Han MH, Bolanos CA, Green TA, Olson VG, Neve RL, Liu RJ, Aghajanian GK et al. Role of cAMP response element-binding protein in the rat locus ceruleus: regulation of neuronal activity and opiate withdrawal behavior. J Neurosci 26: 4624-4629

Harvard University, Cambridge, Massachusetts, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2006; 26(17):4624-9. DOI: 10.1523/JNEUROSCI.4701-05.2006
Source: PubMed


The transcription factor cAMP response element-binding protein (CREB) is implicated in mediating the actions of chronic morphine in the locus ceruleus (LC), but direct evidence to support such a role is limited. Here, we investigated the influence of CREB on LC neuronal activity and opiate withdrawal behaviors by selectively manipulating CREB activity in the LC using viral vectors encoding genes for CREBGFP (wild-type CREB tagged with green fluorescent protein), caCREBGFP (a constitutively active CREB mutant), dnCREBGFP (a dominant-negative CREB mutant), or GFP alone as a control. Our results show that in vivo overexpression of CREBGFP in the LC significantly aggravated particular morphine withdrawal behaviors, whereas dnCREBGFP expression attenuated these behaviors. At the cellular level, CREBGFP expression in the LC in vivo and in vitro had no significant effect on neuronal firing at baseline but enhanced the excitatory effect of forskolin (an activator of adenylyl cyclase) on these neurons, which suggests that the cAMP signaling pathway in these neurons was sensitized after CREB expression. Moreover, in vitro studies showed that caCREBGFP-expressing LC neurons fired significantly faster and had a more depolarized resting membrane potential compared with GFP-expressing control cells. Conversely, LC neuronal activity was decreased by dnCREBGFP, and the neurons were hyperpolarized by this treatment. Together, these data provide direct evidence that CREB plays an important role in controlling the electrical excitability of LC neurons and that morphine-induced increases in CREB activity contribute to the behavioral and neural adaptations associated with opiate dependence and withdrawal.

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Available from: George K Aghajanian, Dec 20, 2013
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    • "For example, lesions of LC, or developmental knockout of CREB activity in LC NE neurons, fail to detectably alter withdrawal symptoms (Christie et al. 1997; Parlato et al. 2010). In contrast, we have shown that modulation of the activity of the cAMP pathway or of CREB in LC of adult animals consistently blocks several withdrawal behaviors (Lane-Ladd et al. 1997; Punch et al. 1997; Han et al. 2006). "
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    ABSTRACT: The study of neuronal adaptations induced by opiate drugs is particularly relevant today given their widespread prescription and nonprescription use. Although much is known about the acute actions of such drugs on the nervous system, a great deal of work remains to fully understand their chronic effects. Here, we focus on longer-lasting adaptations that occur in two catecholaminergic brain regions that mediate distinct behavioral actions of opiates: ventral tegmental area (VTA) dopaminergic neurons, important for drug reward, and locus coeruleus (LC) noradrenergic neurons, important for physical dependence and withdrawal. We focus on changes in cellular, synaptic, and structural plasticity in these brain regions that contribute to opiate dependence and addiction. Understanding the molecular determinants of this opiate-induced plasticity will be critical for the development of better treatments for opiate addiction and perhaps safer opiate drugs for medicinal use.
    Cold Spring Harbor Perspectives in Medicine 07/2012; 2(7):a012070. DOI:10.1101/cshperspect.a012070 · 9.47 Impact Factor
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    • "Although the effects of increased neural activity on CREB phosphorylation in corticostriatal circuits has yet to be determined burst of neural activity has been shown to increase p-CREB in hippocampal neurons (Bito et al., 1996). On the other hand, over-expression of CREB in slice culture of the NAC and locus coeruleus (the main source of NE projection to the cortex) neuronal cell types increased membrane excitability (Dong et al., 2006; Han et al., 2006; Huang et al., 2008) whereas decreased CREB activity in the NAC correlated with increased expression of certain K+ channels and reduced electrical excitability of NAC neurons (Wallace et al., 2009). Thus it could not be excluded that these differential changes in p-CREB along the nodes of corticostriatal circuits may reflect differences in neuronal activity driven by contingent or non-contingent performance. "
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    ABSTRACT: The cyclic-adenosine monophosphate response element-binding protein (CREB) family of transcription factors has been implicated in numerous forms of behavioral plasticity. We investigated CREB phosphorylation along some nodes of corticostriatal circuitry such as frontal cortex (FC) and dorsal (caudate-putamen, CPu) and ventral (nucleus accumbens, NAC) striatum in response to the contingent or non-contingent performance of the five-choice serial reaction time task (5-CSRTT) used to assess visuospatial attention. Three experimental manipulations were used; an attentional performance group (contingent, "master"), a group trained previously on the task but for whom the instrumental contingency coupling responding with stimulus detection and reward was abolished (non-contingent, "yoked") and a control group matched for food deprivation and exposure to the test apparatus (untrained). Rats trained on the 5-CSRTT (both master and yoked) had higher levels of CREB protein in the FC, CPu, and NAC compared to untrained controls. Despite the divergent behavior of "master" and "yoked" rats CREB activity in the FC was not substantially different. In rats performing the 5-CSRTT ("master"), CREB activity was completely abolished in the CPu whereas in the NAC it remained unchanged. In contrast, CREB phosphorylation in CPu and NAC increased only when the contingency changed from goal-dependent to goal-independent reinforcement ("yoked"). The present results indicate that up-regulation of CREB protein expression across cortical and striatal regions possibly reflects the extensive instrumental learning and performance whereas increased CREB activity in striatal regions may signal the unexpected change in the relationship between instrumental action and reinforcement.
    Frontiers in Behavioral Neuroscience 10/2011; 5:65. DOI:10.3389/fnbeh.2011.00065 · 3.27 Impact Factor
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    • "Blockade of cAMP response-element binding protein (CREB) in the LC prevents the opioid-induced AC-VIII up-regulation [58]. Such blockade also diminishes the ability of chronic morphine treatment to increase LC neuronal excitability and to induce dependence and withdrawal [58, 60]. An ex vivo LC slice culture system combined with viral-mediated gene transfer and genetic mutant mice provides direct evidence supporting that prolonged morphine exposure induces homeostatic adaptations intrinsic to LC neurons, involving up-regulation of cAMP-CREB pathway, which enhances LC neuronal excitability [61]. "
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