Activation of the basolateral amygdala (BLA) plays a critical role in the normal adaptive response to negative emotional stimuli. Abnormal activity of BLA output neurons has been implicated in the etiology of several mood disorders. For example, depressed and anxious individuals show exaggerated amygdala activation in response to negative emotional stimuli, which is now recognized as a trait marker for mood disorders. Hyperactivation is also a predictor of positive treatment outcome as it normalizes with the onset of therapeutic action of drug treatment, suggesting that the amygdala is a key component of a mood-regulatory system that is dysregulated in anxiety and depression. Selective serotonin reuptake inhibitors (SSRIs) are a first-line treatment for many mood disorders, and the amygdala has a high density of SSRI binding sites. Significantly, negative emotional stimuli trigger serotonin (5HT) release into the BLA where it acts to decrease the excitability of BLA output neurons. Moreover, 5HT levels in the BLA are finely regulated by the activity of 5HT transporter proteins, suggesting that SSRIs may exert their therapeutic effects by raising BLA 5HT levels and thus normalizing the activity of its output neurons. However, the slow onset of action of SSRIs and their unwanted side effects are driving the search for faster acting, and more targeted treatments for anxiety and depression. Recently, a novel antidepressant agent has been identified, GSK-1, which is a mixed SHTwiB/iD receptor antagonist that has a rapid onset of action. Multiple serotonin receptor subtypes are expressed in the BLA. Hence, drugs acting at one or more 5HT receptors could have a profound impact on the excitability of BLA output neurons, and hence mood disorders. However, little is known about how individual serotonin receptor activation may modulate the activity of BLA output neurons, let alone how mixed 5HT receptor antagonists may affect these neurons. In this study, we will use patch clamp recording in an in vitro slice preparation to compare the response of BLA neurons to administration of a classic SSRI, citalopram, with that of GSK-1 before, during, and after a challenge with exogenous 5HT. The hypothesis to be tested is that: acute administration of GSK-1 will mimic the net effect of chronic administration of SSRIs on the activity of BLA output neurons.
Three specific aims will test this hypothesis:
Aim 1 : Compare and contrast the effects of acute in vitro administration of GSK-1 on serotonin receptor-mediated activity in BLA projection neurons and interneurons.
Aim 2 : Compare and contrast the effects of in vivo administration of GSK-1 on serotonin receptor-mediated activity in BLA projection neurons and interneurons.
Aim 3 : Compare and contrast the effects of GSK-1 and citalopram on serotonin receptor-mediated activity in BLA projection neurons and interneurons following sustained fear conditioning.
Mood and anxiety disorders are the most common of all psychiatric disorders and are associated with very significant morbidity and mortality. The primary goal of this Center is to accelerate the development of novel drugs for the treatment of depression and anxiety. Project 2 of this Center will examine the effects of a novel antidepressant compound on the activity of the amygdala, a brain region that may be dysregulated in anxiety and depression.
|Price, Matthew; Maples, Jessica L; Jovanovic, Tanja et al. (2015) An investigation of outcome expectancies as a predictor of treatment response for combat veterans with PTSD: comparison of clinician, self-report, and biological measures. Depress Anxiety 32:392-9|
|Stehouwer, Jeffrey S; Birnbaum, Matthew S; Voll, Ronald J et al. (2015) Synthesis, F-18 radiolabeling, and microPET evaluation of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines as ligands of the corticotropin-releasing factor type-1 (CRF1) receptor. Bioorg Med Chem 23:4286-302|
|Stehouwer, Jeffrey S; Goodman, Mark M (2015) Preparation of 1-Tosyloxy-4-Substituted-2-butenes Using Ag(I) Salts. Tetrahedron Lett 56:4480-4482|
|Ridgewell, Caitlin; Bray, Allison; Curtis, Kaylah et al. (2015) Enhanced Olfactory Cortex Connectivity in a Patient With PTSD With Olfactory Hallucinations. J Neuropsychiatry Clin Neurosci 27:e170-1|
|Grillon, Christian; Hale, Elizabeth; Lieberman, Lynne et al. (2015) The CRH1 antagonist GSK561679 increases human fear but not anxiety as assessed by startle. Neuropsychopharmacology 40:1064-71|
|Stehouwer, Jeffrey S; Bourke, Chase H; Owens, Michael J et al. (2015) Synthesis, binding affinity, radiolabeling, and microPET evaluation of 4-(2-substituted-4-substituted)-8-(dialkylamino)-6-methyl-1-substituted-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-ones as ligands for brain corticotropin-releasing factor type-1 (CRF1) rec Bioorg Med Chem Lett 25:5111-4|
|Kilts, Clint D; Kennedy, Ashley; Elton, Amanda L et al. (2014) Individual differences in attentional bias associated with cocaine dependence are related to varying engagement of neural processing networks. Neuropsychopharmacology 39:1135-47|
|Dunlop, Boadie W; Rothbaum, Barbara O; Binder, Elisabeth B et al. (2014) Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder: study protocol for a randomized controlled trial. Trials 15:240|
|Kaye, Joanna L; Dunlop, Boadie W; Iosifescu, Dan V et al. (2014) Cognition, functional capacity, and self-reported disability in women with posttraumatic stress disorder: examining the convergence of performance-based measures and self-reports. J Psychiatr Res 57:51-7|
|Miller, Andrew H; Haroon, Ebrahim; Raison, Charles L et al. (2013) Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 30:297-306|
Showing the most recent 10 out of 48 publications