Abstract
The ability of many drugs of abuse, including cocaine, to mediate reinforcement and drug-seeking behaviors is in part mediated by the corticotropin-releasing hormone (CRH) system, in which CRH exerts its effects partly via the CRH receptor subtype 1 (CRHR1) in extra-hypothalamic areas. In fact, CRHR1 expressed in regions of the mesolimbic dopamine (DA) system have been demonstrated to modify cocaine-induced DA release and alter cocaine-mediated behaviors. Here we examined the role of neuronal selectivity of CRHR1 within the mesolimbic system on cocaine-induced behaviors. First we used a transgenic mouse line expressing GFP under the control of the Crhr1 promoter for double fluorescence immunohistochemistry to demonstrate the cellular location of CRHR1 in both dopaminergic and D1 dopaminoceptive neurons. We then studied cocaine sensitization, self-administration, and reinstatement in inducible CRHR1 knockouts using the CreERT2/loxP in either dopamine transporter (DAT)-containing neurons (DAT-Crhr1) or dopamine receptor 1 (D1)-containing neurons (D1-Crhr1). For sensitization testing, mice received five daily injections of cocaine (15 mg/kg IP). For self-administration, mice received eight daily 2 h cocaine (0.5 mg/kg per infusion) self-administration sessions followed by extinction and reinstatement testing. There were no differences in the acute or sensitized locomotor response to cocaine in DAT-Crhr1 or D1-Crhr1 mice and their respective controls. Furthermore, both DAT-Crhr1 and D1-Crhr1 mice reliably self-administered cocaine at the level of controls. However, DAT-Crhr1 mice demonstrated a significant increase in cue-induced reinstatement relative to controls, whereas D1-Crhr1 mice demonstrated a significant decrease in cue-induced reinstatement relative to controls. These data demonstrate the involvement of CRHR1 in cue-induced reinstatement following cocaine self-administration, and implicate a bi-directional role of CRHR1 for cocaine craving.
Highlights
Drug craving and subsequent relapse following abstinence remain major impediments to the treatment of drug addiction in humans
dopamine transporter (DAT)-Crhr1 mice demonstrated a significant increase in cue-induced reinstatement relative to controls, while dopamine receptor 1 (D1)-Crhr1 mice demonstrated a significant decrease in cue-induced reinstatement relative to controls, indicating neuronal selectivity of CRH receptor subtype 1 (CRHR1) receptors on dopaminoceptive neurons in the reinstatement of cocaineseeking
Double fluorescence immunolabelings of (Crhr1-) green fluorescent protein (GFP)-ir with NeuN-ir demonstrated a neuronal location of CRHR1 in all analyzed reward-related brain regions (i.e., accumbens shell (AcbS), bed nucleus of the stria terminalis (BNST), ventral tegmental area (VTA), substantia nigra compacta (SNC), substantia nigra reticulata (SNR); Noori et al, 2012). (Crhr1-)GFP-ir was expressed in TH-ir positive DAergic neurons of the VTA and the SNC, while (Crhr1-)GFP-ir in D1-ir neurons was detected in the BNST and the VTA
Summary
Drug craving and subsequent relapse following abstinence remain major impediments to the treatment of drug addiction in humans. The corticotropin-releasing hormone/corticotropinreleasing factor (CRH/CRF) family of ligands and receptors are important mediators of the neuroendocrine and behavioral response to stress, and hyperfunction of CRH and its type 1 high-affinity receptor (CRHR1) have been implicated in the pathology of chronic stress, including the development of anxiety and mood disorders (Muller and Wurst, 2004; Aubry, 2013). There is high comorbidity of anxiety and mood disorders with substance use disorders in humans (Grant et al, 2004; Bruijnzeel and Gold, 2005), and stress plays an important role in increasing the vulnerability and motivation to abuse drugs in addicted individuals (Koob and Le Moal, 2001, 2008b). CRHR1 is expressed in DAergic terminal regions including the prefrontal cortex (PFC) and amygdala (Amy; Smagin and Dunn, 2000; Van Pett et al, 2000; Jaferi and Bhatnagar, 2007; Miguel et al, 2014), which mediate excitatory drive and associative processes related to drug-mediated behaviors (Everitt et al, 1999; Peters et al, 2009), as well as regions of the extended amygdala (Van Pett et al, 2000; Kash et al, 2008; Silberman and Winder, 2013), the dysregulation of which contributes to drug dependence (Koob and Le Moal, 2008b)
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