Prevention and reversal of social stress-escalated cocaine self-administration in mice by intra-VTA CRFR1 antagonism
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A history of brief intermittent social defeat stress can escalate cocaine self-administration and induce long-term adaptations in the mesolimbic dopamine system. Extra-hypothalamic corticotrophin releasing factor (CRF) has been shown to be closely associated with stress-induced escalation of drug use. How repeated stress modulates CRF release in the ventral tegmental area (VTA) and the roles of CRF receptors during different phases of stress-induced cocaine self-administration remain to be defined.
The current study examines the roles of CRF and CRF receptor 1 (CRFR1) in escalated intravenous cocaine self-administration after exposure to social defeat stress in mice.
Methods and results
First, CRFR1 antagonist (CP 376,395, 15 mg/kg, i.p.) given 30 min prior to each social defeat episode prevented later escalated cocaine self-administration. When CP 376,395 (5 and 15 mg/kg, i.p.) was administered 10 days after the last episode of social stress, the escalation of cocaine intake was dose-dependently reversed. Moreover, socially defeated mice showed increased CRF release in the VTA compared to controls. To further explore the role of CRFR1, CP 376,395 (0.5 and 1 μg/0.2 μl) was infused directly into the VTA before the cocaine self-administration session. Intra-VTA antagonism of CRFR1 was sufficient to reverse social defeat stress-escalated cocaine self-administration.
These findings suggest that CRF and CRFR1 exert multiple roles in the response to social stress that are relevant to escalated cocaine self-administration.
KeywordsSocial defeat stress CRF microdialysis CRFR1 Intravenous cocaine self-administration Microinjection VTA Mice
This research was supported by National Institute on Drug Abuse Grant DA031734, KAM, PI.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
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