Endocannabinoid signals in the control of emotion
Introduction
With the event of the synergistic use of numerous powerful techniques in neurosciences, mechanisms underlying emotion have been elucidated at cellular, synaptic and network levels. This can be illustrated with the detailed understanding of how the fear circuits are organized and which cellular mechanisms are involved in these circuits [1]. Several cortical and subcortical brain regions are engaged in these circuits, among which the amygdala, hippocampus and prefrontal cortex take central stages. In addition, several neurotransmitter systems and gene products are implicated in fear behaviours. Understanding the cellular mechanisms underlying emotion is also of clinical relevance, in order to define novel therapeutic targets for anxiety disorders, such as posttraumatic stress disorders (PTSD), general anxiety, phobia and depression [2].
A recently discovered signalling system modulating emotional responses to environmental impacts is constituted by the endocannabinoids (eCBs), which were identified as endogenous ligands of the cannabinoid receptors, which are G protein coupled receptors, initially characterized as receptors for the psychotropic Cannabis sativa constituent Δ9-tetrahydrocannabinol (THC) [3]. The most prominent eCBs are N-arachidonoyl ethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG). They are engaged in a plethora of physiological functions in the nervous system, both in the adult (e.g. synaptic transmission, behaviours such as stress coping, anxiety, memory processing, neuroprotection, neuroinflammation, reward, feeding behaviour), but also play important roles during neural development (e.g. neuronal proliferation, neuronal migration, axonal growth). Furthermore, dysregulations of the eCB system have been implicated in various pathophysiological states (e.g. neurodegenerative disorders, epilepsy), thus emerging as a promising therapeutic target system [4]. As eCBs are amphipathic molecules and cannot be stored in vesicles, therefore, regulatory mechanisms of the biosynthesis and degradation pathways constitute central points in the appropriate execution of eCB signalling. Recent research has given detailed information on the enzymes involved in their synthesis from membrane lipids and their degradation [5•].
eCBs act via paracrine and autocrine mechanisms on membrane receptors. The most important receptor regarding synaptic plasticity and behaviour is the cannabinoid receptor type 1 (CB1 receptor). However, promiscuity is present, in particular for anandamide, which is able to have several other targets. Most importantly, it activates the transient potential vanilloid receptor 1 (TRPV1, formerly called VR1), and peroxisome proliferator-activated receptor-α [6]. Furthermore, N-arachidonoyl dopamine (NADA) can act via CB1 receptors and TRPV1 [7]. Other eCB-like compounds were also characterized, such as N-arachidonoyl glycine, which signals via a G protein coupled receptor other than cannabinoid receptor [8], suggesting that this family of neuromodulatory lipids is still growing. An interaction between AEA and 2-AG was also reported. Mediated via TRPV1, AEA inhibits synthesis and physiological function of 2-AG in striatal neurons [9•]. Endogenous ligands that activate TRPV1 are called endovanilloids; the most important ones are AEA, NADA and 12-(S)-HPETE (12-hydroxyeicosatetraenoic acid, a 12-lipoxygenase product) [10]. Thus, these features illustrate the increasing complexity of the eCB system.
Section snippets
eCBs in the control of emotional responses
With the use of genetically modified mice lacking components of the eCB system and the pharmacological treatment of rodents with CB1 receptor antagonists and with eCB degradation inhibitors were able to allocate specific functions of the eCB system to distinct emotional responses. Several recent reviews discussed these responses in detail [11, 12•, 13••, 14, 15, 16, 17, 18]. Thus, in order to avoid redundancy, this review will provide an update on recent new insights, to address common features
eCB signalling in synaptic plasticity
After observing that the eCB system is involved in these many aspects of emotional responses, the immanent question arises how to integrate and interpret these phenotypes in terms of synaptic processes and neuronal networks.
The past few years have provided detailed knowledge on the involvement of eCBs in the regulation of synaptic transmission [41]. On the basis of the widespread expression of CB1 receptors in the nervous system, it must be concluded that a large portion of synapses contains
It matters where and when
Despite the detailed knowledge of the involvement of eCBs in the control of synaptic transmission, the link to behavioural phenotypes observed after interference with the activity of the eCB system has remained elusive. In particular, the very widespread occurrence of eCB-mediated suppression of neurotransmitter release contrasts the observation of rather specific phenotypes seen in mutant mice and/or pharmacologically treated rodents.
As discussed above, eCBs are able to suppress both GABAergic
An emotional link to the human eCB system
As the eCB system is involved in the modulation of emotional responses, the question was raised whether or not dysregulations of the eCB system in humans lead to pathological states. To this end, in a first step towards addressing this issue, two recent studies investigated genetic variations of the human CB1 receptor gene (CNR1 gene) in emotion processing. Healthy human subjects were exposed either to happy or to disgust facial expressions, and striatal responses were monitored by fMRI [50].
eCBs in shaping emotional networks
All constituents of the eCB system are highly abundant in the developing nervous system, from earliest stages of proliferation of neural progenitors during embryogenesis to the final events of the fine-tuning of the wiring of the neural networks during puberty and adolescence. Although identified several years ago, it was not until very recently when eCBs acting via CB1 receptors were recognized as signalling molecules controlling fundamental processes of neural development, such as neural
Conclusions
The eCB system offers numerous opportunities of pharmacological intervention in the context of mood disorders, such as anxiety disorders, PTSD, phobia and depression. FAAH inhibition appears to be the preferred strategy, as these drugs are basically without psychotropic side effects. However, as shown in animal model system, long-term FAAH inhibition leads to increased levels not only of AEA, but also of other lipids, which might cause side effects. Both CB1 receptor agonist treatment and FAAH
Conflict of interest
There is no conflict of interest.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The author would like to thank for the generous support by the Hübner-Stiftung and by the German Research Foundation (SFB/TRR 58 ‘Fear, anxiety and anxiety disorders’).
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