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Social defeat stress, sensitization ...

Tufts University., Psychology.

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Social defeat stress, sensitization and escalated cocaine self-administration: Role of ERK-CREB signaling in the mesocorticolimbic dopamine system.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Social defeat stress, sensitization and escalated cocaine self-administration: Role of ERK-CREB signaling in the mesocorticolimbic dopamine system./
作者:	Yap, Jasmine J.
面頁冊數:	141 p.
附註:	Adviser: Klaus A. Miczek.
Contained By:	Dissertation Abstracts International70-04B.
標題:	Biology, Neuroscience. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3354709
ISBN:	9781109118759

Social defeat stress, sensitization and escalated cocaine self-administration: Role of ERK-CREB signaling in the mesocorticolimbic dopamine system.
Yap, Jasmine J.

Social defeat stress, sensitization and escalated cocaine self-administration: Role of ERK-CREB signaling in the mesocorticolimbic dopamine system. - 141 p.

Adviser: Klaus A. Miczek.

Thesis (Ph.D.)--Tufts University, 2009.

Rationale: Repeated social defeat stress experiences can induce long-term changes in neuroplasticity in reward-related circuits that require changes in gene expression and may mediate compulsive drug taking. One signaling cascade of interest is the extracellular signalregulated kinase (ERK) pathway, which when activated by repeated cocaine administration, can promote the downstream activation of the transcription factor cAMP response element binding protein (CREB) and enhance immediate early gene expression of c-fos and zif268. Changes in expression of c-fos and zif268 in the mesocorticolimbic dopamine system persist up to 60 days following defeat. Objective: We hypothesized that changes in ERK function are necessary for the behavioral and neural adaptations that occur as a consequence of defeat stress. Materials and Methods: In the first experiment, rats were microinjected bilaterally with a MEK (MAPK/ERK kinase) inhibitor, U0126 (1 mug/side), or vehicle (20% DMSO) into the ventral tegmental area (VTA) prior to each of 4 defeat episodes. Ten days following the last defeat, locomotor activity was recorded to assess the expression of behavioral cross-sensitization to cocaine (10 mg/kg, i.p.). Rats were then trained to self-administer cocaine under fixed and progressive ratio schedules of reinforcement, including a 24-h continuous access "binge" (0.3 mg/kg/infusion). In a second experiment, rats were exposed to either 4 brief intermittent defeats or 36 days of continuous subordination stress, two stress protocols known to induce either a sensitized or anhedonic phenotype, respectively. Ten days after the last stress episode, rats were challenged with either saline or cocaine (10 mg/kg, i.p.), and phosphorylation levels of ERK and CREB in mesocorticolimbic regions were used to assess endogenous functional activity of these signaling molecules in previously defeated rats. Results: Animals that received U0126 pretreatments were protected against the development Social defeat stress and ERK-CREB signaling of social stress-induced sensitization, and this also prevented the enhancement of cocaine self-administration during a continuous access "binge". Differential changes in ERK and CREB phosphorylation appear to depend on the duration of the stress---whether the stress is intermittent (a type of activating stress) or continuous (a type of debilitating stress). In the medial prefrontal cortex, intermittent defeat resulted in significantly decreased pCREB and CREB levels compared to controls. Continuous defeat resulted in a heightened response to cocaine in the prefrontal cortex, as measured by pERK2 levels. Episodically stressed animals showed profound changes in ERK and CREB function in the VTA as a consequence of pulsatile defeat. CREB phosphorylation in the VTA was significantly reduced in these animals, while ERK1/2 phosphorlation was significantly increased. ERK protein levels were also significantly decreased in the VTA ten days following intermittent defeat. Finally, ERK protein levels in the nucleus accumbens were significantly increased in episodically defeated animals. Conclusions: Changes in ERK and CREB phosphorylation in mesocorticolimbic regions are dependent on the intensity and duration of the stress experience and may contribute to the emergence of divergent behavioral phenotypes. The results suggest that enhanced activation of ERK in the VTA due to brief defeat experiences is critical in the induction of sensitization and may be involved in escalated cocaine taking.

ISBN: 9781109118759Subjects--Topical Terms:

1017680
Biology, Neuroscience.

Social defeat stress, sensitization and escalated cocaine self-administration: Role of ERK-CREB signaling in the mesocorticolimbic dopamine system.
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245 1 0 $a Social defeat stress, sensitization and escalated cocaine self-administration: Role of ERK-CREB signaling in the mesocorticolimbic dopamine system.
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500 $a Source: Dissertation Abstracts International, Volume: 70-04, Section: B, page: 2603.
502 $a Thesis (Ph.D.)--Tufts University, 2009.
520 $a Rationale: Repeated social defeat stress experiences can induce long-term changes in neuroplasticity in reward-related circuits that require changes in gene expression and may mediate compulsive drug taking. One signaling cascade of interest is the extracellular signalregulated kinase (ERK) pathway, which when activated by repeated cocaine administration, can promote the downstream activation of the transcription factor cAMP response element binding protein (CREB) and enhance immediate early gene expression of c-fos and zif268. Changes in expression of c-fos and zif268 in the mesocorticolimbic dopamine system persist up to 60 days following defeat. Objective: We hypothesized that changes in ERK function are necessary for the behavioral and neural adaptations that occur as a consequence of defeat stress. Materials and Methods: In the first experiment, rats were microinjected bilaterally with a MEK (MAPK/ERK kinase) inhibitor, U0126 (1 mug/side), or vehicle (20% DMSO) into the ventral tegmental area (VTA) prior to each of 4 defeat episodes. Ten days following the last defeat, locomotor activity was recorded to assess the expression of behavioral cross-sensitization to cocaine (10 mg/kg, i.p.). Rats were then trained to self-administer cocaine under fixed and progressive ratio schedules of reinforcement, including a 24-h continuous access "binge" (0.3 mg/kg/infusion). In a second experiment, rats were exposed to either 4 brief intermittent defeats or 36 days of continuous subordination stress, two stress protocols known to induce either a sensitized or anhedonic phenotype, respectively. Ten days after the last stress episode, rats were challenged with either saline or cocaine (10 mg/kg, i.p.), and phosphorylation levels of ERK and CREB in mesocorticolimbic regions were used to assess endogenous functional activity of these signaling molecules in previously defeated rats. Results: Animals that received U0126 pretreatments were protected against the development Social defeat stress and ERK-CREB signaling of social stress-induced sensitization, and this also prevented the enhancement of cocaine self-administration during a continuous access "binge". Differential changes in ERK and CREB phosphorylation appear to depend on the duration of the stress---whether the stress is intermittent (a type of activating stress) or continuous (a type of debilitating stress). In the medial prefrontal cortex, intermittent defeat resulted in significantly decreased pCREB and CREB levels compared to controls. Continuous defeat resulted in a heightened response to cocaine in the prefrontal cortex, as measured by pERK2 levels. Episodically stressed animals showed profound changes in ERK and CREB function in the VTA as a consequence of pulsatile defeat. CREB phosphorylation in the VTA was significantly reduced in these animals, while ERK1/2 phosphorlation was significantly increased. ERK protein levels were also significantly decreased in the VTA ten days following intermittent defeat. Finally, ERK protein levels in the nucleus accumbens were significantly increased in episodically defeated animals. Conclusions: Changes in ERK and CREB phosphorylation in mesocorticolimbic regions are dependent on the intensity and duration of the stress experience and may contribute to the emergence of divergent behavioral phenotypes. The results suggest that enhanced activation of ERK in the VTA due to brief defeat experiences is critical in the induction of sensitization and may be involved in escalated cocaine taking.
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