The panicolytic-like effect of fluoxetine in the elevated T-maze is mediated by serotonin-induced activation of endogenous opioids in the dorsal periaqueductal grey

Abstract

Serotonin (5-HT), opioids and the dorsal periaqueductal grey (DPAG) have been implicated in the pathophysiology of panic disorder. In order to study 5-HT-opioid interaction, the opioid antagonist naloxone was injected either systemically (1 mg/kg, i.p.) or intra-DPAG (0.2 μg/0.5 μL) to assess its interference with the effect of chronic fluoxetine (10 mg/kg, i.p., daily for 21 days) or of intra-DPAG 5-HT (8 μg/0.5 μL). Drug effects were measured in the one-escape task of the rat elevated T-maze, an animal model of panic. Pretreatment with systemic naloxone antagonized the lengthening of escape latency caused by chronic fluoxetine, considered a panicolytic-like effect that parallels the drug's therapeutic response in the clinics. Pretreatment with naloxone injected intra-DPAG antagonized both the panicolytic effect of chronic fluoxetine as well as that of 5-HT injected intra-DPAG. Neither the performance of the inhibitory avoidance task in the elevated T-maze, a model of generalized anxiety nor locomotion measured in a circular arena was affected by the above drug treatments. These results indicate that the panicolytic effect of fluoxetine is mediated by endogenous opioids that are activated by 5-HT in the DPAG. They also allow reconciliation between the serotonergic and opioidergic hypotheses of panic disorder pathophysiology.

μ-Opioid and 5-HT1A receptors in the dorsomedial hypothalamus interact for the regulation of panic-related defensive responses

“…These findings are a first indication of interaction between 5-HT and opioids in the DMH. Similar results have been reported in the DPAG with escape performed in the elevated T-maze test (Roncon et al, 2012).…”

“…The doses of the drugs used in all these experiments were selected on the basis of previous results with the DPAG (De Bortoli et al, 2013; Rangel et al, 2014; Roncon et al, 2012, 2013).…”

Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression

“…Recent findings have also shown that chronic pain corresponds with greater functional connections between the ventromedial PFC and PAG in humans (31), and robust mPFC-PAG projections have been confirmed in rodents (32). Rodent models of chronic pain and stress induce plasticity within the PAG (33–35), and PAG activation modulates anxiety-like behaviors (36, 37). …”

Critical neuropsychobiological analysis of panic attack- and anticipatory anxiety-like behaviors in rodents confronted with snakes in polygonal arenas and complex labyrinths: a comparison to the elevated plus- and T-maze behavioral tests

“…These devices have been submitted to extensive ethological and pharmacological validation and are considered useful for the study of anxiolytic and panicolytic drugs. [1][2][3][4][5][6][7][8][9][10] For example, the EPM and ETM tests have been used to compare the effects of anxiolytic/panicolytic drugs delivered via systemic injection or microinjection into specific encephalic structures, [11][12][13][14][15][16] thereby facilitating the study of the neuroanatomical basis of fear-and anxiety-induced reactions 17,18 and the establishment of correlations between behavioral responses and different stress-related models. [19][20][21] More recently, prey-versus-predator paradigms have also been used to investigate innate and conditioned fearrelated reactions and the effects of drugs that act in the neural substrates of aversive stimulus-induced emotional responses.…”