Glucagon-Like Peptide-1 Agonist Exendin-4 Facilitates the Extinction of Cocaine-Induced Condition Place Preference

Accumulating studies suggest that the glucagon-like peptide-1 receptor agonist exendin-4 (Ex4) and toll-like receptor 4 (TLR4) play a pivotal role in the maladaptive behavior of cocaine. However, few studies have assessed whether Ex4 can facilitate the extinction of drug-associated behavior and attenuate the reinstatement of cocaine-induced condition place preference (CPP) in mice. The main objective of the present study was to evaluate Ex4’s ability to regulate the extinction and reinstatement of cocaine-induced CPP. C57BL/6 mice were conditioned to either cocaine (20 mg/kg) or an equivalent volume of saline to establish a cocaine-mediated CPP paradigm. To investigate the potential effects of Ex4 on extinction, animals received an intraperitoneal injection of Ex4 either immediately or 6 h after each extinction or only on the test day. The persistence of extinction was measured using the reinstatement paradigm evoked by 10 mg/kg of cocaine. To explore the possible impacts of Ex4 and neuroinflammation on cocaine, the expression levels of TLR4 within the hippocampus was detected using western blotting. As a result, we found that systemic administration of Ex4 immediately after each extinction training, instead of 6 h after each extinction and on the day of extinction test, was capable of facilitating extinction in the confined or non-confined CPP extinction paradigms and blocking the cocaine-primed reinstatement of cocaine-induced CPP. Additionally, we also observed that Ex4 was competent to alleviate TLR4 signaling that has been up-regulated by cocaine. Altogether, our findings indicated that the combination of Ex4 with daily extinction training was sufficient to facilitate extinction of the conditioned behavior, attenuate reinstatement of cocaine-induced CPP and inhibit TLR4 signaling. Thus, Ex4 deserves further investigation as a potential intervention for the treatment of cocaine use disorder.

HeiDI: A model for Pavlovian learning and performance with reciprocal associations

Associative treatments of how Pavlovian conditioning affects conditioned behavior are rudimentary: A simple ordinal mapping is held to exist between the strength of an association (V) between a conditioned stimulus (CS) and an unconditioned stimulus (US; i.e., VCS-US) and conditioned behavior in a given experimental preparation. The inadequacy of this simplification is highlighted by recent studies that have taken multiple measures of conditioned behavior: Different measures of conditioned behavior provide the basis for drawing opposite conclusions about VCS-US. Here, we develop a simple model involving reciprocal associations between the CS and US (VCS-US and VUS-CS) that simulates these qualitative individual differences in conditioned behavior. The new model, HeiDI (How excitation and inhibition Determine Ideo-motion), enables a broad range of phenomena to be accommodated, which are either beyond the scope of extant models or require them to appeal to additional (learning) processes. It also provides an impetus for new lines of inquiry and generates novel predictions.

Mindfulness Training Disrupts Pavlovian Conditioning

Classical conditioning is a quintessential learning process; however, maladaptive forms of conditioning sustain many unhealthy behaviors (e.g., addiction). Mindfulness training is theorized to de-automatize conditioned behavior by decoupling stimulus and response. This study assessed the effect of mindfulness training on conditioned behavior during a classical conditioning task. Findings indicated mindfulness training decreased classically conditioned behavior relative to an active control condition, delaying the onset of first conditioned response and decreasing conditioned response frequency. Thus, mindfulness training may be one method of increasing volitional control over maladaptive conditioned behaviors that contribute to the development and maintenance of clinical disorders.