Document text
Principal Investigator: Jayme Rose McReynolds
Organization: UNIVERSITY OF CINCINNATI
Fiscal Year: 2024
Award: $440,054
Funding agency: National Institute on Drug Abuse
Project summary/Abstract
Addiction remains a vast problem in the United States and complicating the issue is the lack of FDA-approved
medications for the treatment of cocaine use disorder (CUD) making it a critical unmet need. A difficulty in
identifying treatment options is that CUD is multi-faceted involving interactions among several external factors,
including stress, which is unavoidable in daily life. Despite the prevalence of stress in human populations of
CUD, most pre-clinical addiction research does not incorporate stress as a factor during periods of drug use.
To examine the importance of stress-cocaine interactions on cocaine use and seeking behavior we use a
model where, in rats demonstrating otherwise stable cocaine self-administration (SA), a stressor delivered
daily at the time of cocaine SA, escalates cocaine intake and enhances cocaine-seeking behavior. This likely
involves neurobiological mediators that connect stress-responsive and reward systems in the brain, such as
endocannabinoid signaling (eCB). In support of this, systemic administration of a cannabinoid receptor 1
antagonist attenuates cocaine-induced reinstatement only in rats with a history of stress. Furthermore, we have
localized this effect to the prelimbic cortex (PrL), a key site for regulation of stress and drug-seeking behavior.
Importantly, eCB signaling, through attenuation of inhibitory neurotransmission, is well positioned to regulate
PrL pyramidal neuron activity and output which ultimately results in expression of enhanced cocaine-seeking
behavior. This proposal tests the novel hypothesis that repeated stress at the time of cocaine SA produces
long-lasting upregulation of eCB signaling in the PrL leading to increased pyramidal neuron activity and drug-
seeking behavior through dysregulated GABAergic signaling. To test this hypothesis, we will use behavioral,
molecular, and neurophysiological techniques to assess the involvement of PrL eCB signaling in the long-term
consequences of repeated stress-cocaine interactions. First, we will assess the role of PrL eCB signaling, via
pharmacological manipulation, in enhanced cocaine-induced reinstatement in stress-escalated rats. We will
then identify how combined repeated stress and cocaine SA regulates PrL eCB signaling by quantifying cell
type-specific changes in molecular components of the eCB system using fluorescent in situ hybridization, and
measure changes in PrL eCB content with mass spectrometry following cocaine-induced reinstatement. Lastly,
we will examine changes in eCB-mediated inhibitory synaptic plasticity that are associated with enhanced
cocaine-induced reinstatement, using whole-cell patch clamp recordings in the PrL. We will also use in vivo
fiber photometry measurement of Ca2+signaling to identify the contribution of eCB signaling to changes in PrL
pyramidal neuron activity associated with enhanced cocaine-induced reinstatement. These studies will provide
much needed information about how stress-drug interactions regulate prefrontal cortical circuits and has
treatment implications for those with CUD, especially for those for whom stress is a predominant contributing
factor by identifying unique neurobiological mechanisms that may provide therapeutic targets.
Terms: <2-AG><2-AG signaling><2-arachidonoyl-glycerol><2-arachidonoyl-sn-glycerol><2-arachidonoylglycerol><2-arachidonyl-glycerol><2-arachidonylglycerol><2-arachidonylglycerol signaling><American><Animal Model><Animal Models and Related Studies><Area><Attenuated><Behavior><Behavioral><Brain><Brain Nervous System><CB1><CB1 Receptor><CB1R><CCK><CNR1 gene><Cannabinoid Receptor CB1><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cholecystokinin><Chronic stress><Cocaine><Cocaine Users><Cocaine use disorder><Common Rat Strains><Connector Neuron><Data><Development><Disinhibition><Drug Interactions><Drug usage><Drugs><ECB signaling><Electrophysiology><Electrophysiology (science)><Encephalon><Enzyme Gene><Enzymes><FDA approved><FISH Technic><FISH Technique><FISH analysis><FISH assay><Fiber><Fluorescence In Situ Hybridization><Fluorescent in Situ Hybridization><Goals><Health Care Costs><Health Costs><Health Sciences><Healthcare Costs><History><Human><Intake><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intracellular Communication and Signaling><Life><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measurement><Measures><Mediating><Mediator><Medication><Modeling><Modern Man><Molecular><NIDA><National Institute of Drug Abuse><National Institute on Drug Abuse><Nerve Impulse Transmission><Nerve Transmission><Neurobiology><Neuronal Transmission><Neurophysiology / Electrophysiology><Output><Pancreozymin><Pharmaceutical Preparations><Photometry><Population><Position><Positioning Attribute><Predisposition><Prefrontal Cortex><Prevalence><Pyramidal neuron><Rat><Rats Mammals><Rattus><Recording of previous events><Regulation><Research><Rewards><Role><Signal Transduction><Signal Transduction Systems><Signaling><Site><Slice><Stress><Susceptibility><Synaptic plasticity><System><Techniques><Testing><Therapeutic><Time><United States><Up-Regulation><Upregulation><Uropancreozymin><abused drug><abused drugs><addiction><addictive disorder><antagonism><antagonist><attenuate><attenuates><attenuation><axon signaling><axon-glial signaling><axonal signaling><biological signal transduction><cannabinoid receptor 1><cannabinoid receptor type 1><cannabinoid type 1><cell type><cocaine relapse><cocaine seeking><cocaine self-administration><cocaine use><developmental><drug abused><drug of abuse><drug seeking behavior><drug use><drug/agent><drugs abused><drugs of abuse><eCB system><economic cost><electrophysiological><endocannabinoid signaling><endocannabinoid system><endogenous cannabinoid system><glia signaling><glial signaling><hippocampal pyramidal neuron><histories><in vivo><interest><model of animal><nerve signaling><neural adaptation><neural mechanism><neural signaling><neuroadaptation><neurobiological><neurobiological mechanism><neuromechanism><neuronal signaling><neurophysiological><neurophysiology><neurotransmission><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><patch clamp><pharmacologic><pre-clinical><preclinical><programs><relapse against cocaine><self-administer cocaine><social role><socio-economic><socio-economically><socioeconomically><socioeconomics><stressor><therapeutic target><therapeutically effective>