Merlo Pich EM, Lorang M, Yeganeh M, Rodriguez de Fonseca F, Raber J, Koob GF et al. Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J Neurosci 15: 5439-5447

Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/1995; 15(8):5439-47.
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Previous research has suggested a role for corticotropin-releasing factor (CRF) in the anxiogenic effects of stressful stimuli and ethanol withdrawal. This hypothesis was explored in a series of experiments using intracranial microdialysis to monitor CRF-like immunoreactivity (CRF-IR) in the extracellular compartment of the rat amygdala. The synaptic origin of CRF-IR release in the amygdala was determined in vitro by assessing the Ca2+ dependency of 4-aminopyridine stimulated CRF-IR release from tissue preparations of rat amygdala. In vivo experiments were performed in awake rats after the placement of microdialysis probes in the amygdala. In the first experiment, transient restraint stress (20 min) produced an increase of CRF-IR release (basal levels, 1.19 +/- 0.15 fmol/50 microliters; stress levels, 4.54 +/- 1.33 fmol/50 microliters; p < 0.05) that returned to basal values within 1 hr. When 4-aminopyridine (5 mM) was added to the perfusion medium, it consistently increased CRF-IR release (4.83 +/- 0.92 fmol/50 microliters, p < 0.05). In the second experiment, CRF-IR release was measured during ethanol withdrawal in rats previously maintained for 2-3 weeks on a liquid diet containing ethanol (8.5%). Basal CRF-IR levels were 2.10 +/- 0.43 fmol/50 microliters in ethanol exposed rats and 1.30 +/- 0.19 fmol/50 microliters in control rats. During withdrawal, a progressive increase of CRF-IR levels over time was observed, reaching peak values at 10-12 hr after the onset of withdrawal (10.65 +/- 0.49 fmol/50 microliters vs 1.15 +/- 0.30 fmol/50 microliters of control rats, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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    • "Adverse experiences before or during adolescence increase risk to develop depression or substance use (Andersen and Teicher, 2009;Penza et al., 2003;Teicher et al., 2009;Widom et al., 2007). The neuropeptide corticotropin-releasing factor (CRF) integrates multiple components of the stress response (Dunn and Berridge, 1990;Merlo et al., 1995) and plays a role in the psychopathology of depression and substance abuse (Koob, 2010;Nemeroff, 1996;Nemeroff, 1998;Zorrilla et al., 2014). Corticotropinreleasing factor dose-dependently modulates monoaminergic activity via two receptor subtypes, CRF 1 and CRF 2 (Kirby et al., 2000;Price et al., 1998), each with distinct region-specific effects on serotonin and dopamine release (Isogawa et al., 2000;Lukkes et al., 2008). "
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    ABSTRACT: Interactions between corticotropin-releasing factor (CRF) and monoaminergic systems originating from the dorsal raphe nucleus (DR) and ventral tegmental area (VTA) have been implicated in the etiology and pathophysiology of several stress-related neuropsychiatric disorders such as depression and substance abuse. Sub-regions within the DR and VTA give rise to specific projections that have unique roles in limbic- and reward-related behaviors. Given that these disorders typically emerge during adolescence, it is surprising that few studies have examined the age-, sex- and region-dependent expression of CRF receptors throughout multiple stages of adolescence in these stress-relevant circuits. To determine the ontogeny of CRF receptors during adolescent development, three regions of the DR (dorsal, caudal, and ventrolateral parts) and the posterior VTA were microdissected from Sprague-Dawley male and female rats on postnatal day (P) 25, P35, P42, P56, and P90. Tissue was processed and analyzed with qRT-PCR to measure CRF1 and CRF2 receptors. The serotonin and catecholamine enzymes in the DR and VTA, tryptophan hydroxylase 2 (TPH2) and tyrosine hydroxylase, respectively, were also analyzed for maturational differences. This study identified that CRF1 receptors are lower in males than females within the dorsal, ventrolateral region of the DR (DRVL), which is involved in anxiety-, stress-, and panic-related responses. Females had higher CRF2 receptors compared to males in the DRVL only. Levels of TPH2 mRNA in the DRVL were overproduced transiently in females before declining into adulthood. These fundamental studies suggest that sex differences in CRF receptors should be considered when examining stress-related neuropsychiatric disorders and their treatment. This article is protected by copyright. All rights reserved.
    Full-text · Article · Dec 2015 · Synapse
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    • "as preclinical treatments for EtOH dependence (Phillips et al. 2015) since it was found that CRF increased in the amygdala in rats withdrawing from an EtOH liquid diet (Merlo Pich et al. 1995). CRF-R1 antagonists can reduce anxiety-like behavior during EtOH withdrawal, block responding for EtOH reinforcement in dependent animals, and suppress stressinduced EtOH reinstatement (Valdez et al. 2002; Liu and Weiss 2002). "
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    ABSTRACT: Rationale: Excessive alcohol (EtOH) drinking is difficult to model in animals despite the extensive human literature demonstrating that stress increases EtOH consumption. Objective: The current experiments show escalations in voluntary EtOH drinking caused by a history of social defeat stress and intermittent access to EtOH in C57BL/6J mice compared to non-stressed mice given intermittent EtOH or continuous EtOH. To explore a mechanistic link between stress and drinking, we studied the role of corticotropin-releasing factor type-1 receptors (CRF-R1) in the dopamine-rich ventral tegmental area (VTA). Results: Intra-VTA infusions of a CRF-R1 antagonist, CP376395, infused into the VTA dose-dependently and selectively reduced intermittent EtOH intake in stressed and non-stressed mice, but not in mice given continuous EtOH. In contrast, intra-VTA infusions of the CRF-R2 antagonist astressin2B non-specifically suppressed both EtOH and H2O drinking in the stressed group without effects in the non-stressed mice. Using in vivo microdialysis in the nucleus accumbens (NAc) shell, we observed that stressed mice drinking EtOH intermittently had elevated levels of tonic dopamine concentrations compared to non-stressed drinking mice. Also, VTA CP376395 potentiated dopamine output to the NAc only in the stressed group causing further elevations of dopamine post-infusion. Conclusions: These findings illustrate a role for extrahypothalamic CRF-R1 as especially important for stress-escalated EtOH drinking beyond schedule-escalated EtOH drinking. CRF-R1 may be a mechanism for balancing the dysregulation of stress and reward in alcohol use disorders.
    Full-text · Article · Nov 2015 · Psychopharmacology
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    • "Although this is the first study on the modulation of alcohol-heightened aggression by CRF-R1 signaling, the involvement of CRF systems in alcohol drinking and alcohol dependence has been extensively explored in animal models (Heilig and Koob, 2007). After repeated and chronic exposure to alcohol, rats show hyperactive extrahypothalamic CRF activity, as indicated by increases in CRF levels and its receptors in the extended amygdala (Merlo Pich et al, 1995; Olive et al, 2002; Sommer et al, 2008). Systemic or intra-amygdaloid blockade of CRF-R1 attenuates increased alcohol seeking and intake in alcohol-dependent animals (Funk et al, 2006; Gehlert et al, 2007; Sommer et al, 2008; Heilig and Koob, 2007) or in high-alcohol-consuming mice (Sparta et al, 2008). "
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    ABSTRACT: Alcohol can escalate aggressive behavior in a significant subgroup of rodents, humans, and nonhuman primates. The present study investigated whether blockade of corticotropin-releasing factor receptor type 1 (CRF-R1) could prevent the emergence of alcohol-heightened aggression in mice. The serotonin (5-HT) pathway from the dorsal raphé nucleus (DRN) to the medial prefrontal cortex (mPFC) by CRF-R1 was investigated as a possible target for the prevention of alcohol-heightened aggressive behavior. Male CFW mice that reliably exhibited aggressive behaviors after consuming 1 g/kg of alcohol received systemic or intra-DRN administration of CRF-R1 antagonists, CP-154,526 or MTIP, before a confrontation with a male conspecific. Blockade of DRN CRF-R1 receptors with both antagonists significantly reduced only alcohol-heightened aggression, while systemic administration reduced both alcohol-heightened and species-typical aggression. Next, a 5-HT1A agonist, 8-OH-DPAT, was co-administered with CP-154,526 into the DRN to temporarily disrupt 5-HT activity. This manipulation abolished the anti-aggressive effects of intra-DRN CP-154,526. In the mPFC, in vivo microdialysis revealed that extracellular 5-HT levels were increased in mice that consumed alcohol, and then were injected with CP-154,526, both systemically or intra-DRN. Neither alcohol nor CP-154,526 alone affected 5-HT release in the mPFC. The present results suggest the DRN as a critical site for CRF-R1 to modulate alcohol-heightened aggression via action on the serotonergic DRN-PFC pathway.Neuropsychopharmacology accepted article preview online, 11 June 2014; doi:10.1038/npp.2014.139.
    Full-text · Article · Jun 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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