Long-Term Potentiation (LTP) in the Central Amygdala (CeA) Is Enhanced After Prolonged Withdrawal From Chronic Cocaine and Requires CRF₁ Receptors

Abstract

. The amygdala is part of the brain reward circuitry that plays a role in cocaine-seeking and abstinence in animals and cocaine craving and relapse in humans. Cocaine-seeking is elicited by cocaine-associated cues, and the basolateral amygdala (BLA) and CeA are essential in forming and communicating drugrelated associations that are thought to be critical in long-lasting relapse risk associated with drug addiction. Here we simulated a cue stimulus with high-frequency stimulation (HFS) of the BLA-CeA pathway to examine mechanisms that may contribute to drug-related associations. We found enhanced long-term potentiation (LTP) after 14-day but not 1-day withdrawal from 7-day cocaine treatment mediated through N-methyl-D-aspartate (NMDA) receptors (NRs), Ltype voltage-gated calcium channels (L-VGCCs), and corticotropinreleasing factor (CRF) 1 receptors; this was accompanied by increased phosphorylated NR1 and CRF 1 protein not associated with changes in NMDA/AMPA ratios in amygdalae from cocaine-treated animals. We suggest that these signaling mechanisms may provide therapeutic targets for the treatment of cocaine cravings.The amygdala is essential in forming stimulus-reward associations and associational processing of conditioned cues (Aggleton 1992;Shinnick-Gallagher et al. 2003). Drug-associated cues can induce craving in cocaine users and alter neural activity in the amygdala (Childress et al. 1999), and electrical stimulation of the basolateral amygdala (BLA) can reinstate drug-seeking in animals (Hayes et al. 2003). Drug-cue associations are not well understood, but the mechanisms may be similar to forms of synaptic plasticity and the induction and expression of cocaine sensitization, a model for long-term neuroadaptations important in addiction (De Vries et al. 1999; Kalivas and Alesdatter 1993;Robinson and Berridge 1993). Antagonizing N-methyl-D-aspartate (NMDA) receptors (NRs) in the amygdala can prevent and block locomotor sensitizing effects of chronic cocaine (Kalivas and Alesdatter 1993), and amygdala NR1 protein levels are increased after acute and chronic cocaine (Turchan et al. 2003). Likewise, activation of L-type calcium channels mimics the induction (Lin et al. 2001) and antagonists block expression of cocaine sensitization (Pierce et al. 1998). Furthermore, corticotropin-releasing factor (CRF) systems in the amygdala play a significant role in cocaine addiction (Sarnyai et al. 2001). In cocaine-treated animals, CRF release in the amygdala is enhanced during acute withdrawal (Richter and Weiss 1999) and in response to a cocaine challenge (Richter et al. 1995). Amygdala CRF immunolabeling decreases after short-term, but increases after long-term withdrawal from chronic cocaine (Zorrilla et al. 2001). Furthermore, cocaine-induced locomotor activity is blocked by intracerebroventricular injection of a CRF antagonist (Sarnyai et al. 1992). These data provide strong rationale for testing the role of CRF receptors in synaptic plasticity in the central amygdala (CeA). This study shows that specific coca...

Synaptic physiology of central CRH system

“…We (Fu and Shinnick-Gallagher 2007) demonstrated at the basolateral amygdala to central amygdala nucleus (Fig. 5, #a) synapse that endogenous CRH co-released during high frequency stimulation was blocked by the selective CRH 1 antagonist NBI30775.…”

“…CRH has been suggested to be responsible for "Priming" (Blank et al 2002;Rainnie et al 2004), and as such may also contribute to a functional synonym for priming, namely, "Metaplasticity" (Abraham and Bear 1996). CRH has been implicated directly in long-term potentiation (LTP, Rebaudo et al 2001;Fu et al 2006;Pollandt et al 2006;Wang et al 2000;Wang et al 1998) and long-term depression (LTD, Miyata et al 1999;Schmolesky et al 2007). …”

Corticotropin releasing factor and neuroplasticity in cocaine addiction

“…Fu et al (2007) used HFS in the neural afferents connecting the basolateral amygdala (BLA) and the CeA (BLA-CeA pathway) to simulate cue-stimuli, associated to cocaine consumption. In animals previously treated with intermittent repeated cocaine, HFS enhanced LTP in the BLA-CeA terminals after long-term withdrawal, but not shortly after cocaine cessation.…”

“…In animals previously treated with intermittent repeated cocaine, HFS enhanced LTP in the BLA-CeA terminals after long-term withdrawal, but not shortly after cocaine cessation. CRF-R1 mediated the enhancement of synaptic strength during withdrawal, an effect requiring the activation of NMDA GLU receptors and N-type voltage-gated calcium channels (Fu et al 2007). These results are in agreement with those published by other authors (Pollandt et al 2006) and suggest a role for CRF in encoding cocaine withdrawal related information in the CeA synapses.…”

Cocaine self-administration improves performance in a highly demanding water maze task

“…These behavioral data seemed to be in accordance with earlier data where cocaine impaired hippocampal long-term potentiation (LTP, Smith et al 1993). However, more recently, cocaine administration has been shown to facilitate LTP in the prefrontal cortex , amygdala (Fu et al 2007), and even in the hippocampus (Thompson et al 2002). In fact, previous results from our laboratory and those of others have shown that cocaine self-administration induces an enhancement of LTP in hippocampal slices (del Olmo et al 2006b;Thompson et al 2004) and that this enhancement of LTP after cocaine self-administration appears to be maintained even during the extinction of this behavior (del Olmo et al 2006b).…”