Glutamatergic neurotransmission in the prefrontal cortex mediates the suppressive effect of intra-prelimbic cortical infusion of BDNF on cocaine-seeking

Abstract

Cocaine self-administration induces dysfunctional neuroadaptations in the prefrontal cortex that underlie relapse to cocaine-seeking. Cocaine self-administration disturbs glutamatergic transmission in the nucleus accumbens that is prevented by infusion of brain-derived neurotrophic factor (BDNF) into the prelimbic area of the prefrontal cortex. Intra-prelimbic infusion of BDNF decreases cocaine-seeking in a TrkB-ERK MAP kinase-dependent manner. Neuronal activity triggers an interaction between TrkB receptors and NMDA receptors, leading to ERK activation. In the present study, infusion of the GluN2A-containing NMDA receptor antagonist, TCN-201, or the GluN2B-containing NMDA receptor antagonist, Ro-25-6981, into the prelimbic cortex of rats blocked the suppressive effect of BDNF on cocaine-seeking. During early withdrawal from cocaine self-administration, tyrosine phosphorylation of ERK, GluN2A, and GluN2B in the prelimbic cortex was reduced and this reduction of phospho-proteins was prevented by intra-prelimbic BDNF infusion. TCN-201 infusion into the prelimbic cortex inhibited the BDNF-mediated increase in pERK and pGluN2A whereas Ro-25-6981 infusion into the prelimbic cortex blocked BDNF-induced elevation of pERK and pGluN2B, indicating that both GluN2A- and GluN2B-containing NMDA receptors underlie BDNF-induced ERK activation. These data demonstrate that BDNF-mediated activation of GluN2A- and GluN2B-containing NMDA receptors underlies ERK activation in the prelimbic cortex during early withdrawal, preventing subsequent relapse to cocaine-seeking.

Biphasic effect of abstinence duration following cocaine self-administration on spine morphology and plasticity-related proteins in prelimbic cortical neurons projecting to the nucleus accumbens core

“…This evidence extends previous data from our laboratory showing that cocaine SA leads to a decrease in phospho-protein signaling in the PrL cortex during early withdrawal (Sun et al 2013; Whitfield et al 2011; Go et al 2016; Barry and McGinty 2017) and extends the findings specifically to PrL-NA core neurons.…”

“…Our previous studies demonstrate that intra-PrL administration of BDNF reverses cocaine’s impact on phospho-protein signaling during early withdrawal thereby reducing drug seeking (Berglind et al 2007; Go et al 2016). The data reported herein are consistent with the global changes in PrL cortex we have previously reported and suggest that the changes in PRPs and dendritic spines in the PrL-NA core pathway during early withdrawal also contribute to relapse and would be reversed by intra-PrL BDNF.…”

“…early withdrawal), we have observed dephosphorylation of extracellular signal-regulated kinase 2 (ERK2), cAMP response-element binding protein (CREB), GluN2A/B-containing NMDA receptors, and increased activation of STriatal-Enriched protein Tyrosine Phosphatase (STEP) (Whitfield et al 2011; Go et al 2016; Siemsen et al 2018). Normalizing these dephosphorylation events with a single intra-PrL infusion of Brain-Derived Neurotrophic Factor (BDNF) or the STEP inhibitor, TC-2153, immediately after SA provides an enduring decrease in relapse (Whitfield et al 2011; Go et al 2016; Siemsen et al 2018; Berglind et al 2007) and normalizes dysfunctional glutamate release in the nucleus accumbens (NA) core (Berglind et al 2009). In contrast, after one week of abstinence ( i.e.…”

Exercise as a Sex-Specific Treatment for Substance Use Disorder

“…Specifically, drug-craving and markers of Bdnf signaling in the reward pathway are low during early abstinence, but as abstinence continues, both craving and markers of Bdnf signaling increase (87). Notably, the incubation of craving and associated increase in Bndf signaling can be prevented by upregulating Bdnf during early, but not late, abstinence (88). Given that exercise also upregulates Bdnf (85,89), it’s possible that its ability to block the incubation of drug-craving may occur via upregulation of Bdnf during early abstinence.…”

Cross-talk between the epigenome and neural circuits in drug addiction

“…These include genes that are important for neuronal plasticity, such as the immediate-early genes Erg1, Creb, and Bdnf, which showed an increase in expression following contextual fear learning, concomitant with the increase in histone acetylation (Bannerman et al, 2014; Korzus et al, 2004; Oliveira et al, 2011). Indeed, all of these molecules have been shown to be critically involved in different stages of the addiction process and the expression of maladaptive reward behaviors (Go et al, 2016; Hoffmann et al, 2017; Li et al, 2016; Rovaris et al, 2017; Sun et al, 2015; Zhang et al, 2016). Relevantly, during this time window, Ca 2+ -induced cAMP signaling that engages the ERK and PKA pathways in the hippocampus and the amygdala directly phosphorylate and thus activate the transcription factor cAMP-response element-binding protein (CREB), a process critical to long-term memory (Dash et al, 1990; Freytag et al, 2017; Serita et al, 2017; Stevens, 1994).…”