Developing Small Molecule Nonpeptidergic Drugs for the Treatment of Anxiety Disorders: Is the Challenge Still Ahead?

Steckler, Thomas

doi:10.1007/7854_2009_14

Cited by 18 publications

(12 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, in humans, the concentration of SP-like immunoreactivity in the CSF has been positively correlated with aggressive tendencies in patients with personality disorders (Coccaro et al, 2012). SP antagonists have been tested in humans as anxiolytic and antidepressant agents, although they failed to show efficacy (Keller et al, 2006; Steckler, 2009). The present findings, taken together with mammalian animal studies, suggest that it may be worthwhile to investigate the potential of these antagonists for reducing violent aggression in humans.…”

Section: Discussionmentioning

confidence: 99%

Tachykinin-Expressing Neurons Control Male-Specific Aggressive Arousal in Drosophila

Asahina

Watanabe

Duistermars

et al. 2014

Cell

308

367

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Tachykinin-Expressing Neurons Control Male-Specific Aggressive Arousal in Drosophila

Asahina

Watanabe

Duistermars

et al. 2014

Cell

308

367

View full text Add to dashboard Cite

“…Our previous report of higher serum oxytocin levels in dominant females (Michopoulos et al, 2011c) contributed significantly to the DA as well. Oxytocin is implicated in increasing a vast array of social behaviors in both animals and human beings (Goodson and Thompson, 2010) and has distinct anxiolytic effects in animals (Steckler, 2010). Furthermore, increased oxytocin in dominant females is likely associated increased motivation to initiate affiliative behaviors described here.…”

Section: Discussionmentioning

confidence: 99%

Social subordination produces distinct stress-related phenotypes in female rhesus monkeys

Michopoulos

Higgins

Toufexis

et al. 2012

Psychoneuroendocrinology

View full text Add to dashboard Cite

Social subordination in female macaques is imposed by harassment and the threat of aggression and produces reduced control over one's social and physical environment and a dysregulation of the limbic-hypothalamic-pituitary-adrenal axis resembling that observed in people suffering from psychopathologies. These effects support the contention that this particular animal model is an ethologically relevant paradigm in which to investigate the etiology of stress-induced psychological illness related to women. Here, we sought to expand this model by performing a discriminate analysis (DA) on 33 variables within three domains; behavioral, metabolic/anthropomorphic, and neuroendocrine, collected from socially housed female rhesus monkeys in order to assess whether exposure to social subordination produces a distinct phenotype. A receiver operating characteristic (ROC) curve was also calculated to determine each domain's classification accuracy. DA found significant markers within each domain that differentiated dominant and subordinate females. Subordinate females received more aggression, showed more submissive behavior, and received less of affiliation from others than did dominant females. Metabolic differences included increased leptin, and reduced adiponectin in dominant compared to subordinate females. Dominant females exhibited increased sensitivity to hormonal stimulation with higher serum LH in response to estradiol, cortisol in response to ACTH, and increased glucocorticoid negative feedback. Serum oxytocin, CSF DOPAC and serum PACAP were all significantly higher in dominant females. ROC curve analysis accurately predicted social status in all three domains. Results suggest that socially house rhesus monkeys represent a cogent animal model in which to study the physiology and behavioral consequences of chronic psychosocial stress in humans.

show abstract

“…This line of research was driven by the finding that these neurotransmitters and neuromodulators, as well as their receptors, are found in areas of the brain that are implicated in the control of anxiety. Further support emerged from studies showing that the central infusion or genetic manipulation of neuropeptides modified anxiety-related behaviours 77,78 . A detailed review of the vast preclinical literature in this area is beyond the scope of this article (for a full summary of experiments, see Supplementary information S1 (box)).…”

Section: Neuropeptidesmentioning

confidence: 99%

“…This questioned the idea that CCK represents a valid target for anti-anxiety medications. Clinical trials undertaken with CCK 2 receptor antagonists in anxiety disorders, including GAD and panic disorder, have also been unsuccessful 77,81 and no CCK-based drugs have yet been approved.…”

Section: Neuropeptidesmentioning

confidence: 99%

50 years of hurdles and hope in anxiolytic drug discovery

Griebel

Holmes

2013

Nat Rev Drug Discov

383

346

View full text Add to dashboard Cite

Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials. However, the clinical outcome of these efforts has been disappointing, as promising results with novel agents in rodent studies have very rarely translated into effectiveness in humans. Here, we analyse the major trends from preclinical studies over the past 50 years conducted in the search for new drugs beyond those that target the prototypical anxiety-associated GABA (γ-aminobutyric acid)–benzodiazepine system, which have focused most intensively on the serotonin, neuropeptide, glutamate and endocannabinoid systems. We highlight various key issues that may have hampered progress in the field, and offer recommendations for how anxiolytic drug discovery can be more effective in the future.

show abstract

Developing Small Molecule Nonpeptidergic Drugs for the Treatment of Anxiety Disorders: Is the Challenge Still Ahead?

Cited by 18 publications

References 73 publications

Tachykinin-Expressing Neurons Control Male-Specific Aggressive Arousal in Drosophila

Tachykinin-Expressing Neurons Control Male-Specific Aggressive Arousal in Drosophila

Social subordination produces distinct stress-related phenotypes in female rhesus monkeys

50 years of hurdles and hope in anxiolytic drug discovery

Contact Info

Product

Resources

About