Central Amygdala GluA1 Facilitates Associative Learning of Opioid Reward

Abstract

GluA1 subunits of AMPA glutamate receptors are implicated in the synaptic plasticity induced by drugs of abuse for behaviors of drug addiction, but GluA1 roles in emotional learning and memories of drug reward in the development of drug addiction remain unclear. In this study of the central nucleus of the amygdala (CeA), which is critical in emotional learning of drug reward, we investigated how adaptive changes in the expression of GluA1 subunits affected the learning process of opioid-induced context–reward association (associative learning) for the acquisition of reward-related behavior. In CeA neurons, we found that CeA GluA1 expression was significantly increased 2 h after conditioning treatment with morphine, but not 24 h after the conditioning when the behavior of conditioned place reference (CPP) was fully established in rats. Adenoviral overexpression of GluA1 subunits in CeA accelerated associative learning, as shown by reduced minimum time of morphine conditioning required for CPP acquisition and by facilitated CPP extinction through extinction training with no morphine involved. Adenoviral shRNA-mediated downregulation of CeA GluA1 produced opposite effects, inhibiting the processes of both CPP acquisition and CPP extinction. Adenoviral knockdown of CeA GluA2 subunits facilitated CPP acquisition, but did not alter CPP extinction. Whole-cell recording revealed enhanced electrophysiological properties of postsynaptic GluA2-lacking AMPA receptors in adenoviral GluA1-infected CeA neurons. These results suggest that increased GluA1 expression of CeA AMPA receptors facilitates the associative learning of context-drug reward, an important process in both development and relapse of drug-seeking behaviors in drug addiction.

Bidirectional Modulation of Extinction of Drug Seeking by Deep Brain Stimulation of the Ventral Striatum

“…Overexpression of GluA1 (Gria1) subunits of AMPA receptors in CeA facilitated the extinction of morphine place preference, whereas downregulation of GluA1 subunits in this same region had the opposite effect (60). In addition, drug seeking behaviors can be attenuated by intra-CeA infusion of agonists of metabotropic glutamate receptors (61), D2/D3 dopaminergic receptors (62), or 5HT-2C serotonergic receptors (63).…”

Amygdala Pain Mechanisms

“…A discussion of opioid function in the amygdala is beyond the scope of this article. There is strong evidence for a critical role of the amygdala, and the CeA in particular, in opioid dependent pain modulation (Manning and Mayer 1995a;Zhang et al 2013;Fields 2000;Manning and Mayer 1995b;Manning 1998) and reward mechanisms (Bie et al 2012;Cai et al 2013), and μ-, κ- and δ-opioid agonists can have direct effects on CeA amygdala neurons (Zhu and Pan 2004;Bie et al 2009). However their role in pain-related amygdala processing and plasticity remain to be determined.…”

GluA1 in central amygdala increases pain but inhibits opioid withdrawal-induced aversion

“…Finally, we further verified the results of this GluA1 role by knocking down the GluA1 expression in CeA with an AAV vector expressing a short-hairpin interfering RNA against the GluA1-encoding gene Gria1 (AAV-GluA1-shRNA) and a control vector with scrambled shRNA sequence, as we described and validated previously. 41,44 We found that CeA infusion of the AAV-GluA1-shRNA vector for GluA1 knockdown failed to change the preference/aversion behavior under normal conditions; however, the GluA1 knockdown significantly increased the withdrawal-induced CPA behavior ( Figure 5), an effect opposite to that of GluA1 overexpression shown above. These results further support the notion that the activity of GluA1 AMPARs in CeA reduces the aversive effect of opioid withdrawal.…”

“…The construction and their functional validation of adeno-associated virus (AAV) vectors for GluA1 overexpression (AAV-GluA1) and GluA1 knockdown (AAV-GluA1-shRNA) have been described in our previous studies. 35,41,44 The vector AAV-green fluorescent protein (GFP) was used as control. An animal was injected with 1 ll ($5 Â 10 9 genome copy (GC)/ll) AAV-GluA1 virus, or 1 ll ($2 Â 10 9 GC/ll) AAV-GluA1-shRNA virus into CeA on each side of the brain.…”