Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y

Abstract

The neural circuitry of fear likely underlies anxiety and fear-related disorders such as specific and social phobia, panic disorder, and posttraumatic stress disorder. The primary pharmacological treatments currently utilized for these disorders include benzodiazepines, which act on the GABAergic receptor system, and antidepressants, which modulate the monamine systems. However, recent work on the regulation of fear neural circuitry suggests that specific neuropeptide modulation of this system is of critical importance. Recent reviews have examined the roles of the hypothalamic-pituitary-adrenal axis neuropeptides as well as the roles of neurotrophic factors in regulating fear. The present review, instead, will focus on three neuropeptide systems which have received less attention in recent years but which are clearly involved in regulating fear and its extinction. The endogenous opioid system, particularly activating the μ opioid receptors, has been demonstrated to regulate fear expression and extinction, possibly through functioning as an error signal within the amygdala to mark unreinforced conditioned stimuli. The cholecystokinin (CCK) system initially led to much excitement through its potential role in panic disorder. More recent work in the CCK neuropeptide pathway suggests that it may act in concordance with the endogenous cannabinoid system in the modulation of fear inhibition and extinction. Finally, older as well as very recent data suggests that neuropeptide Y (NPY) may play a very interesting role in counteracting stress effects, enhancing extinction, and enhancing resilience in fear and stress preclinical models. Future work in understanding the mechanisms of neuropeptide functioning, particularly within well-known behavioral circuits, are likely to provide fascinating new clues into the understanding of fear behavior as well as suggesting novel therapeutics for treating disorders of anxiety and fear dysregulation.

ΔFosB Induction in Prefrontal Cortex by Antipsychotic Drugs is Associated with Negative Behavioral Outcomes

“…Furthermore, as DFosB is a transcription factor, further studies will be necessary to identify the exact target genes that are regulated by DFosB following antipsychotic drug treatment and delineating which genes are responsible for the various negative behavioral outcomes seen. One established gene target for DFosB in medial PFC is that which encodes the cholecystokinin B receptor (Vialou et al, 2012), which is highly implicated in anxiogenic responses consistent with observations of our studies (Ang et al, 2001;Bowers et al, 2012;Christoffel et al, 2012;McClung and Nestler, 2003). It will now be interesting to use more open-ended approaches to identify many more relevant DFosB target genes.…”

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

“…The CCK2 receptor is expressed highly in regions modulating pain and fear/emotional processing (Bowers et al, 2012;Chen et al, 2010;Kurrikoff et al, 2004;Li et al, 2013). In preclinical studies, deletion of the CCK2 receptor decreased hyperalgesia in a mouse neuropathic pain model (Kurrikoff et al, 2004), and ablation (CCK2 knockout mice) of the receptor increased μ-and δ-opioid receptors expression in the whole brain (Pommier et al, 2002).…”

Interaction between the Cholecystokinin and Endogenous Cannabinoid Systems in Cued Fear Expression and Extinction Retention

“…The amygdala processes emotionally relevant stimuli via the interactions of neurotransmitters (Bowers et al, 2012) and is enriched in Cnr1, CCK, and CCKBR (Larsson and Rehfeld, 1979;Herkenham et al, 1990;Lein et al, 2007). Prior studies have demonstrated a high degree of colocalization between Cnr1 and CCK mRNA and protein in the BLA (McDonald and Mascagni, 2001;Chhatwal et al, 2009).…”

“…The amygdala processes emotionally relevant stimuli via the interactions of neurotransmitters (Bowers et al, 2012) and it is highly enriched in a number of neuromodulators, in particular the endogenous cannabinoids and cholecystokinin (CCK) (Larsson and Rehfeld, 1979;Herkenham et al, 1990). Studies of the cannabinoid system suggest that the cannabinoid 1 receptor (Cnr1, also abbreviated Cb1) and the endogenous cannabinoids are critical for emotion, pain, feeding, addiction, anxiety, and memory (Richard et al, 2009;Mechoulam and Parker, 2013).…”