Role of benzodiazepine and serotonergic mechanisms in conditioned freezing and antinociception using electrical stimulation of the dorsal periaqueductal gray as unconditioned stimulus in rats

Vm, Castilho; Ce, Macedo; Ml, Brandão

doi:10.1007/s00213-002-1246-4

Cited by 55 publications

(3 citation statements)

References 76 publications

(112 reference statements)

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“…Evidence indicates that neurons in both structures are responsive to both conditioned and unconditioned stimuli 36,57–60 and are necessary for producing fear responses 61,62 . Moreover, stimulation of the amygdala or dPAG is both effective unconditioned stimuli (UCS) in fear conditioning procedures 63,64 .…”

Section: Dpag-amygdala Connectionsmentioning

confidence: 99%

Role of the dorsal periaqueductal gray in posttraumatic stress disorder: mediation by dopamine and neurokinin

Brandão

Lovick

2019

Transl Psychiatry

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In susceptible individuals, exposure to intensely traumatic life events can lead to the development of posttraumatic stress disorder (PTSD), including long-term dysregulation of the contextual processing of aversive stimuli, the overgeneralization of learned fear, and impairments in the ability to learn or respond to safety signals. The neuropathophysiological changes that underlie PTSD remain incompletely understood. Attention has focused on forebrain structures associated with fear processing. Here we consider evidence from human and animal studies that long-lasting changes in functional connectivity between the midbrain periaqueductal gray (dPAG) and amygdala may be one of the precipitating events that contribute to PTSD. Long-lasting neuroplastic changes in the dPAG can persist after a single aversive stimulation and are pharmacologically labile. The early stage (at least up to 24 h poststimulation) involves neurokinin-1 receptor-mediated events in the PAG and amygdala and is also regulated by dopamine, both of which are mainly involved in transferring ascending aversive information from the dPAG to higher brain structures, mainly the amygdala. Changes in the functional connectivity within the dPAG-amygdala circuit have been reported in PTSD patients. We suggest that further investigations of plasticity and pharmacology of the PAGamygdala network provide a promising target for understanding pathophysiological circuitry that underlies PTSD in humans and that dopaminergic and neurokininergic drugs may have a potential for the treatment of psychiatric disorders that are associated with a dysfunctional dPAG.

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Section: Dpag-amygdala Connectionsmentioning

confidence: 99%

Role of the dorsal periaqueductal gray in posttraumatic stress disorder: mediation by dopamine and neurokinin

Brandão

Lovick

2019

Transl Psychiatry

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“…Dorsal PAG stimulation has been used as a US in contextual conditioning paradigms [19], [20], and it has been shown that the integrity of the dlPAG glutamatergic circuit is necessary to support fear conditioning using chemical stimulation of the dorsal premammillary nucleus as a US to mimic predator exposure [21]. Altogether, the dlPAG emerges as a key site to respond to life threatening events and, at the same time, to influence fear learning.…”

Section: Introductionmentioning

confidence: 99%

The Dorsolateral Periaqueductal Gray and Its Role in Mediating Fear Learning to Life Threatening Events

Kincheski

Mota-Ortiz²,

Pavesi³

et al. 2012

PLoS ONE

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The dorsolateral column of the periaqueductal gray (dlPAG) integrates aversive emotional experiences and represents an important site responding to life threatening situations, such as hypoxia, cardiac pain and predator threats. Previous studies have shown that the dorsal PAG also supports fear learning; and we have currently explored how the dlPAG influences associative learning. We have first shown that N-methyl-D-aspartate (NMDA) 100 pmol injection in the dlPAG works as a valuable unconditioned stimulus (US) for the acquisition of olfactory fear conditioning (OFC) using amyl acetate odor as conditioned stimulus (CS). Next, we revisited the ascending projections of the dlPAG to the thalamus and hypothalamus to reveal potential paths that could mediate associative learning during OFC. Accordingly, the most important ascending target of the dlPAG is the hypothalamic defensive circuit, and we were able to show that pharmacological inactivation using β-adrenoceptor blockade of the dorsal premammillary nucleus, the main exit way for the hypothalamic defensive circuit to thalamo-cortical circuits involved in fear learning, impaired the acquisition of the OFC promoted by NMDA stimulation of the dlPAG. Moreover, our tracing study revealed multiple parallel paths from the dlPAG to several thalamic targets linked to cortical-hippocampal-amygdalar circuits involved in fear learning. Overall, the results point to a major role of the dlPAG in the mediation of aversive associative learning via ascending projections to the medial hypothalamic defensive circuit, and perhaps, to other thalamic targets, as well. These results provide interesting perspectives to understand how life threatening events impact on fear learning, and should be useful to understand pathological fear memory encoding in anxiety disorders.

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“…5-HT2 receptors have been implicated in the mechanisms of defensive behavior organized by the central gray (PAG/GC) and amygdala in rats. At different amygdalar subnuclei, 5-HT2 receptors appear to either facilitate (de Paula and Leite-Panissi, 2016) or block (Macedo et al, 2007) unconditioned fear, while at the midbrain 5-HT2 receptors inhibit defensive responses to distal and proximal threat (Castilho et al, 2002;Castilho and Brandão, 2001;Coimbra and Brandão, 1997;Graeff et al, 1986;Oliveira et al, 2007). These receptors have also been implicated in anxiety-like behavior (defense to potential threat), facilitating these responses in the amygdala (Cornélio and Nunes-de-Souza, 2007), hippocampus (Alves et al, 2004), and GC/PAG (Nunes- de-Souza et al, 2008) of rodents.…”

Section: Introductionmentioning

confidence: 99%

5-HT2C agonists and antagonists block different components of behavioral responses to potential, distal, and proximal threat in zebrafish

Silva

Nascimento

Gomes

et al. 2020

Preprint

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Serotonin (5-HT) receptors have been implicated in responses to aversive stimuli in mammals and fish, but its precise role is still unknown. Moreover, since at least seven families of 5-HT receptors exist in vertebrates, the role of specific receptors is still debated. Aversive stimuli can be classified as indicators of proximal, distal, or potential threat, initiating responses that are appropriate for each of these threat levels. Responses to potential threat usually involve cautious exploration and increased alertness, while responses to distal and proximal threat involve a fight-flight-freeze reaction. We exposed adult zebrafish to a conspecific alarm substance (CAS) and observed behavior during (distal threat) and after (proximal threat) exposure, and treated with the 5-HT2C receptor agonists MK-212 or WAY-161503 or with the antagonist RS-102221. The agonists blocked CAS-elicited defensive behavior (distal threat), but not post-exposure increases in defensive behavior (potential threat), suggesting a phasic inhibition of responses to distal threat. MK-212 did not block changes in behavior elicited by acute restraint stress, a model of proximal threat, suggesting that the phasic role of the 5-HT2C receptor is specific to distal threat. We also found that RS-10221, a 5-HT2C receptor antagonist, did not change behavior during exposure, but it produced a small effect on behavior after exposure to CAS, suggesting a tonic facilitation of responses to potential threat.

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Role of benzodiazepine and serotonergic mechanisms in conditioned freezing and antinociception using electrical stimulation of the dorsal periaqueductal gray as unconditioned stimulus in rats

Cited by 55 publications

References 76 publications

Role of the dorsal periaqueductal gray in posttraumatic stress disorder: mediation by dopamine and neurokinin

Role of the dorsal periaqueductal gray in posttraumatic stress disorder: mediation by dopamine and neurokinin

The Dorsolateral Periaqueductal Gray and Its Role in Mediating Fear Learning to Life Threatening Events

5-HT2C agonists and antagonists block different components of behavioral responses to potential, distal, and proximal threat in zebrafish

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