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A healthy stress response is critical for good mental and overall health and promotes neuronal growth and adaptation, but the intricately balanced biological mechanisms that facilitate a stress response can also result in predisposition to disease when that equilibrium is disrupted. The hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine system plays a critical role in the body's response and adaptation to stress, and vasopressinergic regulation of the HPA axis is critical to maintaining system responsiveness during chronic stress. However, exposure to repeated or excessive physical or emotional stress or trauma can shift the body's stress response equilibrium to a "new normal" underpinned by enduring changes in HPA axis function. Exposure to early life stress due to adverse childhood experiences can also lead to lasting neurobiological changes, including in HPA axis function. HPA axis impairment in patients with depression is considered among the most reliable findings in biological psychiatry, and chronic stress has been shown to play a major role in the pathogenesis and onset of depression and other neuropsychiatric disorders. Modulating HPA axis activity, for example via targeted antagonism of the vasopressin V1b receptor, is a promising approach for patients with depression and other neuropsychiatric disorders associated with HPA axis impairment. Despite favorable preclinical indications in animal models, demonstration of clinical efficacy for the treatment of depressive disorders by targeting HPA axis dysfunction has been challenging, possibly due to the heterogeneity and syndromal nature of depressive disorders. Measures of HPA axis function, such as elevated cortisol levels, may be useful biomarkers for identifying patients who may benefit from treatments that modulate HPA axis activity. Utilizing clinical biomarkers to identify subsets of patients with impaired HPA axis function who may benefit is a promising next step in fine-tuning HPA axis activity via targeted antagonism of the V1b receptor. [ABSTRACT FROM AUTHOR]

Sensorimotor gating, the ability to automatically filter sensory information, is deficient in a number of psychiatric disorders, yet little is known of the biochemical mechanisms underlying this critical neural process. Previously, we reported that mice expressing a constitutively active isoform of the G-protein subunit Gαs (Gαs*) within forebrain neurons exhibit decreased gating, as measured by prepulse inhibition of acoustic startle (PPI). Here, to elucidate the biochemistry regulating sensorimotor gating and to identify novel therapeutic targets, we test the hypothesis that Gαs* causes PPI deficits via brain region-specific changes in cyclic AMP (cAMP) signaling. As predicted from its ability to stimulate adenylyl cyclase, we find here that Gαs* increases cAMP levels in the striatum. Suprisingly, however, Gαs* mice exhibit reduced cAMP levels in the cortex and hippocampus because of increased cAMP phosphodiesterase (cPDE) activity. It is this decrease in cAMP that appears to mediate the effect of Gαs* on PPI because Rp-cAMPS decreases PPI in C57BL/6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Gαs* mice and the cPDE inhibitor rolipram also rescues PPI deficits of Gαs* mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Gαs* mice, we coexpressed the R(AB) transgene (a dominant-negative regulatory subunit of protein kinase A (PKA)), which fully rescues the reductions in PPI and cAMP caused by Gαs*. We conclude that expression of Gαs* within forebrain neurons causes PPI deficits because of a PKA-dependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects.Neuropsychopharmacology (2007) 32, 577–588. doi:10.1038/sj.npp.1301099; published online 31 May 2006 [ABSTRACT FROM AUTHOR]

Previous studies suggest that circulating glucocorticoids may influence the encoding and processing of sensory stimuli. The current study investigated this hypothesis by measuring the generation (amplitude), gating (recovery cycle), and sensitivity (intensity function) of auditory evoked responses in C57BL/6 mice treated with chronic corticosterone (0, 1, 5, 15, or 30 mg/kg/day for 14 days). We found that low-dose corticosterone (5 but not 1 mg/kg/day) enhanced the amplitude and improved gating of evoked potentials without affecting the intensity function. In comparison, higher doses (15 and 30 mg/kg/day) decreased the amplitude and impaired gating of evoked potentials, also without altering the stimulus intensity function. At all doses, lower amplitudes of evoked potentials were significantly correlated with higher circulating corticosterone levels. These data highlight the need to consider serum glucocorticoid levels when assessing human disease states associated with aberrations of information processing such as schizophrenia and depression.Neuropsychopharmacology (2006) 13, 897–903. doi:10.1038/sj.npp.1300879; published online 24 August 2005 [ABSTRACT FROM AUTHOR]

The introduction of surgically implantable medication delivery systems provides psychiatric patients with reversible, uninterrupted access to medication for up to 14 months. This study designed and administered a survey to assess patients' attitudes and beliefs towards illness, medication, and this potential new treatment method. The survey included questions about demographics, insight and attitudes towards illness, current and past medication adherence, attitudes towards psychiatric and nonpsychiatric medications, and understanding and attitudes towards surgical implants. The sample of 206 psychiatric patients was almost equally split between favorably and unfavorably considering implants. Patients favorable towards implants ascribed forgetting and failure to refill medication on time as the reasons for missing doses, recognized the benefits of medication in general, and understood that the implant would be inserted under the skin. Favorable consideration of implants was positively correlated with the desire to avoid adverse consequences of missing medicine, stay well, avoid the need for daily oral medications, and decrease family burden. Unfavorable consideration of implants was related to a preference to take medication orally, concern about feeling controlled, unwillingness to try something new, and not understanding that the implant would be placed under the skin. Demographic variables, past/current medications, specific diagnosis, and illness severity did not influence the decision. This survey elucidates patients' attitudes and beliefs towards illness, medication, and surgical implants. The results indicate that a significant proportion of patients recognize the difficulties of medication adherence and the need for better methods to attain therapeutic response. Thus, the study provides impetus for future work in this area. [ABSTRACT FROM AUTHOR]

Schizophrenia is a complex disorder characterized by wide-ranging cognitive impairments, including deficits in learning as well as sensory gating. The causes of schizophrenia are unknown, but alterations in intracellular G-protein signaling pathways are among the molecular changes documented in patients with schizophrenia. Using the CaMKIIα promoter to drive expression in neurons within the forebrain, we have developed transgenic mice that express a constitutively active form of Gsα (Gsα*), the G protein that couples receptors such as the D1 and D5 dopamine receptors to adenylyl cyclase. We have also generated mice in which the CaMKIIα promoter drives expression of a dominant-negative form of protein kinase A, R(AB). Here, we examine startle responses and prepulse inhibition of the startle reflex (PPI) in these Gsα* and R(AB) transgenic mice. Gsα* transgenic mice exhibited selective deficits in PPI, without exhibiting alterations in the startle response, whereas no deficit in startle or PPI was found in the R(AB) transgenic mice. Thus, overstimulation of the cAMP/PKA pathway disrupts PPI, but the cAMP/PKA pathway may not be essential for sensorimotor gating. Gsα* transgenic mice may provide an animal model of certain endophenotypes of schizophrenia, because of the similarities between them and patients with schizophrenia in G-protein function, hippocampus-dependent learning, and sensorimotor gating. [ABSTRACT FROM AUTHOR]

A healthy stress response is critical for good mental and overall health and promotes neuronal growth and adaptation, but the intricately balanced biological mechanisms that facilitate a stress response can also result in predisposition to disease when that equilibrium is disrupted. The hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine system plays a critical role in the body's response and adaptation to stress, and vasopressinergic regulation of the HPA axis is critical to maintaining system responsiveness during chronic stress. However, exposure to repeated or excessive physical or emotional stress or trauma can shift the body's stress response equilibrium to a "new normal" underpinned by enduring changes in HPA axis function. Exposure to early life stress due to adverse childhood experiences can also lead to lasting neurobiological changes, including in HPA axis function. HPA axis impairment in patients with depression is considered among the most reliable findings in biological psychiatry, and chronic stress has been shown to play a major role in the pathogenesis and onset of depression and other neuropsychiatric disorders. Modulating HPA axis activity, for example via targeted antagonism of the vasopressin V 1b receptor, is a promising approach for patients with depression and other neuropsychiatric disorders associated with HPA axis impairment. Despite favorable preclinical indications in animal models, demonstration of clinical efficacy for the treatment of depressive disorders by targeting HPA axis dysfunction has been challenging, possibly due to the heterogeneity and syndromal nature of depressive disorders. Measures of HPA axis function, such as elevated cortisol levels, may be useful biomarkers for identifying patients who may benefit from treatments that modulate HPA axis activity. Utilizing clinical biomarkers to identify subsets of patients with impaired HPA axis function who may benefit is a promising next step in fine-tuning HPA axis activity via targeted antagonism of the V 1b receptor., Competing Interests: S.J.K. and L.D. are employees of and P.P. is a consultant for EmbarkNeuro, Inc. In addition, S.J.K. has a patent “METHODS OF TREATING DEPRESSION WITH 1,2,4-TRIAZOLONE DERIVATIVES” pending to EmbarkNeuro. The authors report no other conflicts of interest in this work., (© 2023 Kanes et al.)

Schizophrenia is a complex disorder characterized by wide-ranging cognitive impairments, including deficits in learning as well as sensory gating. The causes of schizophrenia are unknown, but alterations in intracellular G-protein signaling pathways are among the molecular changes documented in patients with schizophrenia. Using the CaMKIIalpha promoter to drive expression in neurons within the forebrain, we have developed transgenic mice that express a constitutively active form of G(s)alpha (G(s)alpha(*)), the G protein that couples receptors such as the D(1) and D(5) dopamine receptors to adenylyl cyclase. We have also generated mice in which the CaMKIIalpha promoter drives expression of a dominant-negative form of protein kinase A, R(AB). Here, we examine startle responses and prepulse inhibition of the startle reflex (PPI) in these G(s)alpha(*) and R(AB) transgenic mice. G(s)alpha(*) transgenic mice exhibited selective deficits in PPI, without exhibiting alterations in the startle response, whereas no deficit in startle or PPI was found in the R(AB) transgenic mice. Thus, overstimulation of the cAMP/PKA pathway disrupts PPI, but the cAMP/PKA pathway may not be essential for sensorimotor gating. G(s)alpha(*) transgenic mice may provide an animal model of certain endophenotypes of schizophrenia, because of the similarities between them and patients with schizophrenia in G-protein function, hippocampus-dependent learning, and sensorimotor gating.