Alan Frazer

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Department

Pharmacology

Alan Frazer, Ph.D.

Chair of Pharmacology and Professor of Pharmacology and Psychiatry

Personal Statement:

My primary research interest is the mechanism of action of antidepressant drugs. Historically, the focus of my lab has been to study how chronic treatment of rats with antidepressants affects the functioning of two monoamine systems, noradrenergic and serotonergic, that are important targets for their clinical effects. More recently, our interest in treatment refractory depression caused us to study two treatments for it. One, vagal nerve stimulation, is approved by the FDA whereas the other, ketamine, is more experimental. 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 been carried out in collaboration with Dr. Daniel Lodge in this Department, using state-of-the-art techniques such as optogenetics and designer receptors exclusively activated by designer drugs (DREADDs). A Research Instructor in my lab, Dr. Flavia Carreno (pictured below), has been the lead investigator for these studies. This work led us to study effects of selective negative allosteric modulators of α5-GABAA receptors. We found such drugs to have antidepressant-like effects similar to ketamine but not having ketamine’s adverse effect profile. Finally, in collaboration with another faculty member, Dr. David Morilak, we are studying both cognitive and emotional behaviors in animal models of depression on PTSD and the effect that antidepressant treatments and behavior therapies have on such behaviors.
Optogenetic inactivation of the vHipp-mPFC pathway blocks the expression of the antidepressant response to ketamine. Schematic of bilateral viral injection into vHipp and fiber optic implant into mPFC. The yellow triangle represents the yellow laser. eYFP expression in terminals (vanicosites) of the frontal cortex. A schematic and timeline for the optogenetic inhibition procedure. Ketamine (10 mg kg) administration produces a significant decrease in immobility on the FST measured 1 week following its administration. Optogenetic inactivation reversed the antidepressant response in ketamine only when administered during testing (Swim 2) and not during its administration (Swim 1). The response was specific to the vHipp-mPFC pathway, as inactivation of the MD-mPFC pathway was without effect n=8-9. Significantly different from control cal-YFP and significantly different from all other ketamine-treated groups. P = 0.05, Holm Sidak post hoc analysis.
L-655.708 did not produce the reinforcing or psychotomimetic effects of ketamine. Prepulse inhibition (PPI) of startle response. Ketamine mg/kg induced deficits in PPI, particularly at 73 dB. L-856-708 did not affect PPI. Self-administration maintained by ketamine under a fixed ratio (FR) 5 schedule of reinforcement. Substitution for ketamine resulted in low levels of responding that did not differ from vehicle. Replacing L655-708 (or vehicle) with ketamine resulted in a rapid recovery of self-administration to presubstitution levels.

 


Education

Ph.D., University of Pennsylvania

Research

• antidepressants • norepinephrine
• serotonin transporters • vagal nerve stimulation

Affiliations

Dr. Frazer is a member of numerous societies including the American Society of Pharmacology and Experimental Therapeutics, the American College of Neuropsychopharmacology (of which he has been the President), the International College of Neuropsychopharmacology (CINP), of which he is a Councillor, and the Editor-in-Chief of their official publication, International Journal of Neuropsychopharmacology and the Society of Neuroscience. He is on the Scientific Advisory Board of the Brain and Behavior Research Foundation, which awards NARSAD grants. He has been awarded a Merit Award from NIH and has been a Career Scientist of the Department of Veterans Affairs.

Lab Members

Flavia Carreno, Ph.D. Aleeza Stephens, Graduate Student

Publications

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