Kappa-opioid receptor blockade in the inferior colliculus of prey threatened by pit vipers decreases anxiety and panic-like behaviour.

The dorsal midbrain comprises dorsal columns of the periaqueductal grey matter and corpora quadrigemina. These structures are rich in beta-endorphinergic and leu-enkephalinergic neurons and receive GABAergic inputs from substantia nigra pars reticulata. Although the inferior colliculus (IC) is mainly involved in the acoustic pathways, the electrical and chemical stimulation of central and pericentral nuclei of the IC elicits a vigorous defensive behaviour.

The Role of the Thalamus in Nociception: Important but Forgotten.

Pain is a complex response to noxious stimuli. Upon detection of the nociceptive stimulus by first-order neurons or nociceptors, an action potential ascends to the spinal dorsal horn, a crucial site for synapsing with second-order neurons. These second-order neurons carry the nociceptive stimulus to supraspinal regions, notably the thalamus.

GABAergic and glutamatergic inputs to the medulla oblongata and locus coeruleus noradrenergic pathways are critical for seizures and postictal antinociception neuromodulation.

We investigated the participation of the nucleus of the tractus solitarius (NTS) in tonic‒clonic seizures and postictal antinociception control mediated by NMDA receptors, the role of NTS GABAergic interneurons and noradrenergic pathways from the locus coeruleus (LC) in these phenomena. The NTS-lateral nucleus reticularis paragigantocellularis (lPGi)-LC pathway was studied by evaluating neural tract tracer deposits in the lPGi. NMDA and GABAergic receptors agonists and antagonists were microinjected into the NTS, followed by pharmacologically induced seizures.

The anterior cingulate cortex and its interface with the dorsal periaqueductal grey regulating nitric oxide-mediated panic-like behaviour and defensive antinociception.

The anterior cingulate cortex (ACC) Cg1 (24b) area modulates glutamate-mediated unconditioned fear and antinociception organised by hypothalamus. However, it remains unknown whether 24b area also modulates these latter defensive responses through connections with the dorsal periaqueductal grey matter (dPAG), a midbrain structure implicated in the genesis of innate fear-induced defence. The aim of this work is to examine the correlation between the behavioural effects of intra-ACC microinjections of vehicle, NMDA (1 nmol) or lidocaine (2%) with Fos protein expression and nitrergic activity in the dPAG of male C57BL/6 mice that were threatened by snakes.

Litter reduction-induced obesity promotes early depressive-like behavior and elevated prefrontal cortex GFAP expression in male offspring.

Aims: The present study was developed to investigate how litter reduction-induced obesity promotes early depressive-related behaviors in rodent offspring.

Main Methods: We employed a standardized litter size reduction protocol, dividing litters into groups: normal litters (NL), consisting of six males and six females pups and small litters (SL), comprising two males and two females pups. Maternal behavior was monitored during the initial week of lactation.

Unravelling the dorsal periaqueductal grey matter NMDA receptors relevance in the nitric oxide-mediated panic‑like behaviour and defensive antinociception organised by the anterior hypothalamus of male mice.

Rationale: Previous studies suggested that the dorsal column of the periaqueductal grey matter (dPAG) can be a target of neural pathways from hypothalamic nuclei involved in triggering fear-related defensive responses. In turn, evidence is provided suggesting that microinjection of the nitric oxide (NO) donor SIN-1 into the anterior hypothalamus (AH) of mice evokes panic-like behaviours and fear-induced antinociception. However, it is unknown whether the dPAG of mice mediates these latter defensive responses organised by AH neurons.

Methimazole-induced gestational hypothyroidism affects the offspring development and differently impairs the conditioned fear in male and female adulthood rodents.

Gestational hypothyroidism is a prevalent disorder in pregnant women and also impairs fetal development with relevant outcomes. One of the outcomes of greatest interest has been rodent fear- and anxiety-like behavior. However, the relationship between maternal hypothyroidism and onset of conditioned fear-related responses in offspring remains controversial.

Environmental Enrichment Facilitates Anxiety in Conflict-Based Tests but Inhibits Predator Threat-Induced Defensive Behaviour in Male Mice.

Introduction: Environmental enrichment (EE) is a useful and sophisticated tool that improves rodents' well-being by stimulating social behaviour and cognitive, motor, and sensory functions. Exposure to EE induces neuroplasticity in different brain areas, including the limbic system, which has been implicated in the control of anxiety and fear. However, the effects of EE on ethologically relevant naturalistic behaviours, such as those displayed by prey in the presence of predators, remain largely unexplored.

Nitric oxide-mediated defensive and antinociceptive responses organised at the anterior hypothalamus of mice are modulated by glutamatergic inputs from area 24b of the cingulate cortex.

Background: Previous studies suggested that Cg1 area of the cingulate cortex of rats controls glutamate-mediated fear-induced defensive behaviour and antinociception organised at the posterior hypothalamus. In turn, microinjection of the nitric oxide donor SIN-1 into the anterior hypothalamus of mice produced defensive behaviours and fear-induced antinociception. However, it remains unknown whether Cg1 also modulates the latter mechanisms in mice.

The modulation of striatonigral and nigrotectal pathways by CB1 signalling in the substantia nigra pars reticulata regulates panic elicited in mice by urutu-cruzeiro lancehead pit vipers.

Cannabinoid receptor type 1 (CBR) is widely distributed in the substantia nigra pars reticulata (SNpr). However, the role of CBR at the SNpr level in threatening situations is poorly understood. We investigated the role of CBR in the SNpr on the expression of fear responses in mice confronted with urutu-cruzeiro pit vipers.

Anandamide in the anterior hypothalamus diminishes defensive responses elicited in mice threatened by Epicrates cenchria constrictor serpents.

The purpose of this study was to investigate whether the panicolytic‑like effect of different doses of anandamide microinjected into the anterior hypothalamus (AH) follows the same pattern of a bell‑shaped dose‑response curve observed with the same dose treatment in dorsomedial and ventromedial hypothalamus. We investigated this assumption by administering the cannabinoid and vanilloid receptor agonist anandamide into the anterior hypothalamus of mice and exposing them to the real threatening situation by using our experimental model based on confrontations between rodents and wild snakes. Our findings showed a gradual decay of response, with a significant attenuation of the panic attack‑like responses with anandamide at the highest dose but no effect was found after anandamide at the lowest or intermediate doses.

Cannabidiol-induced panicolytic-like effects and fear-induced antinociception impairment: the role of the CB receptor in the ventromedial hypothalamus.

Rationale: The behavioural effects elicited by chemical constituents of Cannabis sativa, such as cannabidiol (CBD), on the ventromedial hypothalamus (VMH) are not well understood. There is evidence that VMH neurons play a relevant role in the modulation of unconditioned fear-related defensive behavioural reactions displayed by laboratory animals.

Objectives: This study was designed to explore the specific pattern of distribution of the CB receptors in the VMH and to investigate the role played by this cannabinoid receptor in the effect of CBD on the control of defensive behaviours and unconditioned fear-induced antinociception.

The alpha- and beta-noradrenergic receptors blockade in the dorsal raphe nucleus impairs the panic-like response elaborated by medial hypothalamus neurons.

Dorsal raphe nucleus (DRN) neurons are reciprocally connected to the locus coeruleus (LC) and send neural pathways to the medial hypothalamus (MH). The aim of this work was to investigate whether the blockade of α-, α- or β-noradrenergic receptors in the DRN or the inactivation of noradrenergic neurons in the LC modify defensive behaviours organised by MH neurons. For this purpose, Wistar male rats received microinjections of WB4101, RX821002, propranolol (α- α- and β-noradrenergic receptor antagonists, respectively) or physiological saline in the DRN, followed 10 min later by MH GABA receptor blockade.

Opposing roles of dorsomedial hypothalamic CB1 and TRPV1 receptors in anandamide signaling during the panic-like response elicited in mice by Brazilian rainbow Boidae snakes.

Rationale: The endocannabinoid system plays an important role in the organization of panic-like defensive behavior. Threatening situations stimulate brain areas, such as the dorsomedial hypothalamus (DMH). However, there is a lack of studies addressing the role of the DMH endocannabinoid system in panic-like responses.

Panicolytic-like effect of µ-opioid receptor blockade in the inferior colliculus of prey threatened by Crotalus durissus terrificus pit vipers.

Background: The endogenous opioid peptide system has been implicated in the neural modulation of fear and anxiety organised by the dorsal midbrain. Furthermore, previous results indicate a fundamental role played by inferior colliculus (IC) opioid mechanisms during the expression of defensive behaviours, but the involvement of the IC µ-opioid receptor in the modulation of anxiety- and panic attack-related behaviours remains unclear. Using a prey-versus-snake confrontation paradigm, we sought to investigate the effects of µ-opioid receptor blockade in the IC on the defensive behaviour displayed by rats in a dangerous situation.

The endogenous opioid system modulates defensive behavior evoked by Crotalus durissus terrificus: Panicolytic-like effect of intracollicular non-selective opioid receptors blockade.

Background: There is a controversy regarding the key role played by opioid peptide neurotransmission in the modulation of panic-attack-related responses.

Aims: Using a prey versus rattlesnakes paradigm, the present work investigated the involvement of the endogenous opioid peptide-mediated system of the inferior colliculus in the modulation of panic attack-related responses.

Methods: Wistar rats were pretreated with intracollicular administration of either physiological saline or naloxone at different concentrations and confronted with rattlesnakes ( Crotalus durissus terrificus).

Neurotoxic lesions of the pedunculopontine tegmental nucleus impair the elaboration of postictal antinociception.

Generalised tonic-clonic seizures, generated by abnormal neuronal hyper-activity, cause a significant and long-lasting increase in the nociceptive threshold. The pedunculopontine tegmental nucleus (PPTN) plays a crucial role in the regulation of seizures as well as the modulation of pain, but its role in postictal antinociceptive processes remains unclear. In the present study, we aimed to investigate the involvement of PPTN neurons in the postictal antinociception.

The Rodent-versus-wild Snake Paradigm as a Model for Studying Anxiety- and Panic-like Behaviors: Face, Construct and Predictive Validities.

Using an innovative approach to study the neural bases of psychiatric disorders, this study investigated the behavioral, morphological and pharmacological bases of panic attack-induced responses in a prey-versus-coral snake paradigm. Mesocricetus auratus was chronically treated with intraperitoneal administration of the selective serotonin uptake inhibitor paroxetine or the gamma aminobutyric acid (GABA)/benzodiazepine receptor agonist alprazolam at three different doses and were then confronted with a venomous coral snake (Micrurus frontalis, Reptilia, Elapidae). The threatened rodents exhibited defensive attention, flat back approaches, defensive immobility, and escape defensive responses in the presence of the venomous snake, followed by increases in Fos protein in limbic structure neurons.

Decrease in NMDA receptor-signalling activity in the anterior cingulate cortex diminishes defensive behaviour and unconditioned fear-induced antinociception elicited by GABAergic tonic inhibition impairment in the posterior hypothalamus.

Acute γ-aminobutyric acid (GABA) disinhibition in the posterior hypothalamus (PH) elicits defensive reactions that are considered anxiety- and panic attack-like behaviour, and these defensive reactions are followed by antinociception. Evidence indicates that the PH connects with the medial prefrontal cortex, particularly the anterior cingulate cortex (ACC), which seems to regulate these unconditioned fear-induced defensive responses. However, few studies have shown the participation of cortical regions in the control of behavioural and antinociceptive responses organised by diencephalic structures.

5-Hydroxytryptamine 2A receptors of the dorsal raphe nucleus modulate panic-like behaviours and mediate fear-induced antinociception elicited by neuronal activation in the central nucleus of the inferior colliculus.

It has been established that chemical stimulation of the inferior colliculus (IC) of laboratory animals evokes fear-related defensive responses, which are considered panic attack-like behaviours. In addition, there is evidence that defensive reactions provoked by chemical stimulation of midbrain tectum neurons may induce an antinociceptive response. Morphologically, the IC receives projections from other mesencephalic structures, such as the dorsal raphe nucleus (DRN), a region rich in serotonergic neurons that play a critical role in the control of defensive behaviours.

Opioid neurotransmission modulates defensive behavior and fear-induced antinociception in dangerous environments.

The effects of endogenous opioid peptide antagonists on panic-related responses are controversial. Using elevated mazes and a prey-versus-predator paradigm, we investigated the involvement of the endogenous opioid peptide-mediated system in the modulation of anxiety- and panic attack-induced responses and innate fear-induced antinociception in the present work. Wistar rats were intraperitoneally pretreated with either physiological saline or naloxone at different doses and were subjected to either the elevated plus- or T-maze test or confronted by Crotalus durissus terrificus.

Connexions between the dorsomedial division of the ventromedial hypothalamus and the dorsal periaqueductal grey matter are critical in the elaboration of hypothalamically mediated panic-like behaviour.

The electrical and chemical stimulation of the dorsal periaqueductal grey matter (dPAG) elicits panic-like explosive escape behaviour. Although neurons of the ventromedial hypothalamus (VMH) seem to organise oriented escape behaviour, when stimulated with excitatory amino acids at higher doses, non-oriented/explosive escape reactions can also be displayed. The aim of this work was to examine the importance of reciprocal projections between the VMH and the dPAG for the organisation of this panic-like behaviour.

Unravelling cortico-hypothalamic pathways regulating unconditioned fear-induced antinociception and defensive behaviours.

The medial prefrontal cortex can influence unconditioned fear-induced defensive mechanisms organised by diencephalic neurons that are under tonic GABAergic inhibition. The posterior hypothalamus (PH) is involved with anxiety- and panic attack-like responses. To understand this cortical mediation, our study characterised anterior cingulate cortex (ACC)-PH pathways and investigated the effect of ACC local inactivation with lidocaine.

CB cannabinoid receptor-mediated anandamide signalling reduces the defensive behaviour evoked through GABA receptor blockade in the dorsomedial division of the ventromedial hypothalamus.

The effects of cannabinoids in brain areas expressing cannabinoid receptors, such as hypothalamic nuclei, are not yet well known. Several studies have demonstrated the role of hypothalamic nuclei in the organisation of behavioural responses induced through innate fear and panic attacks. Panic-prone states are experimentally induced in laboratory animals through a reduction in the GABAergic activity.

Nicotinic and muscarinic cholinergic receptors are recruited by acetylcholine-mediated neurotransmission within the locus coeruleus during the organisation of post-ictal antinociception.

Post-ictal antinociception is characterised by an increase in the nociceptive threshold that accompanies tonic and tonic-clonic seizures (TCS). The locus coeruleus (LC) receives profuse cholinergic inputs from the pedunculopontine tegmental nucleus. Different concentrations (1μg, 3μg and 5μg/0.