Panicolytic-like Effect Research Articles

Enhanced reactivity of 5-HT1A receptors in the rat dorsal periaqueductal gray matter after chronic treatment with fluoxetine and sertraline: Evidence from the elevated T-maze

Behavioral evidence indicates that sensitization of 5-HT1A and 5-HT2A receptors in the dorsal periaqueductal gray (DPAG) may underlie the therapeutic effect of serotonin reuptake inhibitors (SRIs) in panic disorder. These results were obtained from studies using animal models that associate escape behavior with panic attacks, such as the elevated T-maze. In this test, chronic administration of the non-selective SRI imipramine enhances the inhibitory effect on escape caused by the intra-DPAG injection of the 5-HT1A receptor agonist 8-OH-DPAT. We here evaluated the generality of this finding by investigating the effect of chronic administration of two selective SRIs (SSRIs), fluoxetine and sertraline, on the reactivity of the rat DPAG 5-HT1A receptors. The results showed that both SSRIs inhibited escape behavior in the elevated T-maze, suggestive of a panicolytic-like effect. Whereas intra-DPAG injection of a low dose of 8-OH-DPAT (0.4 nmol) had no effect on escape in control animals, it significantly enhanced the inhibitory effect caused by the SSRIs on this response. Microinjection of 8-OH-DPAT in SSRI-treated rats also inhibited the acquisition of inhibitory avoidance, another defensive response measured by the elevated T-maze. The results indicate that chronic administration of fluoxetine and sertraline sensitizes 5-HT1A receptors in the DPAG. Overall, they support the view that facilitation of 5-HT1A receptor-mediated neurotransmission in the DPAG is implicated in the therapeutic effect of SRIs on panic disorder.

Picrotoxin blocks the anxiolytic- and panicolytic-like effects of sodium valproate in the rat elevated T-maze

The effect of acute sodium valproate administration, an anxiolytic and putative panicolytic drug, was evaluated in rats tested in the elevated T-maze, an animal model that measures two defensive reactions: avoidance (inhibitory avoidance), related to generalized anxiety, and escape (escape from open arms), related to panic. Additionally, the involvement of γ-aminobutyric acid (GABA) neurotransmission in sodium valproate effects was studied by picrotoxin co-administration. Sodium valproate (300 mg/kg, intraperitoneally, 30 min before the test) impaired both avoidance latency (time to leave the closed arm) and one-way escape (latency to enter the closed arm) indicating anxiolytic and panicolytic effects, respectively. Pre-treatment with picrotoxin (0.5 mg/kg, intraperitoneally, 5 min before sodium valproate administration) blocked the effects of sodium valproate on inhibitory avoidance and one-way escape. No locomotor effect was seen in the open-field. These data suggest that sodium valproate exerts anxiolytic-like and panicolytic-like effects in the elevated T-maze and that these effects were mediated by picrotoxin-sensitive GABA type A receptors.

P.4.b.004 Stimulation of the lateral habenula inhibits a panic-like behaviour by activation of serotonin-1A receptors in the rat dorsal periaqueductal gray

The transient receptors potential vanilloid type 1 channels (TRPV1) are expressed in several brain regions related to defensive behaviors, including the dorsolateral periaqueductal gray (dlPAG). The endocannabinoid anandamide, in addition to its agonist activity at cannabinoid type 1 (CB1), is also proposed as an endogenous agonist of these receptors, through which it could facilitate anxiety-like responses. The aim of this work was to test the hypothesis that TRPV1 in the dlPAG of rats would mediate panic-like responses in two models, namely the escape responses induced by chemical stimulation of this structure or by exposure to the elevated T-Maze (ETM). Antagonism of TRPV1 with capsazepine injected into the dlPAG reduced the defense response induced by local NMDA-injection, suggesting an anti-aversive effect. In the ETM, capsazepine inhibited escape response, suggesting a panicolytic-like effect. Interestingly, this effect was prevented by a CB1 antagonist (AM251). The present study showed that antagonism of TRPV1 in the dlPAG induces panicolytic-like effects, which can be prevented by a CB1 antagonist. Therefore, these antiaversive effects of TRPV1 blockade may ultimately occur due to a predominant action of anandamide through CB1 receptors.

Chronic imipramine treatment sensitizes 5-HT1A and 5-HT2A receptors in the dorsal periaqueductal gray matter: evidence from the elevated T-maze test of anxiety

The dorsal periaqueductal gray matter (DPAG) has been implicated in the mediation of escape, a defensive behavior associated with panic disorder (PD). Chronic treatment with the anti-panic agent imipramine enhances the inhibitory effect on escape evoked by DPAG electrical stimulation of intra-DPAG administration of the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the preferential 5-HT 2 A receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). In the present study we further explore the hypothesis that sensitization of 5-HT1A and 5-HT 2 A receptors in the DPAG is involved in the anti-panic effect of imipramine. To this end, Wistar rats, subchronically or chronically treated with imipramine, were intra-DPAG injected with 8-OH-DPAT (0.4 or 3.2 nmoles) or DOI (16 nmoles), and tested in the elevated T-maze. In addition to its possible relevance to panic disorder, this test also measures inhibitory avoidance, a behavior that has been associated with generalized anxiety disorder (GAD). The effects of these 5-HT agonists in the DPAG were also investigated in animals chronically injected with buspirone, a drug clinically effective in treating GAD, but not PD. The results showed that intra-DPAG administration of the highest dose of 8-OH-DPAT and of DOI inhibited escape, and this panicolytic-like effect was significantly higher in animals previously treated chronically, but not subchronically, with imipramine. 8-OH-DPAT (0.4 nmole), although not affecting escape in animals systemically treated with saline, had a panicolytic-like effect in those receiving long-term treatment with imipramine. Microinjection of 8-OH-DPAT (3.2 nmoles), but not of DOI, impaired inhibitory avoidance, and this anxiolytic effect did not differ between animals treated with saline or imipramine. Chronic buspirone did not change the effect of 8-OH-DPAT and DOI on inhibitory avoidance and escape. Therefore, chronic imipramine seems to sensitize both 5-HT1A and 5-HT 2 A receptors in the DPAG, strengthening the view that these receptors are involved in the mode of action of anti-panic drugs.

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

Administration of 5-hydroxytryptamine (5-HT)1A and 5-HT2A receptor agonists into the dorsal periaqueductal gray (DPAG) inhibits escape, a defensive behavior associated with panic attacks. Long-term treatment with the antipanic compound imipramine enhances the DPAG 5-HT1A- and 5-HT2A-receptor-mediated inhibition of escape, implicating these receptors in the mode of action of panicolytic drugs. In the present study, we investigated whether the inhibitory effect on escape elicited by the intra-DPAG injection of 5-HT1A and 5-HT2A receptor agonists is also enhanced after treatment with fluoxetine, another widely used antipanic drug. The effects of fluoxetine were compared to those of buspirone, an anxiolytic drug without major effect on panic disorder. Male Wistar rats, subchronically (3-6 days) or chronically (21-24 days) treated with fluoxetine (10 mg/kg i.p.) or chronically treated with buspirone (0.3 mg/kg i.p.), were intra-DPAG injected with 5-HT (20 nmol), the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT; 8 nmol) or the preferential 5-HT2A receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl) piperazine dihydrochloride (DOI; 16 nmol). The intensity of electrical current that applied to the DPAG-evoked escape behavior was measured before and after the microinjection of these agonists. The electrical current necessary to produce escape was increased after the microinjection of the three 5-HT receptor agonists in all groups of animals tested. However, this panicolytic-like effect was significantly higher in animals receiving long-term treatment with fluoxetine. The results suggest that facilitation of the 5-HT1A- and 5-HT2A-receptor-mediated inhibition of DPAG neuronal activity is implicated in the beneficial effect of antidepressants in panic disorder.

Panicolytic-like effect induced by the stimulation of GABAA and GABAB receptors in the dorsal periaqueductal grey of rats

Activation of GABAA and benzodiazepine receptors within the dorsal periaqueductal grey inhibits the escape behaviour evoked by the electrical stimulation of this midbrain area, a defensive reaction that has been related to panic. Nevertheless, there is no evidence indicating whether the same antiaversive effect is also observed in escape responses evoked by species-specific threatening stimuli. In the present study, male Wistar rats were injected intra-dorsal periaqueductal grey with the benzodiazepine receptor agonist midazolam (10, 20 and 40 nmol), the GABAA receptor agonist muscimol (2, 4 and 8 nmol), the GABAB receptor agonist baclofen (2, 4 and 8 nmol), or with the benzodiazepine inverse agonist FG 7142 (20, 40 and 80 pmol) and tested in an ethologically-based animal model of anxiety, the elevated T-maze. Besides escape, this test also allows the measurement of inhibitory avoidance which has been related to generalised anxiety disorder. Midazolam, muscimol and baclofen impaired escape, a panicolytic-like effect, without altering inhibitory avoidance. FG 7142, on the other hand, facilitated both avoidance and escape reactions, suggesting an anxiogenic and panicogenic-like effect, respectively. The data suggest that GABAA/benzodiazepine and GABAB receptors within the dorsal periaqueductal grey are involved in the control of escape behaviour and that a failure in this regulatory mechanism may be of importance in panic disorder.

Systemic and intra-dorsal periaqueductal gray injections of cholecystokinin sulfated octapeptide (CCK-8s) induce a panic-like response in rats submitted to the elevated T-maze

The neuropeptide cholecystokinin (CCK) has been implicated in fear and anxiety. CCK is found in the CNS in several molecular forms such as the tetrapeptide (CCK-4) and, mainly, the sulfated octapeptide (CCK-8s) fragments. Administration of CCK-4 induces panic attacks in humans and increases the expression of different anxiety-related behaviors in laboratory animals. The effects of CCK-8s on fear and anxiety are less straightforward and seem to be influenced, among other factors, by the route of the peptide administration and the animal model employed. In other to further investigate the role of CCK-8s in fear and anxiety, in the present study we analyzed the effect of CCK-8s in male Wistar rats submitted to the elevated T-maze. This animal model of anxiety was developed in order to separate generalized anxiety (inhibitory avoidance) and panic-like (escape) responses in the same rat. The effect of CCK-8s in this test was also investigated after injection of the peptide into the dorsal periaqueductal gray (DPAG). This brainstem area is rich in CCK receptors and has consistently been implicated in the mediation of fear and anxiety responses. The results showed that both the intraperitoneal and intra-DPAG injections of CCK-8s potentiated one-way escape behavior, suggesting a panicogenic action. In contrast, the injection of the CCK2 receptor antagonist CR2945 inhibited the expression of this behavior, a panicolytic-like effect. Therefore, the elevated T-maze, in contrast to other animal models of anxiety, can detect the anxiety-eliciting effects of CCK-8s both after its systemic and central administration. Also, the results provide further evidence about the involvement of a CCK-mediated mechanism within the DPAG in the regulation of panic-related defensive behaviors.

P.1.082 Lamotrigine: An alternative drug in the prophylaxis of bipolar disorders

The elevated T-maze was developed to test the hypothesis that serotonin plays an opposing role in the regulation of defensive behaviors associated with anxiety and panic. Previous pharmacological exploitation of this test supports the association between inhibitory avoidance acquisition and escape expression with anxiety and fear/panic, respectively. In the present study, we extend the pharmacological validation of this test by investigating the effects of other putative or clinically effective anxiety- and panic-modulating drugs. The results showed that chronic, but not acute injection of the reversible monoamine oxidase-A inhibitor moclobemide (3, 10 and 30 mg/kg) inhibited escape expression, indicating a panicolytic-like effect. The same effect was observed after either acute or chronic treatment with alprazolam (1, 2 and 4 mg/kg), a high potency benzodiazepine. This drug also impaired inhibitory avoidance acquisition, suggesting an anxiolytic effect. On the other hand, subcutaneous administration of the 5-HT1D/1B receptor agonist sumatriptan (0.1, 0.5 and 2.5 μg/kg) facilitated escape performance, indicating a panicogenic-like effect, while treatment with α-para-chlorophenylalanine (p-CPA; 4 days i.p injections of 100 mg/kg, or a single i.p injection of 300 mg/kg), which caused marked 5-HT depletion in the amygdala and striatum, was without effect. Altogether, these results are in full agreement with the clinical effects of these compounds and offer further evidence that the elevated T-maze has broad predictive validity for the effects of anxiety- and panic-modulating drugs.