Description of Research Expertise

My primary area of research is the mechanisms of action of antidepressants. Most often, an in vivo approach is taken whereby measurements are made of effects produced by various types of antidepressants on noradrenergic or serotonergic neurons, on neurochemical or behavioral responses elicited by these neurotransmitters, or on their receptors. Neuroanatomical localization of drug-induced effects is emphasized by employing techniques such as quantitative autoradiography, immunohistochemistry, and in vivo voltammetry. Most of our recent work has used the latter technique to measure the rate of clearance of serotonin from extracellular fluid (ECF) in discrete regions of rat brain. Our lab is one of the few in this country that uses this technique to do this.

The clearance of serotonin is primarily a reflection of the functioning of the serotonin transporter (SERT), a membrane protein that is a key target for drugs such as fluoxetine (Prozac). Our results demonstrate differences in the biogenic amine transporters responsible for the clearance of serotonin in different regions of brain. We also found that SERT function is desensitized upon chronic treatment of rats with selective serotonin reuptake inhibitors (SSRIs) such as sertraline (Zoloft) or paroxetine (Paxil). This downregulation had a significantly greater inhibitory effect on the clearance of serotonin from extracellular fluid than acute blockade of the SERT with SSRIs. Importantly, it took about 10-15 days for such downregulation to occur, a time when behavioral improvement that these drugs cause in depressed patients becomes recognizable. Selective norepinephrine reuptake inhibitors, such as the antidepressant desipramine, produce a downregulation of the norepinephrine transporter (NET), but do not cause this effect on the SERT. We have begun recently to study cognitive and emotional behaviors in animal "models" of depression to begin to integrate psychological theories of depression with biological processes in brain affecting relevant behaviors and antidepressant effects.