Research Interests
Dr. Kirby’s laboratory examines the effects of stress and the stress neurohormone corticotropin-releasing factor (CRF) on the serotonin (5-hydroxytryptamine; 5-HT) system. Long-term exposure to stress is known to play a role in psychiatric disorders such as anxiety and depression. Stress is also a potent initiator of relapse in abstinent subjects with a prior history of substance abuse. As part of the Center for Substance Abuse Research, we are testing the hypothesis that stressors dysregulate the 5-HT system in subjects with a history of substance abuse, creating a negative affective state that motivates drug relapse as a form of “self-medication”. To test this hypothesis, we employ a combination of rodent behavioral models of stress-induced opioid relapse and ex vivo electrophysiological recordings from 5-HT neurons in brain slices. Initially, we demonstrated a unique neuroadaptation of 5-HT circuits in rats exposed to a stress-induced relapse model. Opioid exposure and stress interact to sensitize 5-HT neurons in the dorsal raphe nucleus (DRN) to the effects of the inhibitory neurotransmitter GABA. This sensitization would create hypofunction of the 5-HT system, leading to a negative affective state. As acute opioids stimulate 5-HT release, drug-seeking and relapse would normalize both 5-HT neurotransmission and mood, as predicted by the self-medication hypothesis of relapse. Behavioral pharmacology, in vivo microdialysis and electrophysiology studies extended this work to demonstrate that stressors cause the release of CRF in the DRN which indirectly inhibits 5-HT neurotransmission via CRF-R1 receptors on GABA interneurons. Furthermore, both GABAA and CRF-R1 signaling within the DRN are both necessary and sufficient for stress-induced opioid reinstatement. The GABAergic sensitization of 5-HT neurons has since been recapitulated across multiple models (conditioned place-preference and self-administration), multiple stressors (physiological and pharmacological), and multiple classes of abused drugs (opioids and psychostimulants), indicating that this neuroadaptation may have a broad impact on drug relapse. More recently during drug self-administration studies we have begun to record rat ultrasonic vocalizations, naturally occurring calls with which rats communicate either positive (50 kHz) or negative (22 kHz) affective state, to examine the contribution of affective state to drug-seeking behaviors. We are further expanding our studies to examine the role of 5-HT circuits in motivation for alcohol as well as opioids and are testing their causal relationship with chemogenetic strategies in transgenic rats.
Through collaborations with other investigators at Drexel University and Temple, the laboratory has also studied the physiological effects of cannabinoid and candidate cannabinoid receptor stimulation, including exploring cannabinoid effects on cognition, synaptic plasticity and inflammation in models of stroke and traumatic brain injury. We have also participated in collaborations to investigate the effects of chemokine immune molecules in the brain and their interactions with traditional neurotransmitter and neuropeptide systems (5-HT, dopamine, opioids and cannabinoids).
Education, Training & Credentials
- Postdoctoral Fellowship, Children’s Hospital of Philadelphia, Philadelphia, PA
- Postdoctoral Fellowship, MCP Hahnemann University, Philadelphia, PA
- PhD, Neuroscience, University of Pennsylvania, Philadelphia, PA, 1997
- BA, Psychobiology, Swarthmore College, Swarthmore, PA