Quantification of extracellular levels of corticosterone in the basolateral amygdaloid complex of freely-moving rats: a dialysis study of circadian variation and stress-induced modulation.

Corticosterone influences emotion and cognition via actions in a diversity of corticolimbic structures, including the amygdala. Since extracellular levels of corticosterone in brain have rarely been studied, we characterized a specific and sensitive enzymatic immunoassay for microdialysis quantification of corticosterone in the basolateral amygdaloid complex of freely-moving rats. Corticosterone levels showed marked diurnal variation with an evening (dark phase) peak and stable, low levels during the day (light phase). The "anxiogenic agents", FG7142 (20 mg/kg) and yohimbine (10 mg/kg), and an environmental stressor, 15-min forced-swim, induced marked and sustained (1-3 h) increases in dialysis levels of corticosterone in basolateral amygdaloid complex. They likewise increased dialysis levels of dopamine and noradrenaline, but not serotonin and GABA. As compared to basal corticosterone levels of ~200-300 pg/ml, the elevation provoked by forced-swim was ca. 20-fold and this increase was abolished by adrenalectomy. Interestingly, stress-induced rises of corticosterone levels in basolateral amygdaloid complex were abrogated by combined but not separate administration of the corticotrophin releasing factor(1) (CRF(1)) receptor antagonist, CP154,526, and the vasopressin(1b) (V(1b)) receptor antagonist, SSR149,415. Underpinning their specificity, they did not block forced-swim-induced elevations in dopamine and noradrenaline. In conclusion, extracellular levels of corticosterone in the basolateral amygdaloid complex display marked diurnal variation. Further, they are markedly elevated by acute stressors, the effects of which are mediated (in contrast to concomitant elevations in levels of monoamines) by co-joint recruitment of CRF(1) and V(1b) receptors.

Neurokinin1 antagonists potentiate antidepressant properties of serotonin reuptake inhibitors, yet blunt their anxiogenic actions: a neurochemical, electrophysiological, and behavioral characterization.

Though neurokinin(1) (NK(1)) receptor antagonists are active in experimental models of depression, clinical efficacy has proven disappointing. This encourages interest in association of NK(1) receptor blockade with inhibition of serotonin (5-HT) reuptake. The selective NK(1) antagonist, GR205171, dose-dependently enhanced citalopram-induced elevations of extracellular levels of 5-HT in frontal cortex, an action expressed stereospecifically vs its less active distomer, GR226206. Further, increases in 5-HT levels in dorsal hippocampus, basolateral amygdala, nucleus accumbens, and striatum were likewise potentiated, and GR205171 similarly facilitated the influence of fluoxetine upon levels of 5-HT, as well as dopamine and noradrenaline. In parallel electrophysiological studies, the inhibitory influence of citalopram and fluoxetine upon raphe-localized serotonergic neurones was stereospecifically blunted by GR205171. Antidepressant actions of citalopram in a forced-swim test in mice were stereospecifically potentiated by GR205171, and it also enhanced attenuation by citalopram of stress-related ultrasonic vocalizations in rats. Further, GR205171 and citalopram additively abrogated the advance in circadian rhythms provoked by exposure to light in hamsters. By contrast, GR205171 stereospecifically blocked anxiogenic actions of citalopram in social interaction procedures in rats and gerbils, and stereospecifically abolished facilitation of fear-induced foot tapping by fluoxetine in gerbils. By analogy to GR205171, a further NK(1) antagonist, RP67580, enhanced the influence of citalopram upon frontocortical levels of 5-HT and potentiated its actions in the forced swim test. In conclusion, NK(1)receptor blockade differentially modulates functional actions of SSRIs: antidepressant properties are reinforced, whereas anxiogenic effects are attenuated. Combined NK(1) receptor antagonism/5-HT reuptake inhibition may offer advantages in the management of depressed and anxious states.

Partial recovery of dopaminergic pathway after graft of adult mesenchymal stem cells in a rat model of Parkinson's disease.

Cellular therapy with adult stem cells appears as an opportunity for treatment of Parkinson's disease. To validate this approach, we studied the effects of transplantation of rat adult bone-marrow mesenchymal stem cells in a rat model of Parkinson's disease. Animals were unilaterally lesioned in the striatum with 6-hydroxydopamine. Two weeks later, group I did not undergo grafting, group II underwent sham grafting, group III was intra-striatal grafted with cells cultured in an enriched medium and group IV was intra-striatal grafted with cells cultured in a standard medium. Rotational amphetamine-induced behavior was measured weekly until animals were killed 6 weeks later. One week after graft, the number of rotations/min was stably decreased by 50% in groups III and IV as compared with groups I and II. At 8 weeks post-lesion, the density of dopaminergic markers in the nerve terminals and cell bodies, i.e. immunoreactive tyrosine hydroxylase, membrane dopamine transporter and vesicular monoamine transporter-2 was significantly higher in group III as compared with group I. Moreover, using microdialysis studies, we observed that while the rate of pharmacologically induced release of dopamine was significantly reduced in lesioned versus intact striatum in no grafted rats, it was similar in both sides in animals transplanted with mesemchymal stem cells. These data demonstrate that graft of adult mesemchymal stem cells reduces behavioral effects induced by 6-hydroxydopamine lesion and partially restores the dopaminergic markers and vesicular striatal pool of dopamine. This cellular approach might be a restorative therapy in Parkinson's disease.