Intra-accumbal blockade of endocannabinoid CB1 receptors impairs learning but not retention of conditioned relief

Highlights

• Relief learning is associating a stimulus with the offset of an aversive event.

• We tested whether accumbal CB1 receptors are involved in relief learning.

• Injections of a CB1 receptor antagonist blocked relief learning in rats.

• Already established relief memory was not affected by these injections.

Abstract

Humans and animals are able to associate an environmental cue with the feeling of relief from an aversive event, a phenomenon called relief learning. Relief from an aversive event is rewarding and a relief-associated cue later induces an attenuation of the startle magnitude or approach behavior. Previous studies demonstrated that the nucleus accumbens is essential for relief learning. Here, we asked whether accumbal cannabinoid type 1 (CB1) receptors are involved in relief learning. In rats, we injected the CB1 receptor antagonist/inverse agonist SR141716A (rimonabant) directly into the nucleus accumbens at different time points during a relief learning experiment. SR141716A injections immediately before the conditioning inhibited relief learning. However, SR141716A injected immediately before the retention test was not effective when conditioning was without treatment. These findings indicate that accumbal CB1 receptors play an important role in the plasticity processes underlying relief learning.

Introduction

A basic motivation of animals and humans is to avoid potentially threatening events since this can have critical impact on the well-being or survival of the organism (Lang et al., 2000, LeDoux, 2012). While experiencing a threatening event is highly aversive, the relief from such an incident is rewarding (Leknes et al., 2011, Seymour et al., 2005). Notably, animals and humans can associate this rewarding feeling with environmental cues, a phenomenon entitled ‘Relief Learning’ (Denny, 1971, Gerber et al., 2014). In experimental paradigms of relief learning, a conditioned relief stimulus induces behavioral changes such as approach behavior or attenuation of the startle response (Andreatta et al., 2012, Navratilova et al., 2012, Yarali et al., 2008). These behavioral changes are usually observed in the presence of appetitive stimuli (e.g., Conzelmann et al., 2009, Friederich et al., 2006, Lang et al., 1990, Schmid et al., 1995, Schneider and Spanagel, 2008). A series of studies in humans and rodents demonstrated that the nucleus accumbens (NAC), a central part of the brain reward system (e.g., Ikemoto, 2007), is crucial for relief learning in mammals (Andreatta et al., 2012, Bergado Acosta et al., 2017, Bruning et al., 2016, Kahl and Fendt, 2016, Leknes et al., 2011, Mohammadi et al., 2014, Mohammadi and Fendt, 2015, Navratilova et al., 2012).

At the level of the NAC, the endocannabinoid (eCB) system, and in particular cannabinoid type 1 (CB1) receptors, has been reported to act as a fundamental mediator of the encoding of reward and incentive cues by allowing neural synchrony and rhythmicity patterns to emerge during reinforcement processes (Hernandez & Cheer, 2012). The eCB system is an evolutionarily ancient and widely distributed neuromodulatory system (Elphick, 2012) which is critically involved in the regulation and modulation of a plethora of neurophysiological processes, such as motor control, emotional homeostasis, memory storage, or reward processing (Kano et al., 2009, Moreira and Lutz, 2008).

The present study was performed to address the hypothesis whether accumbal CB1 receptors are involved in relief learning. In experiment 1, we submitted animals to different conditioning procedures to demonstrate that the startle attenuation that is observed in relief conditioning experiments is due to the associative status of the conditioned relief stimulus. In two further experiments, we injected the CB1 receptor antagonist/inverse agonist SR141716A (rimonabant) directly into the NAC of rats. In experiment 2, we evaluated the role of accumbal CB1 receptors on the acquisition of conditioned relief, i.e. injections were performed immediately before relief learning and the retention test on learned relief was performed without injections. In experiment 3, the role of accumbal CB1 receptors on the expression of conditioned relief was evaluated, i.e. rats were submitted to relief learning without any treatment and SR141716A injections were performed immediately before the retention test on learned relief.