5-HT1A receptor-effector system responsivity in panic disorder

Abstract

To explore 5-HT1A receptor responsivity in panic disorder (PD), hypothermic, neuroendocrine and behavioral responses to the selective partial 5-HT1A receptor agonist ipsapirone (IPS) were investigated in patients with primary PD and healthy controls. Fourteen patients and matched controls received a single oral dose of 0.3 mg/kg IPS or placebo under double-blind, random-assignment conditions. IPS induced hypothermia and corticotropin (ACTH)/cortisol release but had only minimal effects on behavior. Compared with controls, the patients with PD exhibited significantly attenuated thermoregulatory and neuroendocrine responses to IPS. Although the healthy subjects reported increased drowsiness and the PD patients rated themselves more nervous and less calm following administration of IPS, no consistent changes in ratings of anxiety or panic symptoms were recorded. The impaired hypothermic and ACTH/cortisol responses following 5-HT1A receptor activation reflects subsensitivity of both the pre- and post-synaptic 5-HT1A receptor-effector system, thus supporting the hypothesis that a 5-HT1A receptor-related serotonergic dysfunction may be linked to the pathophysiology of PD. Future studies of 5-HT1A receptor-effector complex function in conjunction with assessment of the responsivity of other subtypes (e.g. 5-HT2, 5-HT3) should promote the evaluation of 5-HT system integrity in anxiety disorders and its involvement in anxiolytic drug effects.

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

“…A SNP (−1019C/G) in the promoter region of the human HTR1A gene is associated with depression, suicide and panic (Huang et al, 2004;Lemonde et al, 2003). There is also an interesting fMRI report that relatively low levels of 5-HT1A-R autoreceptor binding in the midbrain predict increased amygdala reactivity to threatening faces (Fisher et al, 2006), which extends positron emission tomography studies indicating lesser PFC 5-HT1A-R binding and blunted neuroendocrine responses to the 5-HT1A-R partial agonist ipsapirone in patients with panic disorder and depression (Lesch et al, 1992;Lopez-Figueroa et al, 2004;Neumeister et al, 2004b;Sullivan et al, 2005). However, it was not clear in these cases whether this apparent loss of 5-HT1A-R was genetic in origin or a consequence of a stress phenotype.…”

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

“…The opposite phenomenon was observed in mouse models characterized by robust increases in extracellular 5-HT in the brain such as monoamine oxidase A (Maoa) null mutant mice where 5-HT 1A and 5-HT 1B receptors are desensitized and downregulated [119,120] and, to a lesser extent in a brain-region-specific manner, in 5-Htt KO mice [121]. Moreover, 5-HT 1A receptors are downregulated in patients with depression and anxiety disorders as well as during SSRI treatment [122][123][124]. Sensitization and upregulation of 5-HT 1A and 5-HT 1B receptors in 5-HT-deficient mice may therefore be due to a direct cellular mechanism compensating for reduced 5-HT ligand availability by an increased Htr1a and Htr1b gene expression.…”

Smoking Modulates Neuroendocrine Responses to Ipsapirone in Patients with Panic Disorder

“…In order to clarify this question neuroendocrine challenges with oral doses of ipsapirone (0.3 mg/kg) Neuropharmacological challenges with the selective 5-hydroxytryptamine-1A (5-HT1A) receptor agonist, ipsapirone, have been used in several studies to assess 5-HT1A-receptor related functions in patients suffering from various neuropsychiatric disorders (Broocks et al 2000;Lesch et al 1990a;Lesch et al 1991;Lesch et al 1990b;Lesch et al 1992) and in healthy controls (Broocks et al 1999;Kahn et al 1994;Lesch et al 1990c;Lesch et al 1990d).…”

“…In particular, there is evidence for an increased sensitivity of the 5-HT 2C subsystem (Charney et al 1987a;Charney et al 1987b;Kahn et al 1988a Kahn and Wetzler 1991;Kahn et al 1988b). In contrast, stimulation of 5-HT 1A receptors by ipsapirone was followed by an attenuated hypothermic and ACTH/cortisol response in patients with PDA (Broocks et al 2000;Lesch et al 1992). In healthy controls, ipsapirone produces dose-dependent increases in plasma cortisol and ACTH as well as dose-dependent reductions in body temperature (Cowen 2001;Kahn et al 1994;Lesch et al 1989).…”

“…Although many of these patients are regular smokers, it has not been examined whether psychological or neurobiological effects induced by the selective 5-HT1A-receptor agonist, ipsapirone, are affected by the smoking status of the patients.In order to clarify this question neuroendocrine challenges with oral doses of ipsapirone (0.3 mg/kg) Neuropharmacological challenges with the selective 5-hydroxytryptamine-1A (5-HT1A) receptor agonist, ipsapirone, have been used in several studies to assess 5-HT1A-receptor related functions in patients suffering from various neuropsychiatric disorders (Broocks et al 2000;Lesch et al 1990a;Lesch et al 1991;Lesch et al 1990b;Lesch et al 1992) and in healthy controls (Broocks et al 1999;Kahn et al 1994;Lesch et al 1990c;Lesch et al 1990d).Indices of abnormal serotonergic function have been reported in patients with panic disorder (PD) and/or agoraphobia (PDA). In particular, there is evidence for an increased sensitivity of the 5-HT 2C subsystem (Charney et al 1987a;Charney et al 1987b;Kahn et al 1988a Kahn and Wetzler 1991;Kahn et al 1988b).…”