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The Journal of Neuroscience, June 25, 2008, 28(26):6642-6651; doi:10.1523/JNEUROSCI.1336-08.2008

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Behavioral/Systems/Cognitive
Corticotropin-Releasing Factor in the Basolateral Amygdala Enhances Memory Consolidation via an Interaction with the β-Adrenoceptor–cAMP Pathway: Dependence on Glucocorticoid Receptor Activation

Benno Roozendaal,¹ Gustav Schelling,² and James L. McGaugh¹

¹Center for the Neurobiology of Learning and Memory, Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697-3800, and ²Department of Anesthesiology, Ludwig Maximilians University, 81377 Munich, Germany

Correspondence should be addressed to Dr. Benno Roozendaal, Center for the Neurobiology of Learning and Memory, Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697-3800. Email: broozend{at}uci.edu

Extensive evidence indicates that stress hormone effects on the consolidation of emotionally influenced memory involve noradrenergic activation of the basolateral complex of the amygdala (BLA). The present experiments examined whether corticotropin-releasing factor (CRF) modulates memory consolidation via an interaction with the β-adrenoceptor–cAMP system in the BLA. In a first experiment, male Sprague Dawley rats received bilateral infusions of the CRF-binding protein ligand inhibitor CRF_6–33 into the BLA either alone or together with the CRF receptor antagonist -helical CRF_9–41 immediately after inhibitory avoidance training. CRF_6–33 induced dose-dependent enhancement of 48 h retention latencies, which was blocked by coadministration of -helical CRF_9–41, suggesting that CRF_6–33 enhances memory consolidation by displacing CRF from its binding protein, thereby increasing "free" endogenous CRF concentrations. In a second experiment, intra-BLA infusions of atenolol (β-adrenoceptor antagonist) and Rp-cAMPS (cAMP inhibitor), but not prazosin (₁-adrenoceptor antagonist), blocked CRF_6–33-induced retention enhancement. In a third experiment, the CRF receptor antagonist -helical CRF_9–41 administered into the BLA immediately after training attenuated the dose–response effects of concurrent intra-BLA infusions of clenbuterol (β-adrenoceptor agonist). In contrast, -helical CRF_9–41 did not alter retention enhancement induced by posttraining intra-BLA infusions of either cirazoline (₁-adrenoceptor agonist) or 8-br-cAMP (cAMP analog). These findings suggest that CRF facilitates the memory-modulatory effects of noradrenergic stimulation in the BLA via an interaction with the β-adrenoceptor–cAMP cascade, at a locus between the membrane-bound β-adrenoceptor and the intracellular cAMP formation site. Moreover, consistent with evidence that glucocorticoids enhance memory consolidation via a similar interaction with the β-adrenoceptor–cAMP cascade, a last experiment found that the CRF and glucocorticoid systems within the BLA interact in influencing β-adrenoceptor–cAMP effects on memory consolidation.

Key words: -helical CRF_9–41; atenolol; CRF; CRF_6–33; CRF-binding protein; corticosterone; emotional arousal; norepinephrine; inhibitory avoidance

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Received Sept. 11, 2007; revised April 28, 2008; accepted May 15, 2008.

Correspondence should be addressed to Dr. Benno Roozendaal, Center for the Neurobiology of Learning and Memory, Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697-3800. Email: broozend{at}uci.edu

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