergic neurons in the VTA [27]. However, pup presentation did not increase the number of c-Fos-positive cells in the BNST of lactating females, even though the number of c-Fospositive cells expressing TH in the VTA increased ( Figs.…”

Molecular Changes in Opioid Addiction: The Role of Adenylyl Cyclase and cAMP/PKA System

“…The BNST projects inhibitory fibers to the VTA, GABAergic, and GABAergic/enkephalinergic, to modulate response to MOP activation. 140 While behavioral changes are associated with BNST modulation upon chronic morphine administration, AC activity is not affected. 141 While opioid antagonists have been employed experimentally to induce withdrawal in animals treated chronically with opioids, several studies have examined the chronic use of low-dose opioid antagonists to alleviate withdrawal symptoms.…”

Embryonic Origin of the Islet1 and Pax6 Neurons of the Chicken Central Extended Amygdala Using Cell Migration Assays and Relation to Different Neuropeptide-Containing Cells

“…In addition, a recent study in mice has shown that ENK neurons of the BSTL project to the VTA [Kudo et al, 2014] and may play a role in reward [Jennings et al, 2013b]. These projections are GABAergic and end preferentially on nondopaminergic neurons of the VTA, leading to disinhibition of the dopaminergic neurons [Kudo et al, 2014].…”