Involvement of prelimbic medial prefrontal cortex in panic-like elaborated defensive behaviour and innate fear-induced antinociception elicited by GABAA receptor blockade in the dorsomedial and ventromedial hypothalamic nuclei: role of the endocannabinoid CB1 receptor

Abstract

It has been shown that GABAA receptor blockade in the dorsomedial and ventromedial hypothalamic nuclei (DMH and VMH, respectively) induces elaborated defensive behavioural responses accompanied by antinociception, which has been utilized as an experimental model of panic attack. Furthermore, the prelimbic (PL) division of the medial prefrontal cortex (MPFC) has been related to emotional reactions and the processing of nociceptive information. The aim of the present study was to investigate the possible involvement of the PL cortex and the participation of local cannabinoid CB1 receptors in the elaboration of panic-like reactions and in innate fear-induced antinociception. Elaborated fear-induced responses were analysed during a 10-min period in an open-field test arena. Microinjection of the GABAA receptor antagonist bicuculline into the DMH/VMH evoked panic-like behaviour and fear-induced antinociception, which was decreased by microinjection of the non-selective synaptic contact blocker cobalt chloride in the PL cortex. Moreover, microinjection of AM251 (25, 100 or 400 pmol), an endocannabinoid CB1 receptor antagonist, into the PL cortex also attenuated the defensive behavioural responses and the antinociception that follows innate fear behaviour elaborated by DMH/VMH. These data suggest that the PL cortex plays an important role in the organization of elaborated forward escape behaviour and that this cortical area is also involved in the elaboration of innate fear-induced antinociception. Additionally, CB1 receptors in the PL cortex modulate both panic-like behaviours and fear-induced antinociception elicited by disinhibition of the DMH/VMH through microinjection of bicuculline.

Emotional regulatory function of receptor interacting protein 140 revealed in the ventromedial hypothalamus

“…In this context, increased Crhr2 binding was also detected in the VMH of wistar rats bred to demonstrate hyper-anxiety/depressive-like phenotype (37). Importantly, the current study also highlights the Cg1 and PrL cortex as implicated in the detected behavioral phenomena, in line with the association of these brain targets with depressive and anxiety disorders in human and animal models (33, 34, 38–40). Given the evidence for PrL-modulation of VMH/DMH-induced panic-like behavior in mice, probably via the pathways connecting these structures (33, 34), it is possible that RIP140 might have a systemic, rather than discrete modulatory role within this pathway.…”

“…Both nuclei are depicted as part of a neurobiological substrate controlling rodents’ avoidance and defensive behaviors, related to fear, anxiety and panic-like responses (31, 32). Specifically, the manipulation of GABAA receptor in both nuclei was shown to modulate rodents’ defensive behaviour, utilized as an experimental model of panic attack (33, 34). Also, CNS-specific, knockout of the nuclear receptor steroidogenic factor 1 (SF-1), mostly affecting the VMH, was found to result in increased anxiety-like behavior in rodents (35, 36), possibly through altered distribution of stress and anxiety-like behavior related genes, including BDNF and the type-2 receptor for CRH (Crhr2) [for review, see (35)].…”

Relevance of dorsomedial hypothalamus, dorsomedial division of the ventromedial hypothalamus and the dorsal periaqueductal gray matter in the organization of freezing or oriented and non-oriented escape emotional behaviors

“…Some other studies support the involvement of DMH in the organization of instinctive fear-induced responses [51,52,53,54]. In addition, Cullinan et al [55] showed that stressful stimuli such as swimming and restraining activate DMH.…”

Dissociation between the panicolytic effect of cannabidiol microinjected into the substantia nigra, pars reticulata, and fear-induced antinociception elicited by bicuculline administration in deep layers of the superior colliculus: The role of CB1-cannabinoid receptor in the ventral mesencephalon

“…Fear-induced antinociception has been described as the result of electrical and chemical stimulation of the periaqueductal grey matter, the deep layers of the superior colliculus (Coimbra et al, 1992;Coimbra and Brandão, 1997;Coimbra et al, 2006;da Silva et al, 2013b) and the medial hypothalamus (Freitas et al, 2009;Biagioni et al, 2012;de Freitas et al, 2013de Freitas et al, , 2014. However, similar antinociceptive responses can also be elicited after the tonic immobility defensive behaviour, experimentally induced by postural inversion with slightly restriction of movements (Ferreira and Menescal-de-Oliveira, 2012), in which endogenous opioid peptides, GABAergic and serotonergic mechanisms are critically involved.…”