Alan Frazer

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Department

Pharmacology

Alan Frazer, Ph.D.

Professor/Research of Pharmacology

Personal Statement:

Although recently retired, my line of research is continuing to be carried out by collaborators in the Department with my former lab members now working directly with them and my still being involved- but at a distance. My primary research interest has been the mechanism of action of antidepressant drugs. Historically, the focus of my lab was 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, interest in treatment refractory depression led us to study two treatments for it, vagal nerve stimulation or ketamine. These studies 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 Assistant Professor in the Department, Dr. Flavia Carreno (pictured in Lab Members), has been the lead investigator for these studies. This work led us to study effects of selective negative allosteric modulators of α5-GABAA receptors. Such drugs were found to have antidepressant-like effects similar to those of ketamine but not having ketamine’s adverse effect profile. Finally, in collaboration with another faculty member, Dr. David Morilak, both cognitive and emotional behaviors in animal models of depression or PTSD have been studied and the effect that antidepressant have on such behaviors. A graduate student, Aleeza Stephens (pictured in Lab Members), led this work which is continuing under the direction of Dr. Morilak.
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

Aleeza Stephens
Flavia Carreno, Ph.D., Assistant Professor/ResearchAleeza Stephens, Graduate Research Assistant
Alexandra McCoy, Graduate Research Assistant

Publications

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