Serotonin in anxiety and panic: Contributions of the elevated T-maze

doi:10.1016/j.neubiorev.2014.03.007

Neuroscience & Biobehavioral Reviews

Volume 46, Part 3, October 2014, Pages 397-406

https://doi.org/10.1016/j.neubiorev.2014.03.007 Get rights and content

Highlights

•
Escape and inhibitory avoidance in the ETM are pharmacologically distinct reactions.
•
MRN, but not DRN, 5-HT neurons selectively regulate inhibitory avoidance in the ETM.
•
Panicolytic drugs facilitate 5-HT-mediated neurotransmission in the dPAG.
•
5-HT2C receptors in BLA mediate the acute anxiogenesis caused by antidepressants.
•
dPAG 5-HT1A and μ-opioid receptors cooperatively modulate escape expression.

Abstract

The elevated T-maze (ETM) was developed to test the hypothesis that serotonin (5-HT) plays an opposing role in the regulation of defensive behaviors associated with anxiety and panic. This test allows the measurement in the same rat of inhibitory avoidance acquisition, related to generalized anxiety disorder, and of one-way escape, associated with panic disorder. The evidence so far reported with the ETM supports the above hypothesis and indicates that: (1) whereas 5-HT neurons located at the dorsal raphe nucleus are involved in the regulation of both inhibitory avoidance and escape, those of the median raphe nucleus are primarily implicated in the former task; (2) facilitation of 5-HT1A- and 5-HT2A-mediated neurotransmission in the dorsal periaqueductal gray (dPAG) is likely to mediate the panicolytic drug action; (3) stimulation of 5-HT2C receptors in the basolateral amygdala increases anxiety and is implicated in the anxiogenesis caused by short-term administration of antidepressant drugs, and (4) 5-HT1A and the μ-opioid receptors work together in the dPAG to modulate escape or panic attacks. These last results point to the possible benefits of adjunctive opioid therapy for panic patients resistant to antidepressants that act on 5-HT neurotransmission.

Introduction

Until the early 1990s, the role played by serotonin (5-HT) in anxiety was controversial. On the one hand, experimental evidence obtained with conflict models of anxiety in rats treated with 5-HT-acting drugs indicated that 5-HT enhanced anxiety. On the other hand, data from models that used escape from aversive electrical stimulation of the dorsal periaqueductal gray (dPAG) matter of the midbrain pointed to an anxiolytic function of 5-HT (review in Graeff, 2002). To overcome this apparent inconsistency, it was suggested that these two kinds of defensive responses – inhibitory avoidance in the conflict tests and one-way escape in the aversive brain stimulation model – addressed two different emotions, anxiety and panic, respectively. While avoidance was supposed to be enhanced by 5-HT released in forebrain structures, such as the amygdala and the prefrontal cortex, by nerve fibers coming from the dorsal raphe nucleus (DRN), escape would be inhibited by 5-HT released in the dPAG by fibers also originating in the DRN (Graeff, 1991). This construct was soon extended to human psychopathology by Deakin and Graeff (1991), assuming that inhibitory avoidance would be a model of generalized anxiety disorder (GAD) and escape, of panic disorder (PD).

To test the above hypothesis, an animal model was devised that allowed the same rat to perform an inhibitory avoidance task followed by a one-way escape task in one experimental session. The apparatus built to fulfill this aim was named the elevated T-maze (ETM). Since its introduction (Graeff et al., 1993, Viana et al., 1994), evidence gathered in the ETM has largely supported the dual role of 5-HT in GAD and PD. It has also contributed to the investigation of important corollaries of this hypothesis, such as the involvement of distinct 5-HT pathways, 5-HT receptors and/or brain structures in the mechanisms of action of drugs effective in GAD and PD, and in the pathophysiology of these psychiatric conditions.

The present review covers the main contributions of the ETM by addressing: (1) the role played by 5-HT neurons located at the dorsal raphe nucleus and the median raphe nucleus (MRN) in the regulation of inhibitory avoidance acquisition and escape expression; (2) the influence of anxiolytic and panicolytic drugs on 5-HT neurotransmission in key areas involved in the regulation of inhibitory avoidance and escape, (3) the interaction between 5-HT and opioidergic mechanisms in regulation of the defensive tasks generated by the ETM.

Section snippets

Development and validation of the elevated T-maze

The ETM is derived from the widely used elevated X- or plus-maze (Handley and Mithani, 1984, Pellow et al., 1985), which have two arms enclosed by walls that are perpendicular to two unprotected arms, all elevated from the floor. This test is based on the innate fear of height and openness shown by rats (Montgomery, 1955), probably because they are unable to perform thygmotaxis with their vibrissae (Treit et al., 1993).

The ETM was obtained by sealing the entrance to one of the enclosed arms. As

Comparative role of the dorsal and median raphe nuclei

The possibility of measuring an index of anxiety and another of panic in the same rat in one experimental session in the ETM allowed a clarifying analysis of the participation of the serotonergic fibers that originate in the DRN and MRN in the regulation of defensive responses related to GAD and PD.

Both the DRN and the MRN send 5-HT projections to brain areas implicated in the regulation of defensive behaviors. The majority of 5-HT innervation to the forebrain originates from the DRN and, to a

Mode of action of antidepressants

Earlier studies, using the electrical stimulation of the dPAG as a model of panic, showed that 5-HT inhibits the ensuing escape response through the activation of 5-HT1A and 5-HT2A receptors in the dPAG, indicating a panicolytic-like action (Nogueira and Graeff, 1995, Schutz et al., 1985). These findings, among others, led to the proposal that impairment in 5-HT mechanisms controlling defensive behavior at the level of the DPAG underlies the susceptibility to panic attacks that characterizes

Serotonin-opioid interaction

The participation of opioids in the pathophysiology of PD has been suggested by Preter and Klein (2008). Considering the regulatory role of opioids in disordered breathing and separation distress, which are two conditions related to PD, they proposed that a deficit of endogenous opioids underpins the vulnerability to panic attacks. To test this hypothesis, experimental studies were carried out in healthy volunteers to verify whether pretreatment with the opioid antagonist naloxone would render

Conclusion

The ETM model was designed to test an assumption about the role of 5-HT in modulation of anxiety and panic. This hypothesis assumes that anxiety and panic are qualitatively different emotions that are related to two defensive strategies, respectively, the reaction to potential (Blanchard et al., 1986) or post-encounter (Fanselow and Lester, 1988) threat, and to proximal (Blanchard et al., 1986) or circa-strike (Fanselow and Lester, 1988) menace. The former reaction is chiefly structured in the

Acknowledgement

FGG and HZJ are recipients of research fellowships from National Counsel of Technological and Scientific Development (CNPq – Brazil).

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ReviewSerotonin in anxiety and panic: Contributions of the elevated T-maze

Highlights

Abstract

Introduction

Section snippets

Development and validation of the elevated T-maze

Comparative role of the dorsal and median raphe nuclei

Mode of action of antidepressants

Serotonin-opioid interaction

Conclusion

Acknowledgement

Pharmacol. Ther.

Brain Res.

Behav. Brain Res.

Pharmacol. Res.

Phytomedicine

Curr. Opin. Pharmacol.

Brain Res. Bull.

Neuropharmacology

Biol. Psychiatry

Psychiatry Res.

Behav. Brain Res.

Eur. Neuropsychopharmacol.

Behav. Brain Res.

Pharmacol. Biochem. Behav.

Peptides

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Neurosci. Biobehav. Rev.

Behav. Brain Res.

Life Sci.

Pharmacol. Biochem. Behav.

Eur. Neuropsychopharmacol.

Neuroscience

Neuroscience

Neuroscience

Neurosci. Lett.

Brain Res. Rev.

Prog. Neurobiol.

Therapie

Pharmacol. Biochem. Behav.

Brain Res.

J. Neurosci. Methods

Behav. Brain Res.

Prog. Neuropsycho-pharmacol. Biol. Psychiatry

Life Sci.

Behav. Brain Res.

Neuroscience

Neurosci. Lett.

An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat

J. Comp. Neurol.

Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635

Int. J. Neuropsychopharmacol.

Evidence-based pharmacotherapy of panic disorder

Int. J. Neuropsychopharmacol.

Median and dorsal raphe neurons are not electrophysiologically identical

J. Neurophysiol.

Defensive reactions of laboratory and wild Rattus norvegicus

J. Comp. Physiol. Psychol.

Role of somatodendritic 5-HT autoreceptors in modulating 5-HT neurotransmission

Ann. N. Y. Acad. Sci.

Quantitative mapping of tryptophan hydroxylase-2, 5-HT1A, 5-HT1B, and serotonin transporter expression across the anteroposterior axis of the rat dorsal and median raphe nuclei

J. Comp. Neurol.

The role of the amygdala in fear and anxiety

Annu. Rev. Neurosci.

Effects of fluoxetine and buspirone on the panicolytic-like response induced by the activation of 5-HT1A and 5-HT2A receptors in the rat dorsal periaqueductal gray

Psychopharmacology (Berl.)

Alprazolam potentiates the antiaversive effect induced by the activation of 5-HT(1A) and 5-HT (2A) receptors in the rat dorsal periaqueductal gray

Psychopharmacology (Berl.)

Behavioral effects of systemically administered MK-212 are prevented by ritanserin microinfusion into the basolateral amygdala of rats exposed to the elevated plus-maze

Psychopharmacology (Berl.)

Involvement of 5-HT1A and 5-HT2 receptors of the dorsal periaqueductal gray in the regulation of the defensive behaviors generated by the elevated T-maze

Brain Res. Bull.

Review
Serotonin in anxiety and panic: Contributions of the elevated T-maze