Modulation of Anxiety-Like Behavior and Morphine Dependence in CREB-Deficient Mice

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 aD mice, in which the two major transcriptionally active isoforms (a and D) 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.

Deficits in amygdaloid cAMP-responsive element–binding protein signaling play a role in genetic predisposition to anxiety and alcoholism

“…We reported earlier that CREB-haplodeficient mice have lower levels of NPY throughout the brain, display higher anxiety-like behaviors, and also have higher preference for alcohol (31). Other investigators have shown that decreased CREB may be involved in anxiety-like behaviors (29,55,56). We also reported earlier that decreased CREB phosphorylation and NPY expression in the CeA might be involved in anxiety-like behaviors during ethanol withdrawal in an unselected stock of rats (30,57).…”

Neuronal Nitric Oxide Synthase Alteration Accounts for the Role of 5-HT1AReceptor in Modulating Anxiety-Related Behaviors

“…We propose that CREB, a well known nuclear transcription factor, is the target of nNOS for its roles in modulating anxiety-like behaviors in several paradigms (Valverde et al, 2004). In the present study, 5-HT 1A R agonist promoted CREB phosphorylation, whereas 5-HT 1A R antagonist reduced CREB phosphorylation in vitro and in vivo, suggesting a link between 5-HT 1A R activation and CREB phosphorylation.…”

“…nNOS is required for 5-HT 1A R-mediated CREB phosphorylation CREB knock-out mice exhibited increase in anxiety-like behaviors (Valverde et al, 2004). Neuronal NOS controls CREBmediated gene expression in neurons (Riccio et al, 2006).…”

Regulation of anxiety and initiation of sexual behavior by CREB in the nucleus accumbens

“…Moreover, virus-mediated expression of a dominant negative mutant of CREB revealed that local inhibition of CREB activity in the nucleus acccumbens potentiates behavioral responses to emotional stimuli, such as the rewarding effects of drugs of abuse (14,19), but also increases anxiety-like behavior (19). Transgenic mice deficient in CREB expression in the CNS also exhibit an increased-anxiety phenotype (31).…”