mTOR signalling in the nucleus accumbens shell is critical for augmented effect of TFF3 on behavioural response to cocaine

Abstract

Neuropeptides play important roles in modulating the rewarding value of abused drugs. Trefoil factor 3 (TFF3) was recently reported to modulate withdrawal syndrome of morphine, but the effects of TFF3 on the cocaine-induced behavioral changes are still elusive. In the present study, cocaine-induced hyperlocomotion and conditioned place preference (CPP) rat paradigms were provided to investigate the role of TFF3 in the reward response to cocaine. High-performance liquid chromatography (HPLC) analysis was used to analyse the dopamine concentration. The results showed that systemic TFF3 administration (0.1 mg/kg i.p.) significantly augmented cocaine- induced hyperlocomotion and CPP formation, without any effects on locomotor activity and aversive or rewarding effects per se. TFF3 significantly augmented the increment of the dopamine concentration in the NAc and the activity of the mTOR signalling pathway induced by acute cocaine exposure (10 mg/kg, i.p.) in the NAc shell, but not the core. The Intra-NAc shell infusion of rapamycin blocked TFF3-induced hyperactivity in cocaine-treatment rats. These findings indicated that TFF3 could potentiate behavioural response to cocaine, which may be associated with regulating dopamine concentration. Furthermore, the findings indicated that mTOR signalling pathway in the NAc shell is important for TFF3-induced enhancement on the cocaine-induced behavioral changes.

Activation of AMPK‐dependent autophagy in the nucleus accumbens opposes cocaine‐induced behaviors of mice

“…TOR, specifically mTORC1, is the negative regulator of autophagy. It has been reported that acute cocaine exposure activates the mTOR in cerebral cortex as well as in VTA and NAc . However, we failed to find any changes in the mTOR signaling at 15, 30 or 60 min after a single cocaine exposure in the NAc in vivo or in vitro .…”

VTA mTOR Signaling Regulates Dopamine Dynamics, Cocaine-Induced Synaptic Alterations, and Reward

“…Several previous studies have demonstrated roles for mTOR signaling in regulating drug-or alcohol-associated behaviors. Trefoil factor 3 (TFF3), a brain-synthesized peptide thought to activate mTOR signaling, can enhance cocaine-induced mTOR activation, hyperlocomotion, and CPP (Luo et al, 2016). Inhibition of GSK-3, an mTORC1 inhibitor, disrupts the reconsolidation of cocaine-associated reward memories (Shi et al, 2014).…”

Anxiety and cognitive-related effects of Δ 9-tetrahydrocannabinol (THC) are differentially mediated through distinct GSK-3 vs. Akt-mTOR pathways in the nucleus accumbens of male rats

“…Many of the neuropsychiatric, schizophrenia-like side effects of cannabinoids are linked to THC-induced modulation of dopamine (DA) and its downstream signalling pathways, including Akt, GSK-3, mTOR and β-catenin (Renard et al, 2017a,b). These pathways are critical for striatalmediated cognitive and affective processing (Bergeron et al, 2014;Cuesta et al, 2017;Ding et al, 2013;Luo et al, 2016;Xu et al, 2015) and are strongly modulated by THC exposure (Renard et al, 2017a,b). In the mesolimbic pathway, THC is known to modulate DA release dynamics through its actions on CB1 receptors both via pre-synaptic mechanisms and through post-synaptic heteromeric complexes of CB1 and DA receptors (Garcia et al, 2016).…”