Neuroimmune Regulation of GABAergic Neurons Within the Ventral Tegmental Area During Withdrawal from Chronic Morphine

Abstract

Opioid dependence is accompanied by neuroplastic changes in reward circuitry leading to a negative affective state contributing to addictive behaviors and risk of relapse. The current study presents a neuroimmune mechanism through which chronic opioids disrupt the ventral tegmental area (VTA) dopaminergic circuitry that contributes to impaired reward behavior. Opioid dependence was induced in rodents by treatment with escalating doses of morphine. Microglial activation was observed in the VTA following spontaneous withdrawal from chronic morphine treatment. Opioid-induced microglial activation resulted in an increase in brain-derived neurotrophic factor (BDNF) expression and a reduction in the expression and function of the K+Cl− co-transporter KCC2 within VTA GABAergic neurons. Inhibition of microglial activation or interfering with BDNF signaling prevented the loss of Cl− extrusion capacity and restored the rewarding effects of cocaine in opioid-dependent animals. Consistent with a microglial-derived BDNF-induced disruption of reward, intra-VTA injection of BDNF or a KCC2 inhibitor resulted in a loss of cocaine-induced place preference in opioid-naïve animals. The loss of the extracellular Cl− gradient undermines GABAA-mediated inhibition, and represents a mechanism by which chronic opioid treatments can result in blunted reward circuitry. This study directly implicates microglial-derived BDNF as a negative regulator of reward in opioid-dependent states, identifying new therapeutic targets for opiate addictive behaviors.

Stress Increases Ethanol Self-Administration via a Shift toward Excitatory GABA Signaling in the Ventral Tegmental Area

“…In contrast, the ratio of phosphorylated-S940 KCC2 to total KCC2 protein after stress was significantly lower compared to control (Figure 7F, G): 78.3 ± 5.5% for monomer, 79.6 ± 4.7% for dimer. Importantly, as also reported previously (Taylor et al, 2015), immunolabeling analysis in the VTA suggested that KCC2 protein was expressed exclusively on non-DA neurons (data not shown), which is consistent with the presence of another chloride extrusion mechanism in DA neurons (Gulacsi et al, 2003). …”

“…These findings highlight the importance of glucocorticoid signaling within the VTA, but we do not rule out the participation of other stress signaling molecules or hormones, such as CRF, in mediating stress-induced adaptations (Hwa et al, 2016; Ungless et al, 2003). Furthermore, the effect of glucocorticoids on VTA GABA neurons may involve the activity of noradrenaline, glutamate, and glial cells (Coull et al, 2003; Hewitt et al, 2009; Lee et al, 2011; Taylor et al, 2015). …”

Differential patterning of genes involved in serotonin metabolism and transport in extra-embryonic tissues of the mouse

“…Figures were prepared digitally using Adobe Photoshop CS5.1 and Adobe Illustrator CS5.1 (Adobe Systems In., San Jose, CA). To compare the expression differences between yolk sac and labyrinth, fluorescent intensities from Maoa , Tph1 , or Ddc were quantified using FIJI ImageJ software (NIH) [30]. The mean intensities from 3 random areas of the same size (45.19 μm x 34.92 μm) in the labyrinth or yolk sac were measured for each probe.…”

Therapies and Mechanisms of Opioid Withdrawal

“…Hence, brain regions associated with reward and affective behaviors have also been implicated [13]. It has been shown that chronic opioid administration in rodents promoted GABA-mediated excitation [14] and loss of neuronal inhibition via reduction of KCC 2 currents in the ventral tegmental area [15]. Furthermore, acute morphine withdrawal in rats increased c-Fos expression in dopaminergic neurons within nucleus accumbens shell in mice [16], and phosphorylation of NMDARs in the accumbens [17].…”