Alan Frazer, Ph.D.
Mechanisms and sites of action of antidepressant treatments
I have long studied the mechanism of action of antidepressant drugs (ADs). Our interest in treatment refractory depression led us to study two treatments for it, vagal nerve stimulation and ketamine Our studies have focused on both the mechanisms of action of these treatments and the circuits in brain necessary for their beneficial effects. The latter studies have used state-of-the-art techniques such as optogenetics and chemogenetics (DREADDs). A Res. Asst. Prof. in my lab, Dr. Flavia Carreno, has been the lead investigator for these studies. This work led us to study selective negative allosteric modulators (NAMs) of α5-GABAA receptors. These receptors are highly localized in the hippocampus, a site of action for ketamine, and such drugs might reproduce ketamine’s AD effect. We found such drugs to have AD-like effects but not have ketamine’s adverse effect profile
Related Diseases: major depressive disorder, post-traumatic stress disorder (PTSD)
Technniques: animal behavior, western blot analysis, stereotaxic surgery, optogenetics, chemogenetics (DREADDs)
- 1969 - PhD - Pharmacology - University of Pennsylvania
- 1964 - BS - Chemistry (Meritorious Honors) - Philadelphia College of Pharmacy and Science
- 9/1994 - Adjunct Professor - University of Pennsylvania School of Medicine, Pharmacology
- 9/1994 - Adjunct Professor - University of Texas at Austin College of Pharmacy
- 9/1993 - Cross Faculty Appointment - The University of Texas Health Science Center at San Antonio, Psychiatry, San Antonio
- 9/1993 - Chair and Professor - University of Texas Health Science Center, Pharmacology, San Antonio
Instruction & Training
- 1/2018 - Present, Membership on Supervising Committee, The University of Texas Health Science Center at San Antonio
- 5/2011 - Present, Membership on Supervising Committee, The University of Texas Health Science Center at San Antonio
- 2/2009 - Present, Pre-Doctoral Student Supervision, The University of Texas Health Science Center at San Antonio
- 1/2002 - Present, Post-Doctoral Student Supervision
Research & Grants
Funding Agency ASPET Title ASPET Fellowship Program for Undergraduate Students Status Active Period 6/2007 - Present Role Contributor Grant Detail
Funding Agency UTHSCSA President`s Translational and Entrepreneurial Research Fund Title Reducing the abuse liability of prescription opioids Status Active Period 1/2017 - 8/2017 Role Co-Principal Investigator Grant Detail
2 I01BX000559-08 (Frazer, PI) 3/14/2019-3/31/2023
VA Merit Award $316,570/yr
Selective negative allosteric modulators of alpha 5-GABAA receptors: novel psychotherapeutic drugs
This project tests the hypothesis that selective α5 negative allosteric modulators (NAMs) of GABAA receptors have the potential to be antidepressants without having the negative adverse effect profile of ketamine. The behavioral tests used to assess efficacy have relevance not only for depression but for PTSD as well. Experiments will be carried out in rats after their receiving mild electric foot-shock to induce behavioral deficits. Controls will not receive shock. Both male and female rats will be studied. The effect of the selective NAMs will be studied either after foot-shock (treatment) or before (prophylaxis). In addition, a chemogentic approach will be used to determine the pathways involved in specific behavioral effects of the selective NAM.
Carreno FR, Arroyo LD, Lodge DJ, Frazer A. Novel mechanisms contributing to the antidepressant-like effect of pharmacological hippocampal activation; 2017 Jan. (Program No 610.27 Neuroscience Meeting Planner, Society for Neuroscience, Washington, DC). Carreno FR, Frazer A, Lodge DJ. Optogenetic inactivation of the ventral hippocampus-medial prefrontal cortex pathway reverses the antidepressant-like effects of ketamine; 2015 Jan. (Program N. 410.13 Neuroscience Meeting Planner, Society for Neuroscience, Chicago, IL). Carreno FR, Frazer A, Lodge DJ. Involvement of the ventral hippocampus ascending pathway to the medial prefrontal cortex in the antidepressant-like effect of ketamine in rats; 2014 Oct. (Presented at 21st Annual Department of Pharmacology Graduate Student Symposium, San Antonio TX). Carreno FR, Frazer A, Lodge DJ. Involvement of the ventral hippocampus and TrkB in the antidepressant-like effect of ketamine; 2014 May. (Presented at 12th Annual Center for Biomedical Neuroscience (CBN) Retreat, San Antonio TX).
Carreno FR, Frazer A. The allure of transcutaneous vagus nerve stimulation as a novel therapeutic modality Biol Psychiatry 2016 Jan;79(4):260-261. Frazer A. Neuropsychopharmacology: Reflections on 40 Volumes Neuropsychopharmacology 2015 Dec;40(13):2853-2855.
Carreno FR, Lodge DJ, Frazer A. Ketamine: Leading us into the future for development of antidepressants (IN PRESS) Behavioural Brain Research 2020 Jan;. Carreno FR, Collins GT, Frazer A, Lodge DJ. Selective pharmacological augmentation of hippocampal activity produces a sustained antidepressant-like response without abuse-related or psychotomimetic effects Int J Neuropsychopharmacology 2017 Jan;20(6):504-509. Shah AP, Carreno FR, Wu H, Chung YA, Frazer A. Role of TrkB in the anxiolytic-like and antidepressant-like effects of vagal nerve stimulation: Comparison with desipramine Neuroscience 2016 Jan;322:273-286. Carreno FR, Donegan JJ, Boley AM, Shah A, DeGuzman M, Frazer A, Lodge DJ. Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine Mol Psychiatry 2016 Jan;21(9):1298-1308. Benmansour S, Arroyo LD, Frazer A. Comparison of the antidepressant-like effects of estradiol and that of selective serotonin reuptake inhibitors in middle-aged ovariectomized rats (IN PRESS) Frontiers Aging Neuroscience 2016 Jan;. Benmansour S, Adeniji OS, Privratsky AA, Frazer A. Effects of long-term treatment with estradiol and estrogen receptor subtype agonists on serotonergic function in ovariectomized rats Neuroendocrinology 2015 Jan;. Katz MM, Berman N, Bowden CL, Frazer A. Evidence for shortening the duration of clinical trials of antidepressants and a proposed paradigm for such studies Journal of Clinical Psychopharmacology 2015 Jan;35(3):329-332. Cunningham JT, Mifflin SW, Gould GG, Frazer A. Induction of c-Fos and DeltaFosB immunoreactivity in rat brain by Vagal nerve stimulation Neuropsychopharmacology 2008 Jul;33(8):1884-1895. Gould GG, Brooks BW, Frazer A. [(3)H] citalopram binding to serotonin transporter sites in minnow brains Basic Clin Pharmacol Toxicol 2007 Sep;101(3):203-210.
Carreno FR, Frazer A. Vagal nerve stimulation for treatment-resistant depression Neurotherapeutics 2017 Jun;14(3):716-727. Shah A, Carreno FR, Frazer A. Therapeutic modalities for treatment resistant depression: focus on vagal nerve stimulation and ketamine Clin Psychopharmacol Neurosci 2014 Aug;12(2):83-93.