Extinction therapy has been suggested to suppress the conditioned motivational effect of drug cues to prevent relapse. However, extinction forms a new inhibiting memory rather than erasing the original memory trace and drug memories invariably return. Perineuronal nets (PNNs) are a specialized extracellular matrix around interneurons in the brain that have been suggested to be a permissive factor that allows synaptic plasticity in the adolescent brain. The degradation of PNNs caused by chondroitinase ABC (ChABC) may generate induced juvenile-like plasticity (iPlasticity) and promote experience-dependent plasticity in the adult brain. In the present study, we investigated the effect of removing PNNs in the amygdala of rat on the extinction of drug memories. We found that extinction combined with intra-amygdala injections of ChABC (0.01 U/side) prevented the subsequent priming-induced reinstatement of morphine-induced and cocaine-induced, but not food -induced, conditioned place preference (CPP). Intra-amygdala injections of ChABC alone had no effect on the retention, retrieval, or relearning of morphine-induced CPP and storage of acquired food-induced CPP. Moreover, we found that the procedure facilitated the extinction of heroin- and cocaine-seeking behavior and prevented the spontaneous recovery and drug-induced reinstatement of heroin- and cocaine-seeking behavior. We also found that the effect of PNNs degradation combined with extinction may be mediated by the potentiation of several plasticity-related proteins in the amygdala. Altogether, our findings demonstrate that a combination of extinction training with PNNs degradation in the amygdala erases drug memories and suggest that ChABC may be an attractive candidate for the prevention of relapse.

We recently reported that a conditioned stimulus (CS) memory retrieval-extinction procedure decreases reinstatement of cocaine and heroin seeking in rats and heroin craving in humans. Here we show that non-contingent cocaine or methylphenidate injections (UCS retrieval) 1 h before the extinction sessions decreases cocaine-priming-induced reinstatement, spontaneous recovery, and renewal of cocaine seeking in rats. Unlike the CS-based memory retrieval-extinction procedure, the UCS memory retrieval manipulation decreases renewal and reinstatement of cocaine seeking in the presence of cocaine cues that were not present during extinction training and also decreases cocaine seeking when the procedure commences after 28 days of abstinence. The inhibitory effect of the UCS retrieval manipulation on cocaine-priming-induced reinstatement is mediated by regulation of AMPA-receptor endocytosis in the basolateral amygdala. The UCS memory retrieval-extinction procedure has superior relapse prevention characteristics than the CS memory retrieval-extinction procedure and could be a promising method for decreasing relapse in human addicts.

Depression is one of the most common and debilitating psychiatric illnesses around the world, but the current antidepressants used to treat depression have many limitations. Progressively more studies have shown that neuropeptide systems are potential novel therapeutic targets for depression. However, whether the neuropeptide trefoil factor 3 (TFF3) participates in the development of depression has not been examined. In the current experiments, we assessed the antidepressant effects of TFF3 using the forced swim test (FST), tail suspension test (TST), and chronic mild stress (CMS) paradigm. Furthermore, we determined the mechanism that underlies the antidepressant-like effects of TFF3 in the rat FST. TFF3 dose-dependently reduced immobility time in both FST and TST. CMS elevated plasma TFF3 and decreased basolateral amygdala (BLA) TFF3 levels in rats, and acute TFF3 (0.1 mg/kg, i.p.) treatment reversed the depressive-like behaviors induced by CMS. Furthermore, TFF3 (0.1 mg/kg, i.p.) significantly increased Fos expression in the BLA, medial prefrontal cortex, and hypothalamus in rats subjected to the FST. Intra-BLA infusions of TFF3 (1 ng/side) exerted rapid antidepressant-like effects in the rat FST. Additionally, acute systemic TFF3 administration increased the level of phosphorylated-Akt (p-Akt) in the BLA. Finally, intra-BLA infusions of LY294002 (5 mM/side), a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, significantly blocked the antidepressant-like effect of TFF3. Our results demonstrated that TFF3 exerts antidepressant-like effects that might be mediated by the PI3K/Akt signaling pathway in the BLA. These findings suggest a novel neuropeptide system target in the development of new antidepressants.

The claustrum connects with a broad range of cortical areas including the prefrontal cortex (PFC). However, the function of the claustrum (CLA) and its neural projections remains largely unknown. Here, we elucidated the role of the neural projections from the CLA to the PFC in regulating impulsivity in male rats. We first identified the CLA–PFC pathway by retrograde tracer and virus expression. By using immunofluorescent staining of the c-Fos-positive neurons, we showed that chemogenetic activation and inhibition of the CLA–PFC pathway reduced and increased overall activity of the PFC, respectively. In the 5-choice serial reaction time task (5-CSRTT), we found that chemogenetic activation and inhibition of the CLA–PFC pathway increased and reduced the impulsive-like behavior (i.e., premature responses), respectively. Furthermore, chemogenetic inhibition of the CLA–PFC pathway prevented methamphetamine-induced impulsivity, without affecting methamphetamine-induced hyperactivity. In contrast to the role of CLA–PFC pathway in selectively regulating impulsivity, activation of the claustrum disrupted attention in the 5-CSRTT. These results indicate that the CLA–PFC pathway is essential for impulsivity. This study may shed light on the understanding of impulsivity-related disorders such as drug addiction.SIGNIFICANCE STATEMENTThe claustrum is one of the most mysterious brain regions. Although extensive anatomical studies demonstrated that the claustrum connects with many cortical areas, the function of the neural projections between the claustrum and cortical areas remain largely unknown. Here, we showed that the neural projections from the claustrum to the prefrontal cortex regulates impulsivity by using the designer drugs (DREADDs)-based chemogenetic tools. Interestingly, the claustrum–prefrontal cortex pathway also regulates methamphetamine-induced impulsivity, suggesting a critical role of this neural pathway in regulating impulsivity-related disorders such as drug addiction. Our results provided preclinical evidence that the claustrum-prefrontal cortex regulates impulsivity. The claustrum–prefrontal cortex pathway may be a novel target for the treatment of impulsivity-related brain disorders.