Transforming Growth Factor Beta Receptor 1 Is Increased following Abstinence from Cocaine Self-Administration, but Not Cocaine Sensitization

Abstract

The addicted phenotype is characterized as a long-lasting, chronically relapsing disorder that persists following long periods of abstinence, suggesting that the underlying molecular changes are stable and endure for long periods even in the absence of drug. Here, we investigated Transforming Growth Factor-Beta Type I receptor (TGF-β R1) expression in the nucleus accumbens (NAc) following periods of withdrawal from cocaine self-administration (SA) and a sensitizing regimen of non-contingent cocaine. Rats were exposed to either (i) repeated systemic injections (cocaine or saline), or (ii) self-administration (cocaine or saline) and underwent a period of forced abstinence (either 1 or 7 days of drug cessation). Withdrawal from cocaine self-administration resulted in an increase in TGF-β R1 protein expression in the NAc compared to saline controls. This increase was specific for volitional cocaine intake as no change in expression was observed following a sensitizing regimen of experimenter-administered cocaine. These findings implicate TGF-β signaling as a novel potential therapeutic target for treating drug addiction.

E3 Ubiquitin-Protein Ligase SMURF1 in the Nucleus Accumbens Mediates Cocaine Seeking

“…Our sample sizes are similar to those reported in previous publications (32,33,43). All statistical analyses were performed using Prism (GraphPad Software, La Jolla, CA).…”

“…Our data demonstrate that SMURF1 and RUNX2 do not regulate TGFβR1 , a key component of the TGF-β–activin–SMAD3 pathway that we previously demonstrated is upregulated during withdrawal following cocaine self-administration (43) and is essential for structural plasticity and cocaine-primed reinstatement (32). While we did not directly examine the behavioral role of SMAD1/5 in this study, SMURF1 regulates BMP signaling and is involved in cocaine seeking.…”

“…We then identified several putative RUNX2 gene targets based on DNA consensus binding sites (Supplemental Table S1). Following self-administration (two-way repeated-measures ANOVA, drug × session interaction effect, F 9,180 = 3.36, p < .001) (Figure 6B), ChIP assays revealed increased RUNX2 binding in cocaine-treated rats at promoter regions of several target genes that we and others have previously implicated in cocaine-induced plasticity (one-way ANOVA, F 7,29 = 3.087, p = .015) (33,43,62,63) (Figure 6C), including Egr3 ( t test, t 8 = 2.196, p = .029), Dnml1 ( t test, t 7 = 2.419, p = .046), and Smarca4 (gene for Brg1; t test, t 8 = 2.169, p = .031) but not Tgfbr1 ( t test, t 6 = 0.9585, p = .374). Importantly, HSV- wtSmurf1 reduced expression of RUNX2-mediated genes affected by cocaine ( Egr3 : t test, t 13 = 1.872, p = .042; Dnml1: t test, t 14 = 0.746, p = .468; Tgfbr1: t test, t 14 = 0.746, p = .468; Smarca4: t test, t 11 = 2.316, p = .041) (Figure 6D).…”

BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior

“…Self-administration procedures were conducted as previously described (11, 21, 22). Following the 7 d recovery from jugular catheter surgery, rats were assigned to self-administer either saline or 1.0 mg/kg/inf cocaine.…”

Chromatin Remodeling in Addiction: BRG1-SMAD3 Interaction Contributes to Cued Reinstatement of Cocaine Seeking

“…Activin has also been implicated in neuroplasticity by inducing GluN2A phosphorylation and expression, an upward shift of the cocaine dose-response curve, and potentiation of cocaine-primed reinstatement (3,4). In addition to the effects of activin receptor stimulation on SMAD3 and cocaine seeking, this group has also shown that the TGF-β receptor 1 (TGFβ-R1), which is also upstream from SMAD3 signaling, is also increased after cocaine self-administration and abstinence (5). In an important series of control experiments, activin and SMAD3 signaling were each determined not to affect food reinforcement, indicating that these signaling pathways are specifically affected by drugs of abuse.…”