title: Episodic Social Stress-Escalated Cocaine Self-Administration: Role of Phasic and Tonic Corticotropin Releasing Factor in the Anterior and Posterior Ventral Tegmental Area.
abstract: Intermittent social defeat stress escalates later cocaine self-administration. Reward and stress both activate ventral tegmental area (VTA) dopamine neurons, increasing downstream extracellular dopamine concentration in the medial prefrontal cortex and nucleus accumbens. The stress neuropeptide corticotropin releasing factor (CRF) and its receptors (CRF-R1, CRF-R2) are located in the VTA and influence dopaminergic activity. These experiments explore how CRF release and the activation of its receptors within the VTA both during and after stress influence later cocaine self-administration in rats.In vivo microdialysis of CRF in the VTA demonstrated that CRF is phasically released in the posterior VTA (pVTA) during acute defeat, but, with repeated defeat, CRF is recruited into the anterior VTA (aVTA) and CRF tone is increased in both subregions. Intra-VTA antagonism of CRF-R1 in the pVTA and CRF-R2 in the aVTA during each social defeat prevented escalated cocaine self-administration in a 24 h "binge." VTA CRF continues to influence cocaine seeking in stressed animals long after social defeat exposure. Unlike nonstressed controls, previously stressed rats show significant cocaine seeking after 15 d of forced abstinence. Previously stressed rats continue to express elevated CRF tone within the VTA and antagonism of pVTA CRF-R1 or aVTA CRF-R2 reverses cocaine seeking. In conclusion, these experiments demonstrate neuroadaptive changes in tonic and phasic CRF with repeated stress, that CRF release during stress may contribute to later escalated cocaine taking, and that persistently elevated CRF tone in the VTA may drive later cocaine seeking through increased activation of pVTA CRF-R1 and aVTA CRF-R2.
  
  
  CONCLUSIONS
  Corticotropin releasing factor (CRF) within the ventral tegmental area (VTA) has emerged as a likely candidate molecule underlying the fundamental link between stress history and escalated drug self-administration. However, the nature of CRF release in the VTA during acute and repeated stress, as well as its role in enduring neuroadaptations driving later drug taking and seeking, are poorly understood. These experiments explore how CRF is released and interacts with its receptors in specific regions of the VTA both during and after stress to fuel later escalated cocaine taking and seeking behavior. Understanding these acute and persistent changes to the VTA CRF system may lead to better therapeutic interventions for addiction.
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts 02155, McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, eholly@mit.edu.
authors.forename: Elizabeth N
authors.initials: EN
authors.lastname: Holly
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts 02155.
authors.forename: Christopher O
authors.initials: CO
authors.lastname: Boyson
authors.affiliation: Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de València, València, Spain 46010.
authors.forename: Sandra
authors.initials: S
authors.lastname: Montagud-Romero
authors.affiliation: Programa de Pós-Graduação em Ciências Médicas, Psiquiatria, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil 90050, and.
authors.forename: Dirson J
authors.initials: DJ
authors.lastname: Stein
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts 02155.
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Gobrogge
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts 02155.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: DeBold
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts 02155, Departments of Neuroscience and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts 02111.
authors.forename: Klaus A
authors.identifier: http://orcid.org/0000-0002-2696-7266
authors.initials: KA
authors.lastname: Miczek
mesh_terms: D000818:Animals; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000523:psychology*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D058999:Drug-Seeking Behavior; D008297:Male; D017551:Microdialysis; D051381:Rats; D020318:Rats, Long-Evans; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D012646:Self Administration; D012931:Social Environment; D013315:Stress, Psychological / Q000378:metabolism* / Q000523:psychology*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000523:psychology; D017557:Ventral Tegmental Area / Q000378:metabolism*; D000099052:CRF Receptor, Type 1
chemical_list: C101531:CRF receptor type 2; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone
keywords: cocaine seeking; cocaine self-administration; corticotropin releasing factor; social defeat; stress; ventral tegmental area