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).
In addition to the magnocellular hypothalamic nuclei, arginine vasopressin (AVP)-containing neurons have also been identified in limbic structures, including the hippocampus and amygdala. In the present study, we compared the qualitative properties of the in vitro release of AVP from the dissected hypothalamus with the in vitro release from the dissected amygdala and used these release systems to evaluate the interactions with neurotransmitters and cytokines. The areas of the paraventricular nucleus and supraoptic nucleus that contain the AVP neurons and that receive cholinergic innervation are also interleukin (IL)-1β immunoreactive. Acetylcholine or high KC1 (60 mM) induces AVP release in both regions, and the AVP release is calcium dependent. Acetylcholine-induced AVP release is antagonized by atropine or meca-mylamine, indicating that both muscarinic and nicotinic receptors are mediating the cholinergic effect in these brain regions. IL-1β (100 U/ml) had no effect on the basal AVP release from the hypothalamus, but significantly potentiated the acetylcholine-induced AVP release, lowering the threshold from 500 to 100 nM. This effect was completely blocked in the presence of neutralizing antibodies to IL-1β, atropine (10 µM) or mecamylamine (10 µM). IL-6, like IL-1β, also potentiated acetylcholine-induced AVP release, but to a lesser extent. Neither tumor necrosis factor-α nor interferon-γ had any effect on the basal or acetylcholine-induced AVP release from the hypothalamus. None of the cytokines tested had any effect on the basal or acetylcholine-induced AVP release from the amygdala. Our results suggest a hypothalamic site of action of IL-1β and IL-6 on the acetylcholine-induced AVP release. The stimulatory effects of IL-1 and IL-6 on adrenocorticotropin release have been ascribed to an increased release of corticotropin-releasing factor (CRF). These data further suggest that, in addition to CRF, AVP plays a role in the bidirectional communication between neuroendocrine and immune systems. Understanding the mode of interaction between IL-lβ and IL-6 with AVP could clarify pathophysiologic or toxic effects of high brain levels of these cytokines.
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