Adrenergic receptor function in panic disorder. II. Neutrophil beta 2 receptors: Gs protein coupling, effects of imipramine treatment and relationship to treatment outcome.

Panic attacks are associated with increased autonomic symptoms, suggesting increased beta 2-adrenergic receptor (beta 2AR) function in PD. Tricyclic antidepressants downregulate beta AR function. Previous studies on beta AR function in PD, however, are inconsistent. We recently found increased beta AR coupling and density in neutrophils of symptomatic drug-free PD patients. This study evaluated beta AR coupling to Gs protein in 28 controls, 25 drug-free PD patients and 8 PD imipramine-treated patients. PD patients had significantly higher coupling and receptor density, particularly in the high-conformational state. Differences were more pronounced in patients with less depressive symptomatology. Treatment with imipramine was associated with decreased beta AR coupling and density in the high-conformational state. Several beta AR binding parameters were related to severity of anxiety symptoms and treatment outcome. Antidepressants downregulate beta AR density and induce uncoupling from Gs protein in PD. Future studies may investigate beta AR coupling in relationship to treatment outcome and the role of beta AR kinase in PD.

Neutrophil beta2-adrenergic receptor coupling efficiency to Gs protein in subjects with post-traumatic stress disorder and normal controls.

The symptomatology of post-traumatic stress disorder (PTSD) involves sympathetic hyperarousal. Several of these sympathetic symptoms are mediated through end-organ beta2-adrenergic receptors (beta2AR). Increased sympathetic activity in PTSD could therefore be due to increased betaAR function. This study investigated betaAR function in 30 healthy controls and 20 drug-free PTSD patients. BetaAR binding studies were conducted using antagonist-saturation and agonist-displacement experiments. Measures of beta2AR coupling to Gs protein were derived from agonist-displacement experiments. PTSD patients had significantly higher beta2AR density particularly in the high-conformational state and higher beta2AR coupling than controls, as reflected in a higher percentage of receptors in the high conformational state and a higher ratio of the agonist dissociaton constant from the receptor in the low/high-conformational state. Increased betaAR function in PTSD is consistent with the symptomatology of this disorder. Increased betaAR density and coupling may be consistent with downregulation of betaAR density and uncoupling by antidepressants and may underlie their partial efficacy in PTSD. Dysregulation in Gs protein function is postulated and, agonist-mediated regulation of betaAR expression and/or betaAR kinase activity in PTSD should be investigated in future studies.

Adrenergic receptor function in panic disorder. I. Platelet alpha 2 receptors: Gi protein coupling, effects of imipramine, and relationship to treatment outcome.

Various studies suggest alpha 2-adrenergic receptor (alpha 2AR) dysregulation in panic disorder (PD). Platelet alpha 2-AR exist in high- and low-conformational states as a function of their coupling to Gi protein. alpha 2AR coupling is important in signal transduction and is modulated by antidepressants. alpha 2AR density in the high- and low-conformational states, agonist affinity, and coupling efficiency were investigated in 21 healthy controls, 21 drug-free PD patients, and eight imipramine-treated patients using norepinephrine displacement of 3H-yohimbine binding. Percentage of receptors in the high-conformational state (%RH) and the ratio of the agonist dissociation constant to the receptor in the low-/high-conformational state (KL/KH), calculated from displacement experiments, were used as coupling indices. Patients had high alpha 2AR density in both conformational states. %RH and KL/KH ratio were significantly different, particularly in patients with Hamilton scale for depression (HAMD) scores > or = 15. Imipramine treatment (29 weeks) had no effect on alpha 2AR density or coupling, despite improvement in anxiety ratings. High pretreatment alpha 2AR density and coupling predicted low severity of anxiety after treatment. Increased alpha 2AR density and abnormal coupling may represent an adaptive mechanism or trait marker in PD.

Characteristics of agonist displacement of [3H]ketanserin binding to platelet 5-HT2A receptors: implications for psychiatric research.

Brain 5-HT(2A) receptors exist in two agonist affinity states as a function of their coupling to Gq protein. This has not yet been shown in platelets. We examined [3H]ketanserin's saturable binding to platelet 5-HT2A receptors and characteristics of agonist displacement curves of [3H]ketanserin binding in healthy control subjects. [3H]ketanserin saturation curves showed a trend for a two-site model, reflecting two independent binding sites. At low [3H]ketanserin concentrations, agonist displacement curves were flat and best fit a two-site model, indicating the existence of two agonist affinity states. Guanylyl 5'-imidotriphosphate [Gpp(NH)p] induced a significant rightward shift in agonist displacement curves to fit a one-site model. Platelet membrane 5-HT2A receptors exist in two agonist affinity states that are regulated by Gq protein. Platelet 5-HT2A receptors provide an accessible model for examining possible dysregulation in the agonist affinity or coupling efficiency to the phosphoinositide system in psychiatric disorders and their modulation by psychotropic medications.

Adrenergic receptors in premenstrual dysphoric disorder: I. Platelet alpha 2 receptors: Gi protein coupling, phase of menstrual cycle, and prediction of luteal phase symptom severity.

BACKGROUND: Abnormal alpha 2-adrenergic receptor (AR) function is implicated in anxiety and depressive disorders. Premenstrual dysphoric disorder (PMDD) is characterized by anxiety and depressive symptoms, which may be associated with changes in alpha 2AR function. Previous studies on alpha 2AR function during phases of the menstrual cycle in controls and PMDD patients are inconsistent. METHODS: alpha 2AR function was examined in 16 PMDD patients and 15 controls during the follicular phase, and in 10 PMDD patients during late luteal phase. Antagonist-measured maximum binding capacity, agonist-measured receptor density in high- and low-conformational states, and agonist affinity to both states were measured. Coupling efficiency to Gi protein was estimated. RESULTS: There were no significant differences in coupling efficiency. PMDD patients had significantly low antagonist affinity; there were no differences in other binding parameters. There were no changes in alpha 2AR binding parameters between phases of menstrual cycle in PMDD women. alpha 2AR density and symptom severity were inversely related during the follicular phase in controls and patients. During luteal phase, alpha 2AR density correlated positively with symptom severity in patients. High follicular alpha 2AR density predicted more severe luteal symptoms in PMDD patients. CONCLUSIONS: These findings are discussed in view of the molecular biology of alpha 2AR, and their role in PMDD, anxiety, and depressive disorders.

Adrenergic receptors in premenstrual dysphoric disorder. II. Neutrophil beta2-adrenergic receptors: Gs protein coupling, phase of menstrual cycle and prediction of luteal phase symptom severity.

Abnormal beta2-adrenergic receptor coupling to Gs protein is implicated in depressive disorders. Steroid hormones and antidepressants modulate beta-adrenergic receptor coupling, which may relate to the therapeutic efficacy of antidepressants. We examined beta2-adrenergic receptors in 18 patients with premenstrual dysphoric disorder (PMDD), in 15 control subjects during the follicular phase and in 12 patients during late luteal phase. Antagonist-measured receptor density, agonist-measured receptor density in the high- and low-conformational states and agonist affinity to both states were measured. Coupling indices to Gs protein were determined from agonist-displacement experiments. Follicular beta2-adrenergic receptor density was higher in patients than in control subjects, with a trend for higher receptor density in the high-conformational state. The phase of menstrual cycle had no effect on beta2-adrenergic receptor regulation in PMDD. Exploratory correlations showed that the K(L)/K(H) ratio was related to anxiety ratings in control subjects and %R(H) was correlated with symptom severity in patients. In patients, follicular beta2-adrenergic receptor binding measures were correlated with luteal symptom severity. These findings suggest abnormal beta2-adrenergic receptor regulation in PMDD. Further exploration of the role of beta-adrenergic receptor kinase, sex steroid hormones and antidepressants on beta-adrenergic receptor regulation in PMDD is warranted.