Behavioral control of the stressor modulates stress-induced changes in neurogenesis and fibroblast growth factor-2.

The controllability of stressors modulates many of the consequences of stressor exposure. Here, we used immunohistochemistry to examine neural progenitor cell proliferation and survival and basic fibroblast growth factor-2 in the hippocampus of male rats after controllable or uncontrollable tailshock. A series of identical tailshocks were delivered to yoked pairs of rats. One rat could terminate shocks to both rats of the pair. Reductions in neural progenitor cells were observed at 1-2 days and at 28 days in rats exposed to uncontrollable shock. Controllable shock produced an increase in fibroblast growth factor-2 in the dentate gyrus and CA1 2 h after stress and in the dentate gyrus 24 h after stress. Thus, stressor controllability modulates stress-induced decreases in neurogenesis and increases in fibroblast growth factor-2.

The role of glucocorticoids in the uncontrollable stress-induced potentiation of nucleus accumbens shell dopamine and conditioned place preference responses to morphine.

Exposure to stressors can impact on the responsiveness to drugs of abuse, and glucocorticoid hormones (CORT) may interact with dopamine (DA) within the nucleus accumbens shell (NAcs) to mediate these responses. We have previously shown that the CORT response to morphine, but not to a previous uncontrollable stressor, is necessary for the stress-induced potentiation of morphine's rewarding effects. Here, we test (1) the necessity of CORT during inescapable stress (IS) and/or morphine for IS potentiation of morphine-induced NAcs DA and (2) the sufficiency of enhanced CORT, in the absence of prior IS, to potentiate morphine-induced NAcs DA as well as morphine conditioned place preference (CPP) in male Sprague-Dawley rats. In the first experiment, we administered the CORT synthesis inhibitors metyrapone and aminoglutethimide (100mg/kg each, sc) to suppress the CORT response to either IS (100 1 mA tailshocks) or subsequent morphine (3 mg/kg, sc) treatment. Twenty-four hour after IS, microdialysis was performed and morphine was administered. In the next experiments, CORT (1 mg/kg, sc) was injected 20 or 30 min before morphine during either microdialysis or CPP testing, respectively, in non-stressed rats. We found that IS potentiated subsequent morphine-induced NAcs DA and this was completely blocked by CORT suppression before morphine, but not before IS. However, elevated levels of CORT concurrent with morphine, but in the absence of a stressor, failed to potentiate NAcs DA or CPP. These results suggest that the CORT response to morphine is necessary, but not sufficient in the absence of prior IS, for sensitized NAcs DA and CPP responding to morphine, and provide further evidence that CORT is involved in the expression, but not the induction, of this sensitization.

Expression of c-fos and BDNF mRNA in subregions of the prefrontal cortex of male and female rats after acute uncontrollable stress.

Women exhibit higher lifetime prevalences of stress-related disorders than men. These disorders have been associated with changes in prefrontal cortex structure and function. Here, we examine the effects of acute inescapable stress, an animal model of behavioral depression and post-traumatic stress disorder, on plasma corticosterone (CORT) and on c-fos mRNA and brain-derived neurotrophic factor (BDNF) mRNA in regions of the prefrontal and frontal cortex in male and cycling female rats. Inescapable stress consisted of 100 1 mA tailshocks, and no-stress controls remained in their home cages. Rats were sacrificed immediately (0 min) or 60 min after termination of the stressor. CORT levels were increased at both 0 and 60 min post-stress termination relative to controls, and the increase was greater in females at both time points. c-fos mRNA expression increased at 0 min in prefrontal cortical regions, but this increase was greater in males than estrus and proestrus females. At 60 min, c-fos mRNA levels were lower than at 0 min in males but not females. No correlations between CORT and c-fos mRNA levels in prefrontal regions were observed in females in the stress groups, but significant correlations were observed in males in several prefrontal regions. BDNF mRNA expression was greater in control females than control males. Inescapable stress increased BDNF mRNA expression at 0 but not 60 min in males, but there was no effect of inescapable stress on BDNF mRNA in females. These results reveal sex differences in inescapable stress-induced gene expression that may have implications for differences in vulnerability to stress-related disorders.

Surgical and pharmacological suppression of glucocorticoids prevents the enhancement of morphine conditioned place preference by uncontrollable stress in rats.

RATIONALE: Stress and one of the physiological components of most stress responses, glucocorticoid hormones (CORT), are known to influence the rewarding effects of a number of drugs of abuse. We have previously shown that an acute uncontrollable stressor (inescapable shock, IS) potentiates the rewarding effects of morphine using conditioned place preference (CPP). OBJECTIVES: The following experiments were conducted to determine the role of CORT in this process. METHODS: First, the CORT response to 3.0 mg/kg morphine was measured in male Sprague-Dawley rats 24 h following exposure to IS. Second, we determined the effect of adrenalectomy (ADX) on the IS-potentiated CPP to morphine. Finally, we used the temporary CORT synthesis inhibitors metyrapone and aminoglutethimide to determine the necessity of CORT rises during either IS or morphine administration on the potentiated CPP response. RESULTS: Prior IS significantly potentiated the CORT response to morphine. ADX significantly blocked the potentiated CPP to morphine produced by previous IS. However, CORT inhibition during IS had no effect on the IS potentiation of morphine CPP, whereas inhibition during morphine administration completely blocked this potentiation. CONCLUSIONS: The results indicate that the CORT response to morphine is enhanced in rats that were previously exposed to an uncontrollable stressor, and that this response to the drug, not the stressor, is necessary for the stress-enhanced potentiation of morphine CPP.

Prefrontal cortex serotonin, stress, and morphine-induced nucleus accumbens dopamine.

Uncontrollable, but not controllable, stress produces a persistent potentiation of morphine-induced nucleus accumbens dopamine (DA) efflux and morphine-induced medial prefrontal cortex serotonin (5-HT) efflux. Here we investigate medial prefrontal cortex 5-HT mediation of this potentiation. Male Sprague-Dawley rats received bilateral medial prefrontal cortex microinjections of the neurotoxin 5,7-dihydroxytriptamine (5,7-DHT, 8 microg/microl/side), which selectively depleted medial prefrontal cortex 5-HT, or vehicle (Sham), and cannula implantation in the nucleus accumbens shell. After 2 weeks, rats received either uncontrollable stress or no stress. Microdialysis and morphine (3 mg/kg) treatment were performed the following day. Morphine produced an enhanced increase in DA in the Stress-Sham group that was completely blocked by 5,7-DHT lesions, suggesting that 5-HT in the medial prefrontal cortex mediates this potentiation.

Corticotropin releasing hormone type 2 receptors in the dorsal raphe nucleus mediate the behavioral consequences of uncontrollable stress.

Uncontrollable shock produces a constellation of behavioral changes that are not observed after equivalent escapable shock. These include interference with escape and potentiation of fear conditioning. The activation of corticotropin-releasing hormone (CRH) receptors within the caudal dorsal raphe nucleus (DRN) during inescapable tailshock (IS) has been shown to be critical for the development of these behavioral changes. CRH binds to two receptor subtypes, both of which are found in the DRN. The present set of studies examined which CRH receptor subtype mediates the effects of IS. Intra-DRN administration of the CRH(2) receptor antagonist anti-sauvagine-30 before IS dose-dependently blocked IS-induced behavioral changes; the CRH(1) receptor antagonist 2-methyl-4-(N-propyl-N-cycloproanemethylamino)-5-chloro-6-(2,4,6-trichloranilino)pyrimidine (NBI27914), administered in the same manner, did not. Moreover, the highly selective CRH(2) receptor agonist urocortin II (Ucn II) dose-dependently caused behavioral changes associated with IS in the absence of shock. Ucn II was effective at doses 100-fold lower than those previously required for CRH. The relationship between CRH(2) receptors and DRN 5-HT is discussed.

The role of corticotropin-releasing hormone in the dorsal raphe nucleus in mediating the behavioral consequences of uncontrollable stress.

Inescapable shock (IS) produces subsequent interference with escape behavior and increased fear conditioning that has been linked to increased activity and release of serotonin (5-HT) from neurons within the caudal dorsal raphe nucleus (DRN) both at the time of IS and later behavioral testing. Extrahypothalamic corticotropin-releasing hormone (CRH) has been implicated in many stress-related phenomena and has recently been shown to increase DRN 5-HT activity in the same caudal DRN area at which IS increases 5-HT activity. The current set of studies therefore examined the role of CRH in mediating the behavioral sequelae of IS. Intra-DRN microinjection of the nonselective CRH receptor antagonist d-Phe CRH (12-41) blocked the IS-induced behavioral changes when administered before IS but not when administered before later behavioral testing. Furthermore, intra-DRN administration of CRH in the absence of IS dose-dependently mimicked the effects of IS and interfered with escape behavior and increased fear conditioning 24 hr later. This effect was specific to injection of CRH into the caudal DRN and was not produced by microinjection into the rostral DRN. Intracerebroventricular CRH produced escape deficits and potentiated fear conditioning 24 hr later at only much higher doses, further confirming the site specificity of the effects. The potential role of the caudal DRN in states of anxiety is discussed.