Drug use and relapse involve learned associations between drug-associated environmental cues and drug effects. Extinction procedures in the clinic can suppress conditioned responses to drug cues, but the extinguished responses typically reemerge after exposure to the drug itself (reinstatement), the drug-associated environment (renewal), or the passage of time (spontaneous recovery). We describe a memory retrieval-extinction procedure that decreases conditioned drug effects and drug seeking in rat models of relapse, and drug craving in abstinent heroin addicts. In rats, daily retrieval of drug-associated memories 10 minutes or 1 hour but not 6 hours before extinction sessions attenuated drug-induced reinstatement, spontaneous recovery, and renewal of conditioned drug effects and drug seeking. In heroin addicts, retrieval of drug-associated memories 10 minutes before extinction sessions attenuated cue-induced heroin craving 1, 30, and 180 days later. The memory retrieval-extinction procedure is a promising nonpharmacological method for decreasing drug craving and relapse during abstinence.
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.
Stress in adolescence has been widely demonstrated to have a lasting impact in humans and animal models. Developmental risk and protective factors play an important role in the responses to stress in adulthood. Mild-to-moderate stress in adolescence may resist the negative impacts of adverse events in adulthood. However, little research on resilience has been conducted. In this study, we used a predictable chronic mild stress (PCMS) procedure (5 min of daily restraint stress for 28 days) in adolescent rats (postnatal days (PNDs) 28-55) to test the resilience effect of PCMS on depressive-like behavior in the sucrose preference test and forced swim test and anxiety-like behavior in the novelty-suppressed feeding test and elevated plus maze in adulthood. We also investigated the role of mammalian target of rapamycin (mTOR) signaling in the brain during the PCMS procedure in adolescence. Moreover, we investigated the effect of PCMS in adolescence on subsequent responses to chronic unpredictable stress (CUS; PNDs 63-83) in adulthood. The results demonstrated that PCMS during adolescence produced antidepressant- and anxiolytic-like effects and increased mTOR signaling activity in the prefrontal cortex in early adulthood. Either systemic administration or intra-PFC infusion of the mTOR inhibitor rapamycin completely blocked the behavioral effects produced by PCMS in adolescence. PCMS during adolescence resisted depressive- and anxiety-like behavior caused by CUS in adulthood. These findings indicate that PCMS in adolescence can contribute to resilience against depression and anxiety caused by stress in adulthood.
Glycogen synthase kinase 3β (GSK‐3β) is a ubiquitous serine/threonine protein kinase involved in a number of signaling pathways. Previous studies have demonstrated a role for GSK‐3β in the synaptic plasticity underlying dopamine‐associated behaviors and diseases. Drug sensitization is produced by repeated exposure to the drug and is thought to reflect neuroadaptations that contribute to addiction. However, the role of GSK‐3β in cocaine‐induced behavior sensitization has not been examined. The present study investigated the effects of chronic cocaine exposure on GSK‐3β activity in the nucleus accumbens (NAc) and determined whether changes in GSK‐3β activity in the NAc are associated with cocaine‐induced locomotor sensitization. We also explored whether blockade of GSK‐3β activity in the NAc inhibits the initiation and expression of cocaine‐induced locomotor sensitization in rats using systemic or brain region‐specific administration of the GSK‐3β inhibitors lithium chloride (LiCl) and SB216763. GSK‐3β activity in the NAc core, but not NAc shell, increased after chronic cocaine (10 mg/kg, i.p.) administration. The initiation and expression of cocaine‐induced locomotor sensitization was attenuated by systemic administration of LiCl (100 mg/kg, i.p.) or direct infusion of SB216763 (1 ng/side) into the NAc core, but not NAc shell. Collectively, these results indicate that GSK‐3β activity in the NAc core, but not NAc shell, mediates the initiation and expression of cocaine‐induced locomotor sensitization, suggesting that GSK‐3β may be a potential target for the treatment of cocaine addiction.
Post-prandial hyperglycaemia impairs endothelial function as evaluated by brachial artery flow-mediated dilation (FMD). Exercise is an intervention to protect against cardiovascular disease and to improve FMD. In this study, we examined whether the effect of acute hyperglycaemia on endothelial function in healthy young men is restored by aerobic exercise. Using a counterbalanced, randomized crossover design, we measured the brachial artery FMD at baseline and 1, 2, 3 and 4 h after 75 g glucose ingestion in 11 healthy young men, with and without a single bout of aerobic exercise. Brachial artery FMD declined from 11.4 +/- 3.8% at baseline to 7.3 +/- 3.4% 1 h after oral glucose ingestion, and returned to baseline after 4 h. When the oral glucose ingestion was followed immediately by 45 min of treadmill exercise at an intensity of 60% maximal oxygen uptake, FMD demonstrated no significant decrease (11.8 +/- 2.5, 11.3 +/- 2.8, 12.2 +/- 2.7, 13.5 +/- 3.5, and 12.6 +/- 2.4% at baseline and 4 h after ingestion, respectively). The results indicate that the aerobic exercise restores the impaired FMD induced by oral glucose ingestion.
Cocaine use and relapse involves learned associations between cocaine-associated environmental contexts and discrete stimuli and cocaine effects. Initially, these contextual and discrete cues undergo memory consolidation after being paired with cocaine exposure. During abstinence, cocaine cue memories can undergo memory reconsolidation after cue exposure without the drug. We used a conditioned place preference (CPP) procedure in rats to study the role of neuronal protein kinase cyclin-dependent kinase 5 (Cdk5) in consolidation and reconsolidation of cocaine cue memories. We found that the expression of cocaine CPP in drug-free tests 1 d after CPP training (four pairings of 10 mg/kg cocaine with one context and four pairings of saline with a different context) increased Cdk5 activity, and levels of the Cdk5 activator p35 in basolateral but not central amygdala. We also found that basolateral (but not central) amygdala injections of the Cdk5 inhibitor β-butyrolactone (100 ng/side) immediately (but not 6 h) after cocaine–context pairings during training prevented subsequent cocaine CPP expression. After training, acute basolateral (but not central) amygdala β-butyrolactone injections immediately before testing prevented the expression of cocaine CPP; this effect was also observed on a second test performed 1 d later, suggesting an effect on reconsolidation of cocaine cue memories. In support, basolateral β-butyrolactone injections, given immediately (but not 6 h) after a single exposure to the cocaine-paired context, prevented cocaine CPP expression 1 and 14 d after the injections. Results indicate that basolateral amygdala Cdk5 activity is critical for consolidation and reconsolidation of the memories of cocaine-associated environmental cues.
J. Neurochem. (2011) 10.1111/j.1471‐4159.2011.07281.x Abstract As a ubiquitous serine/threonine protein kinase, glycogen synthase kinase 3β (GSK‐3β) has been considered to be important in the synaptic plasticity that underlies dopamine‐related behaviors and diseases. We recently found that GSK‐3β activity in the nucleus accumbens (NAc) core is critically involved in cocaine‐induced behavioral sensitization. The present study further explored the association between the changes in GSK‐3β activity in the NAc and the chronic administration of methamphetamine. We also examined whether blocking GSK‐3β activity in the NAc could alter the initiation and expression of methamphetamine (1 mg/kg, i.p.)‐induced locomotor sensitization in rats using systemic administration of lithium chloride (LiCl, 100 mg/kg, i.p) and brain region‐specific administration of the GSK‐3β inhibitor SB216763 (1 ng/side). We found that GSK‐3β activity increased in the NAc core, but not NAc shell, after chronic methamphetamine administration. The initiation and expression of methamphetamine‐induced locomotor sensitization was attenuated by systemic administration of LiCl and direct infusion of SB216763 into the NAc core, but not NAc shell. These results indicate that GSK‐3β activity in the NAc core mediates the initiation and expression of methamphetamine‐induced locomotor sensitization, suggesting that GSK‐3β may be a potential target for the treatment of psychostimulant addiction.
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