Corticotropin releasing hormone type 2 receptors in the dorsal raphe nucleus mediate the behavioral consequences of uncontrollable stress - PubMed (original) (raw)

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

Sayamwong E Hammack et al. J Neurosci. 2003.

Abstract

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.

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Figures

Fig. 1.

Procedure for measuring escape and fear behavior in the same subject.

Fig. 2.

A, Mean shuttlebox escape latencies for FR-1 trials and five blocks of FR-2 trials. Rats either received IS or were left in their home cages 24 hr previously. Rats also received an intra-DRN injection of 0.1, 0.5, or 1.0 nmol of the CRH1receptor antagonist NBI27914 or vehicle 15 min before IS treatment.B, Mean number of 8 sec periods in which freezing occurred across 2 min blocks, after two shocks in a shuttlebox. Rats either received IS or were left in their home cages 24 hr previously. Rats also received an intra-DRN injection of 0.1, 0.5, or 1.0 nmol of the CRH1 receptor antagonist NBI27914 or vehicle 15 min before IS treatment. Open squares, Home cage plus vehicle; open triangles, home cage plus 0.1 nmol of NBI27914; open diamonds, home cage plus 0.5 nmol of NBI27914; open circles, home cage plus 1 nmol of NBI27914; filled squares, IS plus vehicle; filled triangles, IS plus 0.1 nmol of NBI27914; filled diamonds, IS plus 0.5 nmol of NBI27914; filled circles, IS plus 1 nmol of NBI27914.

Fig. 3.

CeA injection placements for rats injected with 0.5 nmol of NBI27914 per side. Each circle represents the center of one dye injection.

Fig. 4.

Mean number of 8 sec periods in which freezing occurred across 2 min blocks, after two shocks in a shuttlebox. Rats received 0.5 nmol of NBI27914 per side or equivolume vehicle into the CeA 15 min before the two shocks. Although NBI27914 did not affect IS-induced behavioral changes when injected into the DRN, it suppressed fear conditioning when injected into the amygdala. Filled squares, NBI27914; open squares, vehicle.

Fig. 5.

DRN injection placements for rats injected with 1 nmol of anti-sauvagine-30. Each circle represents the center of one dye injection.

Fig. 6.

A, Mean shuttlebox escape latencies for FR-1 trials and five blocks of FR-2 trials. Rats received either inescapable shock or were left in their home cages 24 hr previously. Rats also received an intra-DRN injection of 0.1, 0.5, or 1.0 nmol of the CRH2 receptor antagonist anti-sauvagine-30 or vehicle 15 min before IS treatment. B, Mean number of 8 sec periods in which freezing occurred across 2 min blocks, after two shocks in a shuttlebox. Rats received either inescapable shock or were left in their home cages 24 hr previously. Rats also received an intra-DRN injection of 0.1, 0.5, or 1.0 nmol of the CRH2receptor antagonist anti-sauvagine-30 or vehicle 15 min before IS treatment. Open squares, Home cage plus vehicle;open triangles, home cage plus 0.1 nmol of ASV-30;open triangles, home cage plus 0.5 nmol of ASV-30;open circles, home cage plus 1 nmol of ASV-30;filled squares, IS plus vehicle; filled triangles, IS plus 0.1 nmol of ASV-30; filled diamonds, IS plus 0.5 nmol of ASV-30; filled circles, IS plus 1 nmol of ASV-30.

Fig. 7.

A, Mean shuttlebox escape latencies for FR-1 trials and five blocks of FR-2 trials. Rats either received 0.021 nmol (87 ng), 0.0021 nmol (8.7 ng), or 0.00021 nmol (0.87 ng) of the CRH2 receptor agonist Ucn II or saline vehicle into the DRN 24 hr previously. B, Mean number of 8 sec periods in which freezing occurred across 2 min blocks, after two shocks in the shuttlebox. Filled squares, Vehicle;filled diamonds, 0.00021 nmol of Ucn II; filled circles, 0.0021 nmol of Ucn II; filled triangles, 0.021 nmol of Ucn II.

Fig. 8.

At 24 hr after 0.021 nmol (87 ng) of Ucn II or equivolume vehicle injection into the DRN, locomotor activity was scored in 5 min blocks for 50 min. Ucn II injection did not reliably alter locomotor activity tested 24 hr after injection. White columns, Ucn II; black columns, vehicle.

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Corticotropin releasing hormone type 2 receptors in the dorsal raphe nucleus mediate the behavioral consequences of uncontrollable stress - PubMed (original) (raw)