RESUMO
RATIONALE: Serotonin in the dorsal periaqueductal gray (DPAG) through the activation of 5-HT(1A) and 5-HT(2A) receptors inhibits escape, a defensive behavior associated with panic attacks. Long-term treatment with antipanic drugs that nonselectively or selectively blocks the reuptake of serotonin (e.g., imipramine and fluoxetine, respectively) enhances the inhibitory effect on escape caused by intra-DPAG injection of 5-HT(1A) and 5-HT(2A) receptor agonists. It has been proposed that these compounds exert their effect on panic by facilitating 5-HT-mediated neurotransmission in the DPAG. OBJECTIVES: The objective of this study was to investigate whether facilitation of 5-HT neurotransmission in the DPAG is also observed after treatment with alprazolam, a pharmacologically distinct antipanic drug that acts primarily as a high potency benzodiazepine receptor agonist. MATERIALS AND METHODS: Male Wistar rats, subchronically (3-6 days) or chronically (14-17 days) treated with alprazolam (2 and 4 mg/kg, i.p.) were intra-DPAG injected with (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), (+/-)-1-(2,5-dimethoxy-4-iodophenyl) piperazine dihydrochloride (DOI), and midazolam, respectively, 5-HT(1A), 5-HT(2A/2C), and benzodiazepine receptor agonists. The intensity of electrical current that needed to be applied to the DPAG to evoke escape behavior was measured before and after the microinjection of these agonists. RESULTS: Intra-DPAG injection of the 5-HT agonists and midazolam increased the escape threshold in all groups of animals tested, indicating a panicolytic-like effect. The inhibitory effect of 8-OH-DPAT and DOI, but not midazolam, was significantly higher in animals receiving long-, but not short-term treatment with alprazolam. CONCLUSIONS: Alprazolam as antidepressants compounds facilitates 5-HT(1A)- and 5-HT(2A)-receptor-mediated neurotransmission in the DPAG, implicating this effect in the mode of action of different classes of antipanic drugs.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Alprazolam/farmacologia , Ansiolíticos/farmacologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Anfetaminas/farmacologia , Animais , Relação Dose-Resposta a Droga , Estimulação Elétrica , Masculino , Microinjeções , Substância Cinzenta Periaquedutal/anatomia & histologia , Ratos , Ratos Wistar , Transmissão Sináptica/efeitos dos fármacosRESUMO
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 (0.4nmol) 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.
Assuntos
Fluoxetina/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sertralina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Interações Medicamentosas , Masculino , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacosRESUMO
Electrical stimulation of the dorsal periaqueductal grey matter (DPAG) and deep layers of the superior colliculus (DLSC) of the rat elicits anxiety-like reactions such as freezing and flight. The temporal course of the effects of the aversive electrical stimulation of the DPAG (5, 15 and 30 min afterward) and DLSC (5, 10 and 15 min afterward) on the defensive response of rats exposed to elevated T-maze were determined. The elevated T-maze generates two defensive behaviors, inhibitory avoidance and one-way escape, which have been related, respectively, to generalized anxiety and panic disorders. Prior electrical stimulation of the DPAG (15 min) and DLSC (5 min) enhanced inhibitory avoidance when compared to no-operated and sham animals, although not affecting escape. Therefore, stimulation of the DPAG and DLSC causes a heightened responsivity to anxiogenic stimulus, but not to panicogenic stimulus, inherent to elevated T-maze. These findings support the participation of the DPAG and DLSC in the elaboration of adaptive responses to stressful situations. Besides, the data supports the view that prior electrical stimulation of DPAG and DLSC is selective in sensitizing rats to anxiety-like behaviors, but not to panic-like behaviors in the elevated T-maze test.
Assuntos
Ansiedade/etiologia , Estimulação Elétrica , Aprendizagem em Labirinto/efeitos da radiação , Substância Cinzenta Periaquedutal/efeitos da radiação , Colículos Superiores/efeitos da radiação , Animais , Ansiedade/fisiopatologia , Aprendizagem da Esquiva/efeitos da radiação , Comportamento Animal/efeitos da radiação , Reação de Fuga/efeitos da radiação , Inibição Psicológica , Masculino , Ratos , Ratos Wistar , Tempo de Reação/efeitos da radiação , Fatores de TempoRESUMO
RATIONALE: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Ansiolíticos/farmacologia , Buspirona/farmacologia , Fluoxetina/farmacologia , Substância Cinzenta Periaquedutal/fisiologia , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/metabolismo , Anfetaminas/administração & dosagem , Anfetaminas/farmacologia , Animais , Ansiolíticos/administração & dosagem , Buspirona/administração & dosagem , Fluoxetina/administração & dosagem , Masculino , Microinjeções , Ratos , Ratos Wistar , Serotonina/metabolismo , Agonistas do Receptor de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagemRESUMO
We investigated the effects of chronic oral treatment with a water-alcohol extract from the inflorescence of Erythrina mulungu (Leguminosae-Papilionaceae) (EM, 50, 100, 200 mg/kg) in rats submitted to different anxiety models: the elevated T-maze (ETM, for inhibitory avoidance and escape measurements), the light/dark transition, and the cat odor test. These models were selected for their capacity to elicit specific subtypes of anxiety disorders as recognized in clinical practice. Treatment with EM impaired inhibitory avoidance latencies in a way similar to the reference drug, diazepam (DZP). Additionally, both EM and DZP increased the number of transitions and the time spent in the lighted compartment of the light/dark transition model. Furthermore, neither EM nor DZP altered behavioral responses of rats to a cloth impregnated with cat odor. In contrast to DZP, however, EM also altered ETM one-way escape. These results were not due to motor alterations since no significant effects were detected in the number of crossings or rearings in the arena. The present observations suggest that chronic EM exerts anxiolytic-like effects in defensive behaviors related to generalized anxiety and panic disorder. Although alkaloids appear to be one of the main constituents of EM, the possible mechanisms through which the extract exerts its anxiolytic action should be further investigated.