Medicine and Health Sciences Commons^™

Corticosterone Potentiation Of Cocaine-Induced Reinstatement Of Conditioned Place Preference In Mice Is Mediated By Blockade Of The Organic Cation Transporter 3, Jayme R. Mcreynolds, Analisa Taylor, Oliver Vranjkovic, Terra Ambrosius, Olivia Derricks, Brittany Nino, Beliz Kurtoglu, Robert A. Wheeler, David A. Baker, Paul J. Gasser, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

The mechanisms by which stressful life events increase the risk of relapse in recovering cocaine addicts are not well understood. We previously reported that stress, via elevated corticosterone, potentiates cocaine-primed reinstatement of cocaine seeking following self-administration in rats and that this potentiation appears to involve corticosterone-induced blockade of dopamine clearance via the organic cation transporter 3 (OCT3). In the present study, we use a conditioned place preference/reinstatement paradigm in mice to directly test the hypothesis that corticosterone potentiates cocaine-primed reinstatement by blockade of OCT3. Consistent with our findings following self-administration in rats, pretreatment of male C57/BL6 mice with corticosterone (using …

Antagonism Of Gaba-B But Not Gaba-A Receptors In The Vta Prevents Stress- And Intra-Vta Crf-Induced Reinstatement Of Extinguished Cocaine Seeking In Rats, Jordan M. Blacktop, Oliver Vranjkovic, Matthieu Mayer, Matthew Van Hoof, David A. Baker, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF. Rats underwent repeated daily cocaine self-administration (1.0 mg/kg/ing; 14 × 6 h/day) and extinction and were tested for reinstatement in response to footshock (0.5 mA, 0.5” duration, average every 40 …

Cb1 Receptor Antagonism Blocks Stress-Potentiated Reinstatement Of Cocaine Seeking In Rats, Jayme R. Mcreynolds, Elizabeth M. Doncheck, Oliver Vranjkovic, Geoffrey S. Ganzman, David A. Baker, Cecilia J. Hillard, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

Rationale

Under some conditions, stress, rather than directly triggering cocaine seeking, potentiates reinstatement to other stimuli, including a subthreshold cocaine dose. The mechanisms responsible for stress-potentiated reinstatement are not well defined. Endocannabinoid signaling is increased by stress and regulates synaptic transmission in brain regions implicated in motivated behavior.

Objectives

The objective of this study was to test the hypothesis that cannabinoid type 1 receptor (CB1R) signaling is required for stress-potentiated reinstatement of cocaine seeking in rats.

Methods

Following i.v. cocaine self-administration (2 h access/day) and extinction in male rats, footshock stress alone does not reinstate cocaine seeking but reinstatement is …

Drug Predictive Cues Activate Aversion-Sensitive Striatal Neurons That Encode Drug Seeking, Daniel S. Wheeler, Mykel A. Robble, Emily M. Hebron, Matthew J. Dupont, Amanda L. Ebben, Robert A. Wheeler

Biomedical Sciences Faculty Research and Publications

Drug-associated cues have profound effects on an addict’s emotional state and drug-seeking behavior. Although this influence must involve the motivational neural system that initiates and encodes the drug-seeking act, surprisingly little is known about the nature of such physiological events and their motivational consequences. Three experiments investigated the effect of a cocaine-predictive stimulus on dopamine signaling, neuronal activity, and reinstatement of cocaine seeking. In all experiments, rats were divided into two groups (paired and unpaired), and trained to self-administer cocaine in the presence of a tone that signaled the immediate availability of the drug. For rats in the paired group, …

Stress-Induced Cocaine Seeking Requires A Beta-2 Adrenergic Receptor-Regulated Pathway From The Ventral Bed Nucleus Of The Stria Terminalis That Regulates Crf Actions In The Ventral Tegmental Area, Oliver Vranjkovic, Paul J. Gasser, Clayton H. Gerndt, David A. Baker, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

The ventral bed nucleus of the stria terminalis (vBNST) has been implicated in stress-induced cocaine use. Here we demonstrate that, in the vBNST, corticotropin releasing factor (CRF) is expressed in neurons that innervate the ventral tegmental area (VTA), a site where the CRF receptor antagonist antalarmin prevents the reinstatement of cocaine seeking by a stressor, intermittent footshock, following intravenous self-administration in rats. The vBNST receives dense noradrenergic innervation and expresses β adrenergic receptors (ARs). Footshock-induced reinstatement was prevented by bilateral intra-vBNST injection of the β-2 AR antagonist, ICI-118,551, but not the β-1 AR antagonist, betaxolol. Moreover, bilateral intra-vBNST injection of …

Time Course Of Cocaine-Induced Behavioral And Neurochemical Plasticity, Victoria Lutgen, Linghai Kong, Kristen S. Kau, Aric Madayag, John Mantsch, David A. Baker

Biomedical Sciences Faculty Research and Publications

Factors that result in augmented reinstatement, including increased withdrawal period duration and high levels of cocaine consumption, may provide insight into relapse vulnerability. The neural basis of augmented reinstatement may arise from more pronounced changes in plasticity required for reinstatement and/or the emergence of plasticity expressed only during a specific withdrawal period or under specific intake conditions. In this study, we examined the impact of withdrawal period duration and cocaine intake on the magnitude of cocaine-primed reinstatement and extracellular glutamate in the nucleus accumbens, which has been shown to be required for cocaine-primed reinstatement. Rats were assigned to self-administer under …

Neurobiological Mechanisms That Contribute To Stress-Related Cocaine Use, John R. Mantsch, Oliver Vranjkovic, Robert C. Twining, Paul J. Gasser, Jayme R. Mcreynolds, Jordan M. Blacktop

Biomedical Sciences Faculty Research and Publications

The ability of stressful life events to trigger drug use is particularly problematic for the management of cocaine addiction due to the unpredictable and often uncontrollable nature of stress. For this reason, understanding the neurobiological processes that contribute to stress-related drug use is important for the development of new and more effective treatment strategies aimed at minimizing the role of stress in the addiction cycle. In this review we discuss the neurocircuitry that has been implicated in stress-induced drug use with an emphasis on corticotropin releasing factor actions in the ventral tegmental area (VTA) and an important pathway from the …

Cannabinoid Receptor Involvement In Stress-Induced Cocaine Reinstatement: Potential Interaction With Noradrenergic Pathways, Linda K. Vaughn, John R. Mantsch, Oliver Vranjkovic, G. Stroh, M. Lacourt, M. Kreutter, Cecilia J. Hillard

Biomedical Sciences Faculty Research and Publications

This study examined the role of endocannabinoid signaling in stress-induced reinstatement of cocaine seeking and explored the interaction between noradrenergic and endocannabinergic systems in the process. A well-validated preclinical model for human relapse, the rodent conditioned place preference assay, was used. Cocaine-induced place preference was established in C57BL/6 mice using injections of 15 mg/kg cocaine. Following extinction of preference for the cocaine-paired environment, reinstatement of place preference was determined following 6 min of swim stress or cocaine injection (15 mg/kg, i.p.). The role of endocannabinoid signaling was studied using the cannabinoid antagonist AM-251 (3 mg/kg, i.p.). Another cohort of mice …

Oral Administration Of Levo-Tetrahydropalmatine Attenuates Reinstatement Of Extinguished Cocaine Seeking By Cocaine, Stress Or Drug-Associated Cues In Rats, Yazmin Figueroa-Guzman, Christopher R. Mueller, Oliver Vranjkovic, Samantha Wisniewski, Zheng Yang, Shi-Jiang Li, Colin Bohr, Evan N. Graf, David A. Baker, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

Cocaine addiction is characterized by a persistently heightened susceptibility to drug relapse. For this reason, the identification of medications that prevent drug relapse is a critical goal of drug abuse research. Drug re-exposure, the onset of stressful life events, and exposure to cues previously associated with drug use have been identified as determinants of relapse in humans and have been found to reinstate extinguished cocaine seeking in rats. This study examined the effects of acute oral (gavage) administration of levo-tetrahydropalmatine (l-THP), a tetrahydroprotoberberine isoquinoline with a pharmacological profile that includes antagonism of D1, D2 and D3 dopamine receptors, …

Involvement Of Noradrenergic Neurotransmission In The Stress- But Not Cocaine-Induced Reinstatement Of Extinguished Cocaine-Induced Conditioned Place Preference In Mice: Role For Β-2 Adrenergic Receptors, John R. Mantsch, Andy Meyer, Oliver Vranjkovic, Chad E. Beyer, David A. Baker, Holly Caretta

Biomedical Sciences Faculty Research and Publications

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine …

Stressor- And Corticotropin Releasing Factor-Induced Reinstatement And Active Stress-Related Behavioral Responses Are Augmented Following Long-Access Cocaine Self-Administration By Rats, John R. Mantsch, David A. Baker, David M. Francis, Eric S. Katz, Michael A. Hoks, Joseph P. Serge

Biomedical Sciences Faculty Research and Publications

Rationale Stressful events during periods of drug abstinence likely contribute to relapse in cocaine-dependent individuals. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) responsiveness.

Objectives This study examined stressor- and CRF-induced cocaine seeking and other stress-related behaviors in rats with different histories of cocaine self-administration (SA).

Materials and methods Rats self-administered cocaine under short-access (ShA; 2 h daily) or long-access (LgA; 6 h daily) conditions for 14 days or were provided access to saline and were tested for reinstatement by a stressor (electric footshock), cocaine or an icv injection of CRF and …