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The CRF System as a Therapeutic Target for Neuropsychiatric Disorders.

ABSTRACT: The major neuropsychiatric disorders are devastating illnesses that are only modestly responsive to treatment. Improving the treatment of these conditions will require innovative new strategies that depart from previously focused-on pharmacological mechanisms. Considerable preclinical and clinical data indicate corticotropin-releasing factor (CRF) signaling as a target for new psychotropic drug development. Here we review alterations in the CRF system reported in several psychiatric conditions. We also examine the preclinical work that has dissected the distinctive roles of CRF receptors in specific circuits relevant to these disorders. We further describe the clinical trials of CRF1 receptor antagonists that have been conducted. Although these clinical trials have thus far met with limited therapeutic success, the unfolding complexity of the CRF system promises many future directions for studying its role in the etiology and treatment of neuropsychiatric conditions.

SUBMITTER: Sanders J

PROVIDER: S-EPMC5121012 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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The CRF System as a Therapeutic Target for Neuropsychiatric Disorders.

Sanders Jeff J Nemeroff Charles C

Trends in pharmacological sciences 20161004 12

The major neuropsychiatric disorders are devastating illnesses that are only modestly responsive to treatment. Improving the treatment of these conditions will require innovative new strategies that depart from previously focused-on pharmacological mechanisms. Considerable preclinical and clinical data indicate corticotropin-releasing factor (CRF) signaling as a target for new psychotropic drug development. Here we review alterations in the CRF system reported in several psychiatric conditions. ...[more]

PMID: 27717506

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Project description:To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. ?(9) -Tetrahydrocannabinol (?(9) -THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and ?(9) -THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of ?(9) -THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the ?3 and ?1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:?(9) -THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Project description:Background and purposeThe pathophysiological role of ?6 -subunit-containing GABAA receptors, which are mainly expressed in cerebellar granule cells, remains unclear. Recently, we demonstrated that hispidulin, a flavonoid isolated from a local herb that remitted a patient's intractable motor tics, attenuated methamphetamine-induced hyperlocomotion in mice as a positive allosteric modulator (PAM) of cerebellar ?6 GABAA receptors. Here, using hispidulin and a selective ?6 GABAA receptor PAM, the pyrazoloquinolinone Compound 6, we revealed an unprecedented role of cerebellar ?6 GABAA receptors in disrupted prepulse inhibition of the startle response (PPI), which reflects sensorimotor gating deficits manifested in several neuropsychiatric disorders.Experimental approachPPI disruptions were induced by methamphetamine and NMDA receptor antagonists in mice. Effects of the tested compounds were measured in Xenopus oocytes expressing recombinant ?6 ?3 ?2S GABAA receptors.Key resultsHispidulin given i.p. or by bilateral intracerebellar (i.cb.) injection rescued PPI disruptions induced by methamphetamine, ketamine, MK-801 and phencyclidine. Intracerebellar effects of hispidulin were mimicked by Ro15-4513 and loreclezole (two ?6 GABAA receptor PAMs), but not by diazepam (an ?6 GABAA receptor-inactive benzodiazepine) and were antagonized by furosemide (i.cb.), an ?6 GABAA receptor antagonist. Importantly, Compound 6 (i.p.) also rescued methamphetamine-induced PPI disruption, an effect prevented by furosemide (i.cb.). Both hispidulin and Compound 6 potentiated ?6 ?3 ?2S GABAA receptor-mediated GABA currents.Conclusions and implicationsPositive allosteric modulation of cerebellar ?6 GABAA receptors rescued disrupted PPI by attenuating granule cell activity. ?6 GABAA receptor-selective PAMs are potential medicines for treating sensorimotor gating deficits in neuropsychiatric disorders. A mechanistic hypothesis is based on evidence for cerebellar contributions to cognitive functioning including sensorimotor gating.

Dataset Information

The CRF System as a Therapeutic Target for Neuropsychiatric Disorders.

Publications

The CRF System as a Therapeutic Target for Neuropsychiatric Disorders.

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