1. ¹Laboratori de Neurofarmacologia, Facultat de Ciènces de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain
2. ²Division Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany
3. ³Department of Pharmacology, Faculty of Medicine, University of the Basque Country, Leioa, Bizkaia, Spain
4. ⁴Differentiation and Transcription Laboratory, Peter MacCallum Cancer Institute, East Melbourne, Australia

Correspondence: Dr R Maldonado, Laboratori de Neurofarmacologia, Facultat de Ciènces de la Salut i de la Vida, Universitat Pompeu Fabra, C/ Doctor Aiguader, 80, Barcelona E-08003, Spain. Tel: +34-93-265-14-88; Fax: +34-93-542-28-02; E-mail: rafael.maldonado@upf.edu

⁵These authors contributed equally to this work

Received 19 September 2003; Revised 9 January 2004; Accepted 14 January 2004; Published online 17 March 2004.

Abstract

The transcription factor cAMP-responsive element binding protein (CREB) has been shown to regulate different physiological responses including drug addiction and emotional behavior. Molecular changes including adaptive modifications of the transcription factor CREB are produced during drug dependence in many regions of the brain, including the locus coeruleus (LC), but the molecular mechanisms involving CREB within these regions have remained controversial. To further investigate the involvement of CREB in emotional behavior, drug reward and opioid physical dependence, we used two independently generated CREB-deficient mice. We employed the Cre/loxP system to generate mice with a conditional CREB mutation restricted to the nervous system, where all CREB isoforms are lacking in the brain (Creb1^NesCre). A genetically defined cohort of the previously described hypomorphic Creb1 mice, in which the two major transcriptionally active isoforms ( and ) are disrupted throughout the organism, were also used. First, we investigated the responses to stress of the CREB-deficient mice in several paradigms, and we found an increased anxiogenic-like response in the both Creb1 mutant mice in different behavioral models. We investigated the rewarding properties of drugs of abuse (cocaine and morphine) and natural reward (food) using the conditioned place-preference paradigm. No modification of motivational responses of morphine, cocaine, or food was observed in mutant mice. Finally, we evaluated opioid dependence by measuring the behavioral expression of morphine withdrawal and electrophysiological recordings of LC neurons. We showed an important attenuation of the behavioral expression of abstinence and a decrease in the hyperactivity of LC neurons in both Creb1 mutant mice. Our results emphasize the selective role played by neuronal CREB in emotional-like behavior and the somatic expression morphine withdrawal, without participating in the rewarding properties induced by morphine and cocaine.