The Deakin/Graeff hypothesis proposes that different subpopulations of serotonergic neurons through topographically organized projections to forebrain and brainstem structures modulate the response to acute and chronic stressors which dysfunction of these neurons increases vulnerability to affective and anxiety disorders including Panic Disorder. and physiological responses. Evidence supporting this Asiaticoside comes from the following observations: 1) serotonergic neurons located in the ‘ventrolateral dorsal raphe nucleus (DRVL) as well as the ventrolateral periaqueductal gray (VLPAG) inhibit dorsal periaqueductal gray-elicited panic-like responses; 2) chronic but not acute antidepressant treatment potentiates serotonin’s panicolytic effect; 3) contextual fear activates a Rabbit Polyclonal to UBTD2. central nucleus of the amygdala-DRVL/VLPAG circuit implicated in mediating freezing and inhibiting panic-like escape behaviors; 4) DRVL/VLPAG serotonergic neurons are central chemoreceptors and modulate the behavioral and cardiorespiratory response to panicogenic providers such as sodium lactate and CO2. Implications of the are discussed. (DSM-V) right now lists PAs like a specifier i.e. a prognostic element used to aid in the analysis of the severity program and comorbidity of all DSM-V disorders (American Psychiatric Association 2013 Clearly there is significant demand and significant unmet need for the treatment of panic disorder; considering the ubiquity of PAs future research should not only provide insight into the neurobiological mechanisms of PD and PAs but also additional comorbid psychiatric and medical disorders. 1.2 Experimentally-induced stress: putative panicogenic providers Unlike additional mental disorders PD is relatively unique as its pathognomonic feature the PA can be experimentally-induced in PD individuals but rarely in healthy individuals by exposure to a rapidly expanding list of putative panicogenic providers with diverse pharmacological profiles including sodium lactate (Pitts Jr. and McClure Jr. 1967 carbon dioxide (CO2; Gorman et al. 1984 cholecystokinin tetrapeptide (CCK-4; Bradwejn et al. 1991 et al. 1992 yohimbine (α2-receptor antagonist)(Charney et al. 1987 sodium bicarbonate (Gorman et al. 1989 caffeine (Charney et al. 1985 isoproterenol hydrochloride (Nesse et al. 1984 Jr. et al. 1984 meta-chlorophenylpiperazine (vehicle der Wee et al. 2004 5 agonist; vehicle Veen et al. 2007 and fenfluramine (a serotonin-releasing agent; Targum and Marshall 1989 At least a well-validated panicogenic agent should fulfill the following criteria: 1) the agent should be safe for use in humans; 2) the agent should specifically and reliably induce PAs in PD individuals but not healthy individuals; 3) the induced PA should be transient and reversible; 4) the PA should be clogged by therapeutics known to be effective in treating naturally happening PAs in PD Asiaticoside (e.g. selective-serotonin reuptake inhibitors SSRIs); and 5) the induced PA should share the symptomatology of naturally happening PAs (Griez and Schruers 1998 et al. 1983 2011 Based on these criteria and the pharmacological reactivity of the various challenges others have argued that some of these compounds may elicit a behavioral cognitive and physiological response more akin to anticipatory or discord anxiety fear stress or pain (Griez and Schruers 1998 2011 1993 Among these candidate panicogenic providers the sodium lactate and CO2 difficulties are the most widely used and well-validated experimental methods to induce stress (Amaral et al. 2013 and Schruers 1998 1993 the CCK-4 challenge shows promise as an experimental model of PAs but several issues remain unresolved (Kellner 2011 1.3 Towards a Panic Disorder hypothesis: hyperventilation theories exaggerated fear networks and false suffocation alarms A unifying feature of these experimentally-induced panic attacks and naturally happening panic attacks is that the individual often experiences respiratory abnormalities including dyspnea (air flow hunger breathlessness) hyperventilation and increased minute air flow (Sinha et al. 2000 These reports taken together with evidence showing high comorbidity between PD and a number of respiratory disorders (e.g. asthma COPD; Simon and Fischmann 2005 led many to postulate respiratory dysfunction as possessing a central part in PD. Ley’s hyperventilation theory of stress (Ley 1985 and later on updated as the dyspnea/suffocation theory of stress (Ley 1989 for example proposed that acute hyperventilation induced PAs Asiaticoside (or a subtype of hyperventilatory PAs observe Ley 1992 and that the dyspnea (air flow Asiaticoside food cravings breathlessness) experienced during the PA Asiaticoside offered rise to the intense feelings of fear often accompanying the attack. In contrast Klein’s false suffocation alarm.
