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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    • "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.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2014; 39(12). DOI:10.1038/npp.2014.139 · 8.68 Impact Factor
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    • "The lateral part of the CeA contains the highest density of CRH cell bodies within the amygdaloid complex while a more modest amount is found within the basolateral nucleus of the amygdala (BLA) (Hsu et al., 1998; Pitts et al., 2009). It is worthy of note that exposure to various stressors as well as ischemia increase extracellular CRH release and/or mRNA expression at the CeA (Hsu et al., 1998; Merali et al., 1998; Merlo Pich et al., 1995). "
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    ABSTRACT: Abnormal function of the neuroendocrine stress system has been implicated in the behavioral impairments observed following brain ischemia. The current study examined long-term changes in stress signals regulation 30 days following global cerebral ischemia. Experiment 1 investigated changes in the expression of corticotropin releasing hormone (CRH) and its subtype 1 receptor (CRHR1), glucocorticoid receptors (GR) in the paraventricular nucleus of the hypothalamus (PVN), the central nucleus of the amygdala (CeA), and the CA1 subfield of the hippocampus. Tyrosine hydroxylase (TH) was determined at the locus coeruleus (LC). Experiment 2 investigated the role of central CRHR1 activation on corticosterone (CORT) secretion at multiple time intervals following global ischemia after exposure to an acute stressor. Findings from Experiment 1 demonstrated a persistent increase in GR, CRH and CRHR1 immunoreactivity (ir) at the PVN, reduced GR and CRHR1 expression in pyramidal CA1 neurons, and increased LC TH expression in ischemic rats displaying working memory errors in the radial arm Maze. Findings from Experiment 2 revealed increased CORT secretion up to 7 days, but no longer present 14 and 21 days post ischemia. However upon an acute restraint stress induced 27 days following reperfusion, ischemic rats had increased plasma CORT secretions compared to sham-operated animals, suggesting HPA axis hypersensitivity. Antalarmin (2μg/2μl) pretreatment significantly attenuated post ischemic elevation of basal and stress-induced CORT secretion. These findings support persistent neuroendocrine dysfunctions following brain ischemia likely to contribute to emotional and cognitive impairments observed in survivors of cardiac arrest and stroke.
    Hormones and Behavior 01/2014; 65(3). DOI:10.1016/j.yhbeh.2014.01.003 · 4.63 Impact Factor
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    • "Many studies, conducted using a variety of experimental techniques, indicate that the amygdala has a crucial role in drug dependence and ethanol-reinforcing actions (Koob and Le Moal, 2001; Koob et al, 1998). Specifically, the central nucleus of the amygdala (CeA) is considered critical in mediating the behavioral effects of ethanol (Eckardt et al, 1998; Pich et al, 1995; Rassnick et al, 1993; Roberts et al, 1996). In particular, alcohol dependence is defined by the emergence of a negative emotional state mediated in part by the recruitment of pro-and antistress peptides in the amygdala (Koob, 2008; Koob and Le Moal, 2008; Roberto et al, 2012). "
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    ABSTRACT: The central nucleus of the amygdala (CeA) mediates several addiction-related processes and nociceptin/orphanin FQ (nociceptin) regulates ethanol intake and anxiety-like behaviors. Glutamatergic synapses, in the CeA and throughout the brain, are very sensitive to ethanol and contribute to alcohol reinforcement, tolerance, and dependence. Previously, we reported that in the rat CeA, acute and chronic ethanol exposures significantly decrease glutamate transmission by both pre-and postsynaptic actions. In this study, using electrophysiological techniques in an in vitro CeA slice preparation, we investigated the effects of nociceptin on glutamatergic transmission and its interaction with acute ethanol in naive and ethanol-dependent rats. We found that nociceptin (100-1000 nM) diminished basal-evoked compound glutamatergic receptor-mediated excitatory postsynaptic potentials (EPSPs) and spontaneous and miniature EPSCs (s/mEPSCs) by mainly decreasing glutamate release in the CeA of naive rats. Notably, nociceptin blocked the inhibition induced by acute ethanol (44 mM) and ethanol blocked the nociceptin-induced inhibition of evoked EPSPs in CeA neurons of naive rats. In neurons from chronic ethanol-treated (ethanol-dependent) rats, the nociceptin-induced inhibition of evoked EPSP amplitude was not significantly different from that in naive rats. Application of Nphe1 Nociceptin(1-13)NH2, a nociceptin receptor (NOP) antagonist, revealed tonic inhibitory activity of NOP on evoked CeA glutamatergic transmission only in ethanol-dependent rats. The antagonist also blocked nociceptin-induced decreases in glutamatergic responses, but did not affect ethanol-induced decreases in evoked EPSP amplitude. Taken together, these studies implicate a potential role for the nociceptin system in regulating glutamatergic transmission and a complex interaction with ethanol at CeA glutamatergic synapses.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2013; 39(5). DOI:10.1038/npp.2013.308 · 7.05 Impact Factor
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