NMDA and AMPA/Kainate Glutamatergic Receptors in the Prelimbic Medial Prefrontal Cortex Modulate the Elaborated Defensive Behavior and Innate Fear-Induced Antinociception Elicited by GABAA Receptor Blockade in the Medial Hypothalamus

Abstract

The aim of the present study was to investigate the involvement of N-methyl-d-aspartate (NMDA) and amino-3-hydroxy-5-methyl-isoxazole-4-proprionate (AMPA)/kainate receptors of the prelimbic (PL) division of the medial prefrontal cortex (MPFC) on the panic attack-like reactions evoked by γ-aminobutyric acid-A receptor blockade in the medial hypothalamus (MH). Rats were pretreated with NaCl 0.9%, LY235959 (NMDA receptor antagonist), and NBQX (AMPA/kainate receptor antagonist) in the PL at 3 different concentrations. Ten minutes later, the MH was treated with bicuculline, and the defensive responses were recorded for 10 min. The antagonism of NMDA receptors in the PL decreased the frequency and duration of all defensive behaviors evoked by the stimulation of the MH and reduced the innate fear-induced antinociception. However, the pretreatment of the PL cortex with NBQX was able to decrease only part of defensive responses and innate fear-induced antinociception. The present findings suggest that the NMDA-glutamatergic system of the PL is critically involved in panic-like responses and innate fear-induced antinociception and those AMPA/kainate receptors are also recruited during the elaboration of fear-induced antinociception and in panic attack-related response. The activation of the glutamatergic neurotransmission of PL division of the MPFC during the elaboration of oriented behavioral reactions elicited by the chemical stimulation of the MH recruits mainly NMDA receptors in comparison with AMPA/kainate receptors.

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

“…Recently, such defensive responses triggered by stimulation of the dorsal midbrain (Nashold et al, 1969;Ribeiro et al, 2005;CastellanBaldan et al, 2006) have also been elicited by the stimulation of medial hypothalamus (Freitas et al, 2009;Wilent et al, 2010;Biagioni et al, 2012Biagioni et al, , 2013de Freitas et al, 2014), although escape behaviour elaborated by hypothalamic neurons are preceded by more intense exploratory behaviour (Schmitt et al, 1985). Interestingly, the escape responses organised by medial hypothalamus nuclei are mainly expressed by vertical jumps, toward the top of the aversive environment (de Freitas et al, 2014) instead of horizontal (long jumps) which is elicited by superior colliculus strata, as seen in the present work.…”

“…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.…”