Bargmann, L.Vosshall, and members of the Young Lab for critical comments on the manuscript and discussions. This research was supported by NIH grants NS053087, GM054339, and MH015125 to M.W.Y., and by NIH Ruth L. Kirchstein postdoctoral fellowship GM080934 to N.S. “
“A major neural substrate for the rewarding actions of opiates is dopaminergic (DA) neurons within the ventral tegmental area (VTA). Opiates acutely activate VTA DA neurons by inhibiting

their GABAergic input through hyperpolarization of local GABA interneurons (Johnson and North, 1992), and decreasing long-term potentiation of GABAergic synapses onto DA neurons (Niehaus et al., 2010). Additionally, VTA DA neuron activity in vivo is increased in morphine-dependent rats, an effect normalized by either spontaneous or naloxone-precipitated Autophagy Compound Library research buy withdrawal (Georges et al., 2006). However, the influence of chronic opiates on the intrinsic excitability of VTA DA neurons remains unknown. selleck chemicals llc At a cellular level, we have shown that both chronic morphine administration and heroin self-administration in rats decreases the soma size

of VTA DA neurons (Russo et al., 2007 and Sklair-Tavron et al., 1996). This reduced soma size is mediated by downregulation of a specific brain-derived neurotrophic factor (BDNF) signaling pathway involving insulin receptor substrate 2 (IRS2): the decrease in DA cell size is blocked by local infusion of BDNF (Sklair-Tavron et al., 1996) or viral-mediated overexpression of IRS2 in VTA, and mimicked by viral-mediated overexpression of a dominant-negative mutant of IRS2 (IRS2dn) in this brain

region (Russo et al., 2007). Importantly, the decrease in soma size correlates with reward tolerance (Russo et al., 2007), where repeated drug use decreases the rewarding effect of the drug and leads to an escalation heptaminol of drug intake, as seen in humans (O’Brien, 2001). While these studies suggest that the protein kinase AKT, which is downstream of IRS2, is necessary and sufficient for the morphine-induced decrease in VTA cell size, the downstream signaling mechanisms involved remain unexplored. Moreover, the net effect of this decrease in VTA DA neuron soma size, along with any change in cell excitability, is unknown, although there are several reports of altered VTA DA soma size under other conditions (see Discussion). Here, we focused on adaptations that chronic opiates induce in VTA DA neurons by further characterizing morphine-induced changes in VTA soma size, excitability, and functional output to target brain regions. We focus on AKT and one of its major downstream pathways, mammalian target of rapamycin (mTOR), as the critical mediators of morphine action, given the widely established role of this signaling pathway in cell growth. The serine/threonine kinase activity of mTOR, and its downstream substrates, depend on mTOR’s association into two distinct complexes designated mTORC1 and mTORC2 (Foster and Fingar, 2010 and Laplante and Sabatini, 2009).