RESUMO
Activation of GABA(A) 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 GABA(A) receptor agonist muscimol (2, 4 and 8 nmol), the GABA(B) 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 GABA(A)/benzodiazepine and GABA(B) 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.
Assuntos
Transtorno de Pânico/fisiopatologia , Substância Cinzenta Periaquedutal/fisiopatologia , Receptores de GABA-A/fisiologia , Receptores de GABA-B/fisiologia , Análise de Variância , Animais , Transtornos de Ansiedade/fisiopatologia , Transtornos de Ansiedade/prevenção & controle , Aprendizagem da Esquiva/efeitos dos fármacos , Baclofeno/administração & dosagem , Baclofeno/farmacologia , Comportamento Animal/efeitos dos fármacos , Carbolinas/administração & dosagem , Carbolinas/farmacologia , Relação Dose-Resposta a Droga , Reação de Fuga/efeitos dos fármacos , Agonistas de Receptores de GABA-A , Agonistas dos Receptores de GABA-B , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microinjeções , Midazolam/administração & dosagem , Midazolam/farmacologia , Muscimol/administração & dosagem , Muscimol/farmacologia , Transtorno de Pânico/prevenção & controle , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Context fear conditioning has been widely used as an animal model of anxiety whereas electrical stimulation of the dorsal portion of the periaqueductal gray (DPAG) as a model of panic attack. The present study employed these two animal models in order to investigate the influence of anxiety in the occurrence of panic attack. Results indicated that animals exposed to contextual cues that were previously associated with electrical footshocks engaged in robust defensive freezing behavior and were less likely to display flight evoked by electrical stimulation of the DPAG when compared with control animals that were not exposed to the context fear conditioning procedure. These results indicate that activation of the brain mechanisms that underlie anxiety produces an inhibitory effect on panic attack.
Assuntos
Condicionamento Psicológico/fisiologia , Modelos Animais de Doenças , Medo/fisiologia , Medo/psicologia , Pânico/fisiologia , Animais , Estimulação Elétrica/métodos , Masculino , Ratos , Ratos WistarRESUMO
The dorsal periaqueductal gray has been implicated in the modulation of escape behavior, a defensive behavior that has been related to panic disorder. Intra-dorsal periaqueductal gray injection of serotonin or drugs that mimic its effects inhibits escape induced by electrical or chemical stimulation of this brainstem area. In this study, we investigate whether intra-dorsal periaqueductal gray injection of 5-HT receptor agonists attenuates escape generated by an ethologically based model of anxiety, the elevated T-maze. This test also allows the measurement of inhibitory avoidance, which has been related to generalized anxiety disorder. The effects of the 5-HT receptor agonists were compared in animals with or without a previous exposure to the open arms of the elevated T-maze. In these two test conditions, intra-dorsal periaqueductal gray injection of the endogenous agonist serotonin or the 5-HT(2B/2C) receptor agonist m-chlorophenylpiperazine (mCPP) enhanced inhibitory avoidance, suggesting an anxiogenic effect. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) impaired this response, suggesting an anxiolytic effect, and the preferential 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) was ineffective. All these agonists inhibited escape behavior. Apart from mCPP, the effect on escape was detected only in animals pre-exposed to the open arm. None of the drugs tested affected locomotion in the open-field test. Taken altogether, our findings suggest that 5-HT1A and 5-HT2c receptors in the dorsal periaqueductal gray exert opposed control on inhibitory avoidance, implicating these receptors in anxiety conditioning. As previously observed in tests employing the aversive stimulation of the dorsal periaqueductal gray, 5-HT1A and 5-HT2A receptors in this brain area are involved in escape inhibition. Therefore, in different animal models, the activation of these two subtypes of receptors in the dorsal periaqueductal gray consistently attenuates the expression of a panic-related behavior.
Assuntos
Aprendizagem da Esquiva/fisiologia , Reação de Fuga/fisiologia , Aprendizagem em Labirinto/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Anfetaminas/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Reação de Fuga/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Piperazinas/farmacologia , Ratos , Ratos Wistar , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Electrical stimulation of the dorsal periaqueductal gray (DPAG) has been used to induce panic-like behavior in rats. In the present study, we investigated the effect of chronic imipramine treatment on the sensitivity of different 5-HT receptor subtypes in inhibiting aversion induced by electrical stimulation of this brain area. For that, the effects of intra-DPAG administration of the endogenous agonist 5-HT (20 nmol), the 5-HT(1A) receptor agonist 8-OH-DPAT (8 nmol) and the 5-HT(2A/2C) receptor agonist DOI (16 nmol) were measured in female Wistar rats given either chronic injection of imipramine (15 mg/kg, 3 weeks, ip) or saline. The results showed that the three receptor agonists raised the threshold of aversive electrical stimulation in both groups of animals, but this antiaversive effect was significantly higher in rats treated with imipramine. Treatment with imipramine did not change the basal threshold of aversive electrical stimulation measured before intra-DPAG injection of the 5-HT agonists. The results suggest that sensitization of both 5-HT(1A) and 5-HT(2) receptors within the DPAG may be involved in the beneficial effect of imipramine in panic disorder (PD).