Cooperative regulation of anxiety and panic-related defensive behaviors in the rat periaqueductal grey matter by 5-HT_1A and µ-receptors

Abstract

Previous results with the elevated T-maze (ETM) test indicate that the antipanic action of serotonin (5-HT) in the dorsal periaqueductal grey (dPAG) depends on the activation endogenous opioid peptides. The aim of the present work was to investigate the interaction between opioid- and serotonin-mediated neurotransmission in the modulation of defensive responses in rats submitted to the ETM. The obtained results showed that intra-dPAG administration of morphine significantly increased escape latency, a panicolytic-like effect that was blocked by pre-treatment with intra-dPAG injection of either naloxone or the 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl] ethyl] -N- 2- pyridinyl-ciclohexanecarboxamide maleate (WAY-100635). In addition, previous administration of naloxone antagonized both the anti-escape and the anti-avoidance (anxiolytic-like) effect of the 5-HT1A agonist (±)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), but did not affect the anti-escape effect of the 5-HT2A agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). Moreover, the combination of sub-effective doses of locally administered 5-HT and morphine significantly impaired ETM escape performance. Finally, the µ-antagonist D-PHE-CYS-TYR-D-TRP-ORN-THR-PEN (CTOP) blocked the anti-avoidance as well as the anti-escape effect of 8-OHDPAT, and the association of sub-effective doses of the µ-opioid receptor agonist [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin acetate salt (DAMGO) and of 8-OHDPAT had anti-escape and anti-avoidance effects in the ETM. These results suggest a synergic interaction between the 5-HT1A and the µ-opioid receptor at post-synaptic level on neurons of the dPAG that regulate proximal defense, theoretically related to panic attacks.

Panicolytic-like effect of µ1-opioid receptor blockade in the inferior colliculus of prey threatened by Crotalus durissus terrificus pit vipers

“…In conclusion, the present study and previous findings from our laboratory (Calvo and Coimbra, 2006; Calvo et al, 2019; Coimbra et al, 2017b; Osaki et al, 2003) reinforce the modulatory role played by the opioid system both in the IC and in more rostral structures of the midbrain tectum (Da Silva et al, 2013; Roncon et al, 2013) during the organisation of instinctive fear-related behaviours. Furthermore, our study supports the contribution of the μ 1 -opioid receptor at the level of the IC during the expression and/or modulation of panic attack-like responses.…”

“…The recruitment of endogenous opioid peptides in the modulation of defensive behaviour has already been described in the dPAG, dlSC and IC (Coimbra et al, 2000; Eichenberger et al, 2002; Roncon et al, 2013), even though some studies demonstrate contradictory effects of opioid drugs on laboratory animals submitted to experimental models of anxiety and panic attack-like behavioural responses (Asakawa et al, 1998; Colasanti et al, 2011; Jenck et al, 1986; Roncon et al, 2013). It is known that at least three types of opioid receptors, µ, δ and κ, are involved and that part of the explanation of such controversial results are linked to the specific role played by each opioid receptor in the organisation and expression of unconditioned fear-related defensive behaviours.…”

Cannabidiol as a Potential Treatment for Anxiety Disorders

“…Buspirone and other 5-HT 1A R agonists are approved for the treatment of GAD, with fair response rates [50]. In preclinical studies, 5-HT 1A R agonists are anxiolytic in animal models of general anxiety [51], prevent the adverse effects of stress [52], and enhance fear extinction [53]. Both pre-and postsynaptic 5-HT 1A Rs are coupled to various members of the G i/o protein family.…”

The endocannabinoid system as a target for novel anxiolytic drugs

“…This would mean that for CBD to be fully effective as an anxiolytic there would need to be basal 5-HT1A-R occupancy (Rock et al, 2012). This is notable because 5-HT1A-R agonists, such as Buspirone, display also anxiolytic-like properties in assorted preclinical assays (e.g., Roncon et al, 2013;Saito et al, 2013;Zhou et al, 2014) and are clinically prescribed for various Anxiety Disorders, with reasonable response rates (Blessing et al, 2015;Chessick et al, 2006). Thus, one could envision a treatment strategy entailing the use of CBD as an adjunct that augment Buspirone efficacy via the two drugs additive or synergistic action at the 5-HT1A-R. An added benefit would be that the limited psychoactive profile of CBD, as compared to, for instance, THC, should produce fewer sideeffects.…”