Regulation of a putative neurotransmitter effect of corticotropin-releasing factor: effects of adrenalectomy - PubMed (original) (raw)
Regulation of a putative neurotransmitter effect of corticotropin-releasing factor: effects of adrenalectomy
L A Pavcovich et al. J Neurosci. 1997.
Abstract
This study tested the hypothesis that endogenous glucocorticoids regulate a putative neurotransmitter function of corticotropin-releasing factor (CRF) in the locus coeruleus (LC). LC spontaneous discharge and activation by intracerebroventricularly administered CRF, hypotensive challenge, sciatic nerve stimulation, and carbachol were compared in adrenalectomized and sham-operated halothane-anesthetized rats. LC spontaneous discharge was higher in adrenalectomized versus sham-operated rats. Intracoerulear microinfusion of a CRF antagonist decreased LC discharge rates of adrenalectomized rats to rates comparable with those observed in sham-operated rats but had no effect in sham-operated rats. The CRF dose-response curve was shifted in a complex manner in adrenalectomized rats, suggesting that a proportion of CRF receptors were occupied before CRF administration, and low doses of CRF were additive. Higher doses of CRF produced effects that were greater than predicted by simple additivity. Hypotensive challenge increased LC discharge rates of adrenalectomized rats by a magnitude greater than that predicted on the basis of additivity. In contrast, LC responses to carbachol and sciatic nerve stimulation were similar in both groups. The results suggest that adrenalectomy enhances tonic and stress-induced CRF release within the LC and also alters postsynaptic sensitivity of LC neurons to CRF. Because adrenalectomy also alters release of neurohormone CRF, the present study suggests that CRF actions as a neurohormone and as a neurotransmitter in the LC may be co-regulated. Such parallel regulation may underlie the coexistence of neuroendocrine and noradrenergic dysfunctions in stress-related psychiatric disorders.
Figures
Fig. 1.
LC spontaneous discharge rate and effects of DPheCRF12–41 in sham-operated (solid bars) and adrenalectomized (open bars) rats. The ordinate indicates LC discharge rate (Hz). Bars_indicate the mean discharge rate for 126 neurons in sham-operated rats and 162 LC neurons in adrenalectomized rats (ALL CELLS); or eight cells in sham-operated and six cells in adrenalectomized rats before (Pre) and 3 min after (Post) DPheCRF12–41. Vertical lines represent ± 1 SEM; *p < 0.05, **p < 0.001, t test for independent samples, comparison between sham-operated and adrenalectomized rats; Zv_p < 0.02, t test for matched pairs, comparison between Pre and Post.
Fig. 2.
Time course of the effect of DPheCRF12–41. A, Continuous chart record of LC discharge rate before and after intracoerulear infusion of DPheCRF12–41 (10 ng in 30 nl). The abscissae indicate time (s). The ordinates indicate LC discharge rate (Hz). The time of infusion is indicated by the_bar_ and D above the traces. The_solid horizontal line_ represents the mean LC discharge rate determined over 6 min before DPheCRF12–41 infusion.Top and bottom traces were from single neurons recorded in a sham-operated and adrenalectomized rat, respectively. B, Mean effect of DPheCRF12–41 in sham-operated (solid symbols, n = 8) versus adrenalectomized rats (open symbols, n = 6). The abscissa indicates time after DPheCRF12–41 infusion. The ordinate indicates the change in LC discharge rate from baseline (Hz). The effects of DPheCRF12–41 were significantly different in adrenalectomized versus sham-operated rats (F(1,97) = 8.3, p < 0.02). Additionally, DPheCRF12–41 significantly decreased LC discharge rate in adrenalectomized (F(5,41) = 4.9, p < 0.002) but not sham-operated (F(7,55) = 0.72) rats.
Fig. 3.
CRF dose–response curves in sham-operated and adrenalectomized rats. The abscissa indicates the dose of CRF_(log scale_), and the ordinate indicates the increase in LC discharge above pre-CRF rates (Δ Hz). Solid symbols represent experimental data, and open symbols represent theoretical curves. Solid circles show the CRF dose–response curve generated in sham-operated rats. Solid squares represent the experimentally determined CRF dose–response curve in adrenalectomized rats. Each point represents the mean of 4–10 cells, vertical lines represent mean ± 1 SEM. _Open circles_represent the theoretical curve based on the equation E =_E_max[CRF]/ED50 + [CRF] and assuming that _E_max = 1.25 Hz and ED50 = 0.82 μg. Open squares represent the theoretical curve that would be expected in adrenalectomized rats based on additivity, E = (_E_max[CRF + 0.8]/_K_d + [CRF + 0.8]) − 0.6.
Fig. 4.
Effect of hypotensive challenge on LC discharge rate and mean arterial blood pressure in sham-operated (solid circles) and adrenalectomized (open circles) rats. The abscissae indicate time (min). Nitroprusside was administered from 0 to 15 min, as indicated by the_bar_ above the abscissae. A, The ordinate indicates the change in LC discharge rate above the baseline rate determined over 9 min before nitroprusside infusion. Each point is the mean of at least five rats. _Vertical lines_represent ± 1 SEM. Hypotensive challenge increased LC discharge rates in both adrenalectomized and sham-operated rats (F(5,41) = 4.9, p < 0.001 and F(4,29) = 6.7,p < 0.01, respectively), and the magnitude of the increase was not different (F(1,9) = 0.15). Mean LC discharge rates before nitroprusside infusion were 1.5 ± 0.2 and 3.1 ± 0.4 for sham-operated and adrenalectomized rats, respectively. B, The ordinate indicates mean arterial blood pressure (mm Hg). The magnitude of hypotension produced by nitroprusside infusion was similar in adrenalectomized and sham-operated rats (F(1,101) = 2.06,p = 0.17).
Fig. 5.
LC activation by sciatic nerve stimulation (A) and carbachol (B) in sham-operated (solid bars) versus adrenalectomized (open bars) rats. A, The ordinate represents LC discharge rate (Hz). Bars represent the mean rate during the tonic and evoked components of the LC response to repeated sciatic nerve stimulation for 21 neurons of sham-operated and adrenalectomized rats. Vertical lines represent mean ± 1 SEM *p < 0.05, _t_test for independent samples. B, The ordinate indicates the increase in LC discharge rate above the mean discharge rate determined over 9 min before carbachol (0.09 μg, i.c.v.) administration. Bars are the mean of eight rats in both sham-operated and adrenalectomized groups. Carbachol produced a similar increase in LC discharge rate in both groups of rats (_t_test, independent samples). The mean LC discharge rates before carbachol administration were 1.6 ± 0.2 and 2.4 ± 0.4 Hz for sham-operated and adrenalectomized rats, respectively.
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