Enhanced CRFR1-Dependent Regulation of a Ventral Tegmental Area to Prelimbic Cortex Projection Establishes Susceptibility to Stress-Induced Cocaine Seeking

Vranjkovic, Oliver; Newenhizen, Erik C. Van; Nordness, Michael; Blacktop, Jordan M.; Urbanik, Luke A.; Mathy, Jacob C.; McReynolds, Jayme R.; Miller, Anna M.; Doncheck, Elizabeth M.; Kloehn, Tyler M.; Stinnett, Gwen S.; Gerndt, Clayton H.; Ketchesin, Kyle D.; Baker, David A.; Seasholtz, Audrey F.; Mantsch, John R.

doi:10.1523/jneurosci.2080-18.2018

Cited by 22 publications

(16 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Altogether, these findings suggest that CRF release into the VTA from neurons originating in the BNST activates CRFR1 receptors to excite VTA dopamine neurons that project to the prelimbic cortex, resulting in dopamine release, D1 receptor activation, and cocaine seeking. Consistent with this model, we have found that pharmacological disconnection of the VTA-prelimbic cortex pathway by administration of the CRF-R1 antagonist, antalarmin, into the VTA in one hemisphere, and administration of the D1 receptor antagonist SCH 23,390 into the prelimbic cortex of the contralateral hemisphere prevents shock-triggered cocaine seeking following self-administration in rats (Vranjkovic et al, 2018).…”

Section: Prelimbic Pfc Dopamine and D1 Receptorssupporting

confidence: 66%

“…As is the case with footshock stress, the ability of intra-VTA micro-infusions to reinstate drug seeking is only observed in rats with a history of long-access cocaine self-administration (Blacktop et al, 2011). We have found that this recruitment of CRF-dependent cocaine seeking is associated with increased CRF-R1 mRNA levels in the VTA and a heightened CRF-R1-dependent Fos response in the prelimbic cortex (Vranjkovic et al, 2018). Based on these observations, we hypothesize that excessive cocaine use produces persistent increases in CRF-R1 receptors on VTA dopamine neurons that project to the prelimbic cortex, thereby promoting stress-induced drug seeking.…”

Section: History Of Drug Usementioning

confidence: 68%

“…Our research has focused on pathway from the VTA to the dorsomedial PFC, including the prelimbic cortex -a region considered to have homology with components of the human PFC (e.g., dorsolateral PFC and anterior cingulate cortex; Uylings et al, 2003) that have been implicated in cocaine craving (Breiter et al, 1997;Grant et al, 1996;Kilts et al, 2001;Maas et al, 1998;Wexler et al, 2001). Shock-triggered cocaine seeking in rats is associated with increased Fos reactivity in the prelimbic cortex and in retro-labeled prelimbic-projecting VTA neurons (Vranjkovic et al, 2018), which aligns with findings that subpopulations of VTA neurons encode aversive events (Brischoux et al, 2009;Ungless et al, 2010). Consistent with findings that inhibiting the prelimbic cortex using baclofen/muscimol (McFarland et al, 2004) or tetrodotoxin (Capriles et al, 2003) prevents shock-triggered cocaine seeking, we have found that inhibition of prelimbic-projecting VTA neurons using an intersectional DREADD (Designer Receptor Exclusively Activated by Designer Drug) approach in which CNO administration following delivery of a virus encoding retro-AAV Cre into the prelimbic cortex and a Cre-dependent hM 4 D i -expressing vector into the VTA prevents shock-triggered reinstatement of cocaine seeking following self-administration in rats (Vranjkovic et al, 2018).…”

Section: Vta Projections To the Prelimbic Pfcmentioning

confidence: 99%

See 2 more Smart Citations

Neurochemical mechanisms and neurocircuitry underlying the contribution of stress to cocaine seeking

Caccamise

Newenhizen

Mantsch

2021

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

In individuals with substance use disorders, stress is a critical determinant of relapse susceptibility. In some cases, stressors directly trigger cocaine use. In others, stressors interact with other stimuli to promote drug seeking, thereby setting the stage for relapse. Here, we review the mechanisms and neurocircuitry that mediate stress-triggered and stress-potentiated cocaine seeking. Stressors trigger cocaine seeking by activating noradrenergic projections originating in the lateral tegmentum that innervate the bed nucleus of the stria terminalis to produce beta adrenergic receptor-dependent regulation of neurons that release corticotropin releasing factor (CRF) into the ventral tegmental area (VTA). CRF promotes the activation of VTA dopamine neurons that innervate the prelimbic prefrontal cortex resulting in D1 receptor-dependent excitation of a pathway to the nucleus accumbens core that mediates cocaine seeking. The stage-setting effects of stress require glucocorticoids, which exert rapid non-canonical effects at several sites within the mesocorticolimbic system. In the nucleus accumbens, corticosterone attenuates dopamine clearance via the organic cation transporter 3 to promote dopamine signaling. In the prelimbic cortex, corticosterone mobilizes the endocannabinoid, 2-arachidonoylglycerol (2-AG), which produces CB1 receptor-dependent reductions in inhibitory transmission, thereby increasing excitability of neurons which comprise output pathways responsible for cocaine seeking. Factors that influence the role of stress in cocaine seeking, including prior history of drug use, biological sex, chronic stress/co-morbid stress-related disorders, adolescence, social variables, and genetics are discussed.Better understanding when and how stress contributes to drug seeking should guide the development of more effective interventions, particularly for those whose drug use is stress related.

show abstract

Section: Prelimbic Pfc Dopamine and D1 Receptorssupporting

confidence: 66%

Section: History Of Drug Usementioning

confidence: 68%

Section: Vta Projections To the Prelimbic Pfcmentioning

confidence: 99%

See 1 more Smart Citation

Neurochemical mechanisms and neurocircuitry underlying the contribution of stress to cocaine seeking

Caccamise

Newenhizen

Mantsch

2021

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Indeed, basal CRF levels in the VTA are elevated during drug withdrawal following cocaine self-administration, 8 which could potentially occlude the behavioral effect of exogenously applied CRF and/or elicit changes in CRF receptor expression within the VTA. Prior drug experience increases CRF receptor levels within the VTA 15,38,39 and alters the electrophysiological effects of CRF on VTA dopamine neurons. 14,16,17,37 As such, the cocaine-mediated loss in the capacity for CRF to regulate motivation could be mediated by (a) CRF losing the ability to inhibit dopamine transmission or (b) CRF engaging a local excitatory circuit to counteract its inhibitory influence over dopamine neurons.…”

Section: Discussionmentioning

confidence: 99%

Cocaine experience abolishes the motivation suppressing effect of CRF in the ventral midbrain

et al. 2019

View full text Add to dashboard Cite

Stress affects dopamine-dependent behaviors in part through the actions of corticotropin releasing factor (CRF) in the ventral tegmental area (VTA). For example, acute stress engages CRF signaling in the VTA to suppress the motivation to work for food rewards. In contrast, acute stress promotes drug-seeking behavior through the actions of CRF in the VTA. These diverging behavioral effects in food-and drugbased tasks could indicate that CRF modulates goal-directed actions in a reinforcerspecific manner. Alternatively, prior drug experience could functionally alter how CRF in the VTA regulates dopamine-dependent behavior. To address these possibilities, we examined how intra-VTA injections of CRF influenced cocaine intake and whether prior drug experience alters how CRF modulates the motivation for food rewards. Our results demonstrate that intra-VTA injections of CRF had no effect on drug intake when self-administering cocaine under a progressive ratio reinforcement schedule. We also found that a prior history of either contingent or noncontingent cocaine infusions abolished the capacity for CRF to reduce the motivation for food rewards. Furthermore, voltammetry recordings in the nucleus accumbens illustrate that CRF in the VTA had no effect on cocaine-evoked dopamine release. These results collectively illustrate that exposure to abused substances functionally alters how neuropeptides act within the VTA to influence motivated behavior.

show abstract

“…Exposure to abused substances elicits an array of intrinsic and synaptic changes within the VTA [32]. Prior drug experience increases CRF receptor levels within the VTA [9,33,34], and alters the electrophysiological effects of CRF on VTA dopamine neurons [8,10,11,31]. As such, the cocaine-mediated loss in the capacity for CRF to regulate motivation could be mediated by a drug-induced alteration in which CRF engages a local circuit to reverse its inhibitory influence on reward-evoked dopamine release.…”

Section: Discussionmentioning

confidence: 99%

Cocaine experience abolishes the motivation suppressing effect of CRF in the ventral midbrain

Oliva

Donate

Lefner

et al. 2019

Preprint

View full text Add to dashboard Cite

Stress affects dopamine-dependent behaviors in part through the actions of corticotropin releasing factor (CRF) in the ventral tegmental area (VTA). In particular, CRF signaling in the VTA mediates how acute stress suppresses the motivation to work for food rewards, as well as how stress promotes drug seeking behavior. These diverging behavioral effects in food-and drug-based tasks could indicate that CRF modulates goal-directed actions in a reinforcer-specific manner. Alternatively, prior drug experience could functionally alter how CRF in the VTA regulates dopamine-dependent behavior. To address these possibilities, we examined how intra-VTA injections of CRF influenced cocaine intake and whether prior drug experience alters how CRF modulates the motivation for food rewards. Our results demonstrate that intra-VTA injections of CRF had no effect on drug intake when self-administering cocaine under a progressive ratio reinforcement schedule. We also found that a prior history of either contingent or non-contingent cocaine infusions abolished the capacity for CRF to reduce the motivation for food rewards. Furthermore, voltammetry recordings in the nucleus accumbens illustrate that CRF in the VTA had no effect on cocaine-evoked dopamine release. These results collectively illustrate that exposure to abused substances functionally alters how neuropeptides act within the VTA to influence motivated behavior. Introduction:Stress induces the release of corticotropin releasing factor (CRF), which is responsible for initiating the hormonal and physiological responses to stress [1]. CRF signaling within the mesocorticolimbic system also mediates the effects of stress on motivation and decision-making processes [2]. For example, CRF receptor activation within the ventral tegmental area (VTA) is required for the stress-induced reduction in the motivation to work for food rewards [3]. Acute stress also decreases the preference for high effort / large reward options in decision making tasks [4]. This alteration in effort-based decision making is blocked by antagonizing CRF receptors and recapitulated by administering CRF directly into the VTA [4]. Therefore, the actions of CRF in the ventral midbrain are critical for how stress regulates behavioral responding for natural rewards.Whereas acute stress reduces the motivation to work for food rewards, stress promotes the reinstatement of drug seeking in a CRF-dependent manner [5]. Antagonizing CRF receptors in the VTA prevents stress-induced cocaine seeking [6,7]. Furthermore, intra-VTA injections of CRF are sufficient to reinstate cocaine seeking in the absence of stress [6,7], which together highlights the involvement of midbrain CRF signaling in how stress promotes drug-dependent behaviors.

show abstract

Enhanced CRFR1-Dependent Regulation of a Ventral Tegmental Area to Prelimbic Cortex Projection Establishes Susceptibility to Stress-Induced Cocaine Seeking

Cited by 22 publications

References 52 publications

Neurochemical mechanisms and neurocircuitry underlying the contribution of stress to cocaine seeking

Neurochemical mechanisms and neurocircuitry underlying the contribution of stress to cocaine seeking

Cocaine experience abolishes the motivation suppressing effect of CRF in the ventral midbrain

Cocaine experience abolishes the motivation suppressing effect of CRF in the ventral midbrain

Contact Info

Product

Resources

About