Role for mTOR Signaling and Neuronal Activity in Morphine-Induced Adaptations in Ventral Tegmental Area Dopamine Neurons

Abstract

SUMMARY While the abuse of opiate drugs continues to rise, the neuroadaptations that occur with long-term drug exposure remain poorly understood. We describe here a series of chronic morphine-induced adaptations in ventral tegmental area (VTA) dopamine neurons, which are mediated via downregulation of AKT-mTORC2 (mammalian target of rapamycin complex-2). Chronic opiates decrease the size of VTA dopamine neurons in rodents, an effect seen in humans as well, and concomitantly increase the excitability of the cells but decrease dopamine output to target regions. Chronic morphine decreases mTORC2 activity, and overexpression of Rictor, a component of mTORC2, prevents morphine-induced changes in cell morphology and activity. Further, local knock-out of Rictor in VTA decreases DA soma size and reduces rewarding responses to morphine, consistent with the hypothesis that these adaptations represent a mechanism of reward tolerance. Together, these findings demonstrate a novel role for AKT-mTORC2 signaling in mediating neuroadaptations to opiate drugs of abuse.

Opiate-Induced Molecular and Cellular Plasticity of Ventral Tegmental Area and Locus Coeruleus Catecholamine Neurons

“…Similar to the in vivo study by Georges et al discussed above, we found that VTA DA firing rate was increased at the same time-point at which soma size is decreased in mice exposed to chronic morphine (Mazei-Robison et al 2011). However, we found that DA output to the NAc, as measured by in vivo cyclic voltammetry, is actually decreased, suggesting a break in the normal activation and output in the mesolimbic reward circuit.…”

“…It is known that prolonged decreases in the basal firing rate of LC neurons is not sufficient to alter soma size, as early CREB knockout from LC NE neurons did not alter neuronal size but decreased basal activity (Parlato et al 2010). However, we also did not detect a difference in VTA DA soma size when we overexpressed a K þ channel to decrease firing rate (Mazei-Robison et al 2011), so the Parlato et al observations do not preclude the possibility of a morphine withdrawal-induced change. Still, it should be noted that the mechanism mediating the changes in firing rate between the two brain regions is very different, with changes in AKT signaling, GABA A currents, and K þ channel expression implicated in VTA and cAMP-CREB signaling implicated in LC.…”

“…Additionally, this change could be blocked by systemic naltrexone, suggesting that MOR signaling was required, and local brain-derived neurotrophic factor (BDNF) infusion in VTA also prevented the decrease, suggesting that decreased neurotrophic signaling may underlie the morphological change. Importantly, this reduction in VTA DA neuron soma size is observed with chronic administration of heroin as well as morphine (Russo et al 2007), in passive and self-administration protocols (Spiga et al 2003;Chu et al 2007;Russo et al 2007), and across species, as we have recently characterized this effect in mouse and in postmortem tissue from human heroin abusers (Mazei-Robison et al 2011). Follow-up studies found no evidence of VTA DA neuronal death or injury (Sklair-Tavron et al 1996;Russo et al 2007) and that the decrease in cell size persists for 14 days after chronic morphine administration, but returns to baseline by 30 days.…”

“…Although there is some controversy as to whether BDNF levels themselves are altered in VTA in response to chronic opiate administration (Numan et al 1998;Chu et al 2007;Koo et al 2010), regulation has been reported in the three main signaling pathways downstream from BDNF: PLCg, phosphatidylinositol 3 0 -kinase (PI3K), and mitogen-activated protein kinase (MAPK) (Russo et al 2009). Chronic morphine increases activity of the PLCg pathway (Wolf et al 1999(Wolf et al , 2007, decreases activity of the PI3K pathway, as measured by decreased insulin receptor substrate-2 (IRS2) and phospho-AKT levels (Wolf et al 1999;Russo et al 2007;Mazei-Robison et al 2011), and increases MAPK signaling, as measured by increased phosphorylation and catalytic activity of extracellular-related protein kinase (ERK) (Ortiz et al 1995;Berhow et al 1996;Liu et al 2007). Using viral-mediated overexpression, we found that it was the chronic morphine-induced change in PI3K signaling that contributes to the morphological change: overexpression of a dominant-negative IRS2 (IRS2dn) or AKTdn was sufficient to decrease VTA DA soma size, while overexpression of wild-type IRS2 prevented the morphine-induced decrease and overexpression of a constitutively active AKT (AKTca) increased soma size (Russo et al 2007;Mazei-Robison et al 2011).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Second, experimental protocols that induce LTD are linked with shrinkage or retraction of spines, whereas induction of LTP enhances formation of new spines and enlargement of existing spines (Nagerl et al, 2004). In sharp contrast to psychomotor stimulants that increase dendritic branching and density, chronic morphine exposure reduces the size of VTA DA neurons (Sklair-Tavron et al, 1996;Russo et al, 2007;Mazei-Robison et al, 2011) and the density of dendritic spines in brain areas considered relevant for drug addiction, such as the NAc, OFC, and HC (Robinson and Kolb, 1999b;Robinson et al, 2002). Because stimulants and opioids similarly induce transcription factors (e.g., CREB, DFosB) that regulate expression of cytoskeletal proteins, the disparate findings on spine density are perplexing.…”