RESUMO
INTRODUCTION AND OBJECTIVES: Oxytocin (OT) has been widely linked to positive social interactions, and there is great interest in OT as a therapy for a variety of neuropsychiatric conditions. Recent evidence also suggests that OT can play an important role in the mediation of anxiety-associated defensive responses, including a role for serotonin (5-HT) neurotransmission in this action. However, it is presently unknown whether OT additionally regulates the expression of panic-related behaviors, such as escape, by acting in the dorsal periaqueductal gray (dPAG), a key panic-regulating area. This study aimed to investigate the consequence of OT injection in the dPAG on escape expression and whether facilitation of 5-HT neurotransmission in this midbrain area is implicated in this action. METHODS: Male Wistar rats were injected with OT in the dPAG and tested for escape expression in the elevated T-maze (ETM) and dPAG electrical stimulation tests. Using the latter test, OT's effect was also investigated after previous intra-dPAG injection of the OT receptor antagonist atosiban, the preferential antagonists of 5-HT1A and 5-HT2A receptors, WAY-100635 and ketanserin, respectively, or systemic pretreatment with the 5-HT synthesis inhibitor p-CPA. RESULTS: OT impaired escape expression in the two tests used, suggesting a panicolytic-like effect. In the ETM, the peptide also facilitated inhibitory avoidance acquisition, indicating an anxiogenic effect. Previous administration of atosiban, WAY-100635, ketanserin, or p-CPA counteracted OT's anti-escape effect. CONCLUSIONS: OT and 5-HT in the dPAG interact in the regulation of panic- and anxiety-related defensive responses. These findings open new perspectives for the development of novel therapeutic strategies for the treatment of anxiety disorders.
Assuntos
Ansiolíticos/farmacologia , Ocitocina/farmacologia , Pânico/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Serotonina/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Estimulação Elétrica , Eletrodos Implantados , Reação de Fuga/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptores de Ocitocina/antagonistas & inibidores , Antagonistas da Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Vasotocina/análogos & derivados , Vasotocina/farmacologiaRESUMO
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 30mg/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 4mg/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 2.5µg/kg) facilitated escape performance, indicating a panicogenic-like effect, while treatment with α-para-chlorophenylalanine (p-CPA; 4days i.p injections of 100mg/kg, or a single i.p injection of 300mg/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.
Assuntos
Ansiolíticos/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Pânico/efeitos dos fármacos , Alprazolam/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Reação de Fuga/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Fenclonina/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Moclobemida/farmacologia , Ratos , Ratos Wistar , Serotonina/metabolismo , Sumatriptana/farmacologiaRESUMO
RATIONALE: Electrical stimulation of the dorsal periaqueductal gray (dPAG) evokes escape, a defensive response associated with panic attacks. Stimulation of 5-HT1A or 5-HT2A receptors in this midbrain area equally inhibits escape performance, even though at the molecular level these receptors cause opposite effects, i.e., activation of the former hyperpolarizes the cell membrane, while the latter excites it. A proposal has been made that 5-HT2A receptor agonists exert their inhibitory effect on escape by activating GABAergic interneurons located in the dPAG. OBJECTIVES: In the present study, we evaluated this hypothesis by investigating whether previous intra-dPAG administration of the GABAA receptor antagonist bicuculline blocks the anti-escape effect caused by the local injection of different 5-HT2A/2C receptor agonists. RESULTS: Intra-dPAG administration of 5-HT, the preferential 5-HT2A receptor agonist DOI, the nonselective 5-HT2C receptor agonist mCPP or the 5-HT2C receptor agonist RO 60-0175 significantly inhibited the escape reaction induced by electrical stimulation of the same brain area. In all cases, this panicolytic-like effect was blocked by previous microinjection of bicuculline. This GABAA antagonist, however, failed to antagonize the anti-escape effect caused by the 5-HT1A receptor agonist 8-OH-DPAT. The inhibitory effect caused by DOI, RO 60-0175, and mCPP was also blocked by previous intra-dPAG injection of the preferential 5-HT2A receptor antagonist ketanserin. Pre-administration of the 5-HT2C receptor antagonist SB-242084 in the dPAG did not block the anti-escape effect of RO 60-0175. CONCLUSIONS: Stimulation of 5-HT2A but not 5-HT2C receptors in the dPAG causes a panicolytic-like effect that is mediated by facilitation of GABAergic neurotransmission.