Towards a translational model of panic attack.

Abstract

About 20 years ago, Deakin and Graeff proposed that whereas generalized anxiety disorder is produced by the overactivity of 5-HT excitatory projections from dorsal raphe nucleus to the areas of prefrontal cortex and amygdala which process distal threat, panic attacks are a dysfunction of 5-HT inhibitory projections from dorsal raphe nucleus to the dorsal periaqueductal gray matter, thereby releasing the responses to proximal threat, innate fear or anoxia. Besides, they suggested that the decrease in 5-HT1A neurotransmission in the hippocampus results in learned helplessness and depression. Accordingly, the Deakin Graeff hypothesis provided a unified frame to the widespread use of 5-HT selective reuptake inhibitors in generalized anxiety, panic disorder and depression. Competitor hypotheses implicate panic attacks with the abnormal functioning of locus coeruleus, basolateral amygdala, dorsomedial hypothalamus or an as-yet-unknown suffocation alarm system. Conversely, cognitive psychologists suggest that panic attacks result from the catastrophic (cortical) interpretation of bodily symptoms. In any event, translational models of panic attack are expected to reproduce the main features of clinical panic, namely, the patient's higher sensitivity to both lactate and CO2, the drug specific sensitivity, the lack of stress hormone responses during panic attacks, the higher vulnerability of women and the high comorbidity with agoraphobia, major depression and childhood separation anxiety. Therefore, here we review the main steps in the experimental approach to anxiety disorders which are paving the route towards a translational model of panic attack.

Long‐lasting marked inhibition of periaqueductal gray‐evoked defensive behaviors in inescapably‐shocked rats

“…In rats, electrical and chemical stimulations of the PAG produce freezing (tense immobility plus exophthalmos) and flight (trotting, galloping or jumping) behaviors (Bittencourt et al ., ; Schenberg et al ., ) along with marked visceral responses (Schenberg et al ., ; Schenberg & Lovick, ; Sampaio et al ., ) that have been regarded as the animal analogue of panic (Deakin & Graeff, ; Jenck et al ., ; Graeff et al ., ; Schenberg, ). In particular, pharmacological studies with chronic administration of low doses of panicolytics suggested that galloping is the rat panic attack best‐candidate response (Schenberg et al ., ; Vargas & Schenberg, ).…”

Development and psychometric properties of a novel depression measure

“…Recent studies have shown comorbidity or an association of major depression with several other psychopathologies, such as anxiety (Brady & Kendall, 1992;Kemp & Felmingham, 2008;Schoevers, Beekman, Deeg, Jonker, & van Tulburg, 2003), panic syndrome (Kessler et al, 1998;Schenberg, 2010), alcoholism (Driessen et al, 2001), and eating disorders (Bulik, 2002), among others.…”

Envolvimento da neurotransmissão CRFérgica das asas laterais do núcleo dorsal da rafe na expressão de comportamentos defensivos associados ao pânico

“…Estudos utilizando a técnica de estimulação elétrica mostram que o hipotálamo medial e a substância cinzenta periaquedutal (SCP) são estruturas envolvidas na evocação destas respostas defensivas (para revisão ver SCHENBERG, 2010). Este padrão de resposta evidenciado no nível proximal tem sido sistematicamente relacionado aos ataques de pânico nos seres humanos, uma vez que estes comportamentos são sensíveis a drogas que na clínica são eficazes no tratamento do transtorno do pânico (BLANCHARD et al, 1997;GRAEFF, 1994;SCHENBERG, 2010).…”

“…Evidências pré-clínicas obtidas em modelos animais de conflito, nos quais o comportamento operante é simultaneamente mantido por um reforço positivo e suprimido por um estímulo aversivo, apontaram para o papel ansiogênico da 5-HT(GELLER;BLUM, 1970;SCHOENFELD, 1970;ROBICHAUD;SLEDGE, 1969). Somados a estas evidências, estudos farmacológicos mostraram que a 5-HT promovia um aumento nos níveis de ansiedade devido sua ação em substratos neurais como o complexo amigdaloide (HODGES; GREEN;GLENN, 1987;PETERSEN; SCHEEL-KRUGER, 1984).Todavia, utilizando o modelo animal de estimulação elétrica da substância cinzenta periaquedutal dorsal (SCPD), caracterizado por induzir a resposta defensiva de fuga, apontava para o papel ansiolítico da 5-HT (KISER;LEBOVITZ, 1975;SANFORD KISER;GERMAN, 1978;SCHENBERG;GRAEFF, 1978;SCHÜTZ;DE AGUIAR;GRAEFF, 1985) Diante desta e de outras evidências aparentemente contraditórias sobre o envolvimento da serotonina na mediação de comportamentos defensivos associados à ansiedade e ao pânico (para uma revisão abrangente, ver(GRAEFF, 2002), Deakin e Graeff(1991)propuseram a chamada teoria do papel dual da serotonina na ansiedade. No cerne desta teoria está o núcleo dorsal da rafe (NDR).…”