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Science 18 December 1998:
Vol. 282. no. 5397, pp. 2272 - 2275
DOI: 10.1126/science.282.5397.2272
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Reports

Regulation of Cocaine Reward by CREB

William A. Carlezon Jr., Johannes Thome, Valerie G. Olson, Sarah B. Lane-Ladd, Edward S. Brodkin, Noboru Hiroi, Ronald S. Duman, Rachael L. Neve, Eric J. Nestler *

Cocaine regulates the transcription factor CREB (adenosine 3',5'-monophosphate response element binding protein) in rat nucleus accumbens, a brain region that is important for addiction. Overexpression of CREB in this region decreases the rewarding effects of cocaine and makes low doses of the drug aversive. Conversely, overexpression of a dominant-negative mutant CREB increases the rewarding effects of cocaine. Altered transcription of dynorphin likely contributes to these effects: Its expression is increased by overexpression of CREB and decreased by overexpression of mutant CREB. Moreover, blockade of kappa  opioid receptors (on which dynorphin acts) antagonizes the negative effect of CREB on cocaine reward. These results identify an intracellular cascade--culminating in gene expression--through which exposure to cocaine modifies subsequent responsiveness to the drug.

W. A. Carlezon Jr., J. Thome, V. G. Olson, S. B. Lane-Ladd, E. S. Brodkin, N. Hiroi, R. S. Duman, E. J. Nestler, Division of Molecular Psychiatry, Center for Genes and Behavior, Yale University School of Medicine and Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06508, USA. R. L. Neve, Department of Genetics, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02178, USA.
*   To whom correspondence should be addressed.

Cocaine causes complex molecular adaptations in brain reward systems, some of which affect its addictive qualities (1). For example, chronic cocaine use increases formation of adenosine 3',5'-monophosphate (cAMP) and activity of cAMP-dependent protein kinase (PKA) in the nucleus accumbens (2), a neural substrate for the rewarding actions of cocaine (3, 4). Stimulation of PKA in the nucleus accumbens counteracts the rewarding properties of cocaine (5), which suggests a neural mechanism of drug tolerance. Increased PKA activity would be expected to lead to increased phosphorylation of CREB, which mediates many of the effects of cAMP and PKA on gene expression (6, 7). However, direct evidence for a role of CREB in cocaine actions has been lacking. To address this issue, we selectively induced CREB overexpression in the nucleus accumbens with microinjections of a herpes simplex virus vector (HSV-CREB) and measured alterations in the rewarding properties of cocaine with place conditioning (8). We performed the same experiments in other rats after overexpression of a dominant negative mutant CREB (mCREB) (8), which contains a single point mutation (Ala for Ser at residue 133) that prevents its phosphorylation and transactivation (6).

In our place conditioning protocol, control rats given intraperitoneal (ip) injections of cocaine at 5.0 mg/kg or more spend significantly more time in environments previously associated with the drug, whereas cocaine at 1.25 mg/kg or less does not reliably affect preferences. The effect of cocaine at 1.25 mg/kg was not altered by bilateral microinjections (9) of vehicle (10% sucrose) or of HSV-LacZ (expressing beta -galactosidase, a control protein) (10) into the nucleus accumbens shell (Fig. 1A), an especially sensitive substrate of drug reward (4, 11). However, this threshold dose of cocaine established conditioned place preferences in rats microinjected with HSV-mCREB. The rewarding effect was "inversed" to place avoidance in rats given HSV- CREB, which suggests that this dose of cocaine was made aversive by increased quantities of CREB in this region. Qualitatively similar differences were observed between animals given HSV-CREB and HSV-mCREB into the core subregion of the nucleus accumbens, although the effects--particularly the rewarding effect of HSV-mCREB--were less reliable and not statistically significant (Fig. 1B). The effects of gene transfer were transient: when cocaine was administered a week (rather than 3 days) after HSV treatment, cocaine was devoid of rewarding or aversive effects (Fig. 1C). This finding is consistent with our previous observations (12) that the behavioral consequences of HSV viral vectors are transient and reversible and have a time course that parallels that of transgene expression (see below).

Fig. 1. Sensitivity to cocaine after gene transfer. (A) Rats spent significantly less time in cocaine-associated environments after microinjections of HSV-CREB into the nucleus accumbens shell but significantly more time after similar microinjections of HSV-mCREB (mean ± SEM) (treatment × days interaction: F3,25 = 4.16, P < 0.02). (B) Effects were not statistically reliable with nucleus accumbens core microinjections (treatment × days interaction: F1,12 = 2.70, not significant). (C) Differences between groups did not persist when place conditioning occurred on day 7 or 8 rather than on day 3 or 4 after gene transfer (treatment × days interaction: F1,14 = 0.16, not significant). (D) Dose dependency of changes in effects of cocaine expressed as change (before minus after) in time spent in the cocaine-associated environment. Effects of cocaine depended on vector treatment and dose (treatment × dose interaction: F4,67 = 2.77, P < 0.05). In rats given vehicle microinjections, cocaine was rewarding at 5.0 mg/kg only. In rats given HSV-mCREB, cocaine was maximally rewarding at 1.25 mg/kg. In rats given HSV-CREB, cocaine was maximally aversive at 1.25 mg/kg, whereas higher doses occasionally established place preferences. Groups consisted of 7 to 11 rats; *P < 0.05 compared with vehicle, ††P < 0.01 compared with HSV-mCREB (Fisher's t test). NASh, nucleus accumbens shell; NACo, nucleus accumbens core. [View Larger Version of this Image (34K GIF file)]

Dose-response analyses suggested that HSV-mCREB and HSV-CREB were producing, respectively, approximately parallel leftward (more rewarding) and rightward (less rewarding) shifts in the effects of cocaine (Fig. 1D). At a high dose of cocaine (5.0 mg/kg), rats given HSV-mCREB and those given vehicle displayed equivalent place preferences, which is consistent with previous observations that there is an upper limit to the magnitude of place preferences that can be observed in this model (8). In rats given HSV-CREB, cocaine at 5.0 mg/kg was less aversive than at 1.25 mg/kg; this suggests a rightward shift in the effects of cocaine and that higher concentrations of cocaine can counteract the aversive consequences of increased amounts of CREB.

Histological examination confirmed viral-mediated gene expression. Vector microinjections intended for the nucleus accumbens shell were aimed at the ventromedial region of the nucleus accumbens, whereas those intended for the nucleus accumbens core were aimed more laterally (Fig. 2A). In rats given HSV-LacZ (Fig. 2B), expression of beta -galactosidase (13) peaked between days 3 and 4, was restricted to an area of the nucleus accumbens of ~1.5 mm in diameter, and was accompanied by minimal damage (for example, gliosis) (Fig. 2C) that was indistinguishable from that caused by microinjection of vehicle. On day 3, about 2000 beta -galactosidase-labeled cells were visible in the area of the injection. In rats given HSV-CREB, moderate numbers of highly CREB-immunoreactive cells (13) were observed at the injection site (Fig. 2, D and E); however, the number of neurons overexpressing CREB is likely underrepresented because the immunohistochemical conditions used minimized detection of endogenous CREB. CREB immunoreactivity did not increase in rats given HSV-LacZ, confirming that increased CREB expression is not a nonspecific reaction to surgery or viral infection. Although there has been concern about potential toxicity of viral vectors (12), there was little evidence of gliosis found with Nissl staining (as in Fig. 2C). Moreover, there was no detectable toxicity on the dopamine-containing terminals in the nucleus accumbens (Fig. 2F), the proximate neural substrate of the rewarding actions of cocaine (3, 4). Viral-mediated expression of mCREB was immunohistochemically indistinguishable from that of CREB (Fig. 2G), as expected because the antibody used cannot distinguish between CREB and mCREB. Expression of LacZ, CREB, and mCREB transgenes in the nucleus accumbens dissipated by day 7, consistent with previous in vitro and in vivo studies (10, 12).

Fig. 2. Histological examination of nucleus accumbens after gene transfer. (A) Schematic of nucleus accumbens (9). Red box shows field of view in (B), (C), (D), and (F); blue box shows field of view in (G). (B) Expression of beta -galactosidase 3 days after unilateral microinjection of HSV-LacZ (×25) (13). Brain slices were reacted in sodium phosphate buffer solution (pH 7.4) containing 5-bromo-4-chloro-3-indolyl beta -D-galactopyranoside (0.2 mg/ml; American Bioanalytical). (C) An adjacent, Nissl-stained slice from the same brain. (D) Expression of CREB 3 days after microinjection of HSV-CREB into the right nucleus accumbens shell (13). (E) Higher magnification (×100) of the injection site in (D), showing nuclear localization of CREB expression. (F) Tyrosine hydroxylase expression (13) in a slice adjacent to that in (D). (G) Expression of mCREB 3 days after injection of HSV-mCREB into the right nucleus accumbens core (×100), using the same antibody to CREB as in (D). AC, anterior commissure; NASh, nucleus accumbens shell; NACo, nucleus accumbens core; ICj, Islands of Calleja. [View Larger Version of this Image (124K GIF file)]

Although the effects of CREB on nucleus accumbens neurons (and hence on cocaine reward) are likely mediated via many targets, we focused on the effects of HSV-CREB and HSV-mCREB on expression of dynorphin, an endogenous ligand of kappa  opioid receptors (14). The dynorphin gene is known to be CREB regulated in vitro (7), and repeated cocaine administration increases its expression in the nucleus accumbens and dorsal striatum (15). Microinjections of a kappa  opioid agonist into the nucleus accumbens establish place aversions (16) that are qualitatively similar to those observed in this study with cocaine in animals given HSV-CREB (Fig. 1A). Northern blot analysis (17) 3 days after treatment with HSV vectors revealed a 42% increase in dynorphin mRNA in rats overexpressing CREB and a 33% decrease in dynorphin mRNA in rats overexpressing mCREB (Fig. 3). These results show that CREB regulates dynorphin expression in the nucleus accumbens in vivo.

Fig. 3. Northern blot of dynorphin (DYN) mRNA in nucleus accumbens shell after gene transfer. L, LacZ; C, CREB; mC, mCREB. Dynorphin mRNA concentrations were significantly increased by HSV-CREB and significantly decreased by HSV-mCREB (F2,15 = 13.4, P < 0.001). Data are expressed as percentage (mean ± SEM) of HSV-LacZ and are corrected for cyclophilin (CYC) mRNA content. *P < 0.05 compared with HSV-LacZ (Fisher's t test). [View Larger Version of this Image (28K GIF file)]

To determine whether increased dynorphin expression is involved in cocaine aversions caused by HSV-CREB, we blocked brain kappa  receptors with intracerebroventricular microinjection of the irreversible kappa  receptor antagonist norBNI (18). Treatment with norBNI before cocaine place conditioning blocked the aversive effects associated with a 1.25-mg/kg dose of cocaine in animals given HSV-CREB into the nucleus accumbens shell but did not have a significant effect in rats given microinjections of vehicle or HSV-mCREB (Fig. 4). The fact that only the aversive properties of cocaine are altered by norBNI suggests that microinjections of HSV-CREB into the nucleus accumbens shell enhance the aversive aspects of cocaine by promoting dynorphin actions at kappa  opioid receptors.

Fig. 4. Effects of norBNI (5.0 µg, intracerebroventricularly) on cocaine (1.25 mg/kg, ip) place conditioning in rats given gene transfer, expressed as change (before minus after) in time spent in the cocaine-associated environment. The effects of norBNI on place conditioning depended on HSV vector treatment (vector × intracerebroventricular treatment interaction: F2,45 = 4.77, P < 0.02). Aversive effects of cocaine were blocked by norBNI in rats given HSV-CREB but were not significantly altered in rats given HSV-mCREB or vehicle. Groups consisted of 7 to 10 rats; **P < 0.01 compared with HSV-CREB/no intracerebroventricular (ICV) treatment (Fisher's t test). [View Larger Version of this Image (21K GIF file)]

Our results indicate that kappa  opioid receptors are involved in cocaine valence (reward versus aversion) and suggest that CREB-mediated transcription in the nucleus accumbens shell serves as a "drug reward rheostat" in part via effects on dynorphin expression (15, 19). Moreover, they suggest a sequence of intracellular events, initiated by drug administration and culminating in altered gene transcription, through which previous exposure to cocaine can influence the subsequent subjective qualities of the drug. Repeated exposure to cocaine causes an up-regulation of dynorphin expression through stimulation of dopamine D1-type receptors and the cAMP pathway (2, 7, 15). Upon subsequent exposure to cocaine, augmented release of dynorphin could inhibit local dopamine release through actions at kappa  opioid receptors on terminals of mesolimbic dopaminergic neurons that innervate the nucleus accumbens (19, 20). Diminished release of dopamine in the nucleus accumbens may be aversive, or it may unmask other actions of cocaine that oppose drug reward (3, 21).

With repeated use of cocaine in humans, rewarding effects of the drug reportedly diminish and are overshadowed by unpleasant side effects including anxiety and irritability (22). Our data provide evidence that cocaine-induced increases in CREB and dynorphin in the forebrain could contribute to these changes. Indeed, cocaine users exhibit increased expression of dynorphin mRNA in the nucleus accumbens (23). Up-regulation of CREB-mediated transcription in the nucleus accumbens may counteract positive feedback-type adaptations that tend to intensify drug reward [for example, see (12, 24)]. Sensitization to the reward-related properties of psychostimulants also contributes importantly to addictive behavior (25). Individual variability in the balance and time course of positive and negative feedback-type changes in brain biochemistry may ultimately influence vulnerability to addiction and relapse.

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19 August 1998; accepted 5 November 1998


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   Abstract »    Full Text »    PDF »
Depressive-Like Effects of the {kappa}-Opioid Receptor Agonist Salvinorin A on Behavior and Neurochemistry in Rats.
W. A. Carlezon Jr., C. Beguin, J. A. DiNieri, M. H. Baumann, M. R. Richards, M. S. Todtenkopf, R. B. Rothman, Z. Ma, D. Y.-W. Lee, and B. M. Cohen (2006)
J. Pharmacol. Exp. Ther. 316, 440-447
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CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum.
A. A. Levine, Z. Guan, A. Barco, S. Xu, E. R. Kandel, and J. H. Schwartz (2005)
PNAS 102, 19186-19191
   Abstract »    Full Text »    PDF »
The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal.
A. Contarino and F. Papaleo (2005)
PNAS 102, 18649-18654
   Abstract »    Full Text »    PDF »
Parsing Molecular and Behavioral Effects of Cocaine in Mitogen- and Stress-Activated Protein Kinase-1-Deficient Mice.
K. Brami-Cherrier, E. Valjent, D. Herve, J. Darragh, J.-C. Corvol, C. Pages, A. J. Simon, J.-A. Girault, and J. Caboche (2005)
J. Neurosci. 25, 11444-11454
   Abstract »    Full Text »    PDF »
The "Ups and Downs" of Signaling Cascades in Addiction.
D. Ron and R. Jurd (2005)
Sci. STKE 2005, re14
   Abstract »    Full Text »    PDF »
Addiction: A Disease of Learning and Memory.
S. E. Hyman (2005)
Am J Psychiatry 162, 1414-1422
   Abstract »    Full Text »    PDF »
Regulation of Drug Reward by cAMP Response Element-Binding Protein: Evidence for Two Functionally Distinct Subregions of the Ventral Tegmental Area.
V. G. Olson, C. P. Zabetian, C. A. Bolanos, S. Edwards, M. Barrot, A. J. Eisch, T. Hughes, D. W. Self, R. L. Neve, and E. J. Nestler (2005)
J. Neurosci. 25, 5553-5562
   Abstract »    Full Text »    PDF »
Regulation of anxiety and initiation of sexual behavior by CREB in the nucleus accumbens.
M. Barrot, D. L. Wallace, C. A. Bolanos, D. L. Graham, L. I. Perrotti, R. L. Neve, H. Chambliss, J. C. Yin, and E. J. Nestler (2005)
PNAS 102, 8357-8362
   Abstract »    Full Text »    PDF »
Radioligands for Brain Imaging of the {kappa}-Opioid System.
H.-J. Machulla and A. Heinz (2005)
J. Nucl. Med. 46, 386-387
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REGULATORs OF G PROTEIN SIGNALING & DRUGS OF ABUSE.
J. R. Traynor and R. R. Neubig (2005)
Mol. Interv. 5, 30-41
   Abstract »    Full Text »    PDF »
Induction of {Delta}FosB in Reward-Related Brain Structures after Chronic Stress.
L. I. Perrotti, Y. Hadeishi, P. G. Ulery, M. Barrot, L. Monteggia, R. S. Duman, and E. J. Nestler (2004)
J. Neurosci. 24, 10594-10602
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RACK1 and Brain-Derived Neurotrophic Factor: A Homeostatic Pathway That Regulates Alcohol Addiction.
N. N. H. McGough, D.-Y. He, M. L. Logrip, J. Jeanblanc, K. Phamluong, K. Luong, V. Kharazia, P. H. Janak, and D. Ron (2004)
J. Neurosci. 24, 10542-10552
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cAMP Response Element-Binding Protein Is Required for Stress But Not Cocaine-Induced Reinstatement.
A. S. Kreibich and J. A. Blendy (2004)
J. Neurosci. 24, 6686-6692
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Partial Deletion of the cAMP Response Element-Binding Protein Gene Promotes Alcohol-Drinking Behaviors.
S. C. Pandey, A. Roy, H. Zhang, and T. Xu (2004)
J. Neurosci. 24, 5022-5030
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A single cocaine exposure enhances both opioid reward and aversion through a ventral tegmental area-dependent mechanism.
J. A. Kim, K. A. Pollak, G. O. Hjelmstad, and H. L. Fields (2004)
PNAS 101, 5664-5669
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Cocaine-Induced Intracellular Signaling and Gene Expression Are Oppositely Regulated by the Dopamine D1 and D3 Receptors.
L. Zhang, D. Lou, H. Jiao, D. Zhang, X. Wang, Y. Xia, J. Zhang, and M. Xu (2004)
J. Neurosci. 24, 3344-3354
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Discrete Cell Gene Profiling of Ventral Tegmental Dopamine Neurons after Acute and Chronic Cocaine Self-Administration.
E. Backes and S. E. Hemby (2003)
J. Pharmacol. Exp. Ther. 307, 450-459
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Phospholipase C{gamma} in Distinct Regions of the Ventral Tegmental Area Differentially Modulates Mood-Related Behaviors.
C. A. Bolanos, L. I. Perrotti, S. Edwards, A. J. Eisch, M. Barrot, V. G. Olson, D. S. Russell, R. L. Neve, and E. J. Nestler (2003)
J. Neurosci. 23, 7569-7576
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{kappa} Opioid Receptor Antagonism and Prodynorphin Gene Disruption Block Stress-Induced Behavioral Responses.
J. P. McLaughlin, M. Marton-Popovici, and C. Chavkin (2003)
J. Neurosci. 23, 5674-5683
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Early Odor Preference Learning in the Rat: Bidirectional Effects of cAMP Response Element-Binding Protein (CREB) and Mutant CREB Support a Causal Role for Phosphorylated CREB.
Q. Yuan, C. W. Harley, A. Darby-King, R. L. Neve, and J. H. McLean (2003)
J. Neurosci. 23, 4760-4765
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Kappa Opioid Receptor Activation in the Nucleus Accumbens Inhibits Glutamate and GABA Release Through Different Mechanisms.
G. O. Hjelmstad and H. L. Fields (2003)
J Neurophysiol 89, 2389-2395
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Interactions with PDZ Proteins Are Required for L-Type Calcium Channels to Activate cAMP Response Element-Binding Protein-Dependent Gene Expression.
J. P. Weick, R. D. Groth, A. L. Isaksen, and P. G. Mermelstein (2003)
J. Neurosci. 23, 3446-3456
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Antidepressant-Like Effects of kappa -Opioid Receptor Antagonists in the Forced Swim Test in Rats.
S. D. Mague, A. M. Pliakas, M. S. Todtenkopf, H. C. Tomasiewicz, Y. Zhang, W. C. Stevens Jr., R. M. Jones, P. S. Portoghese, and W. A. Carlezon Jr. (2003)
J. Pharmacol. Exp. Ther. 305, 323-330
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Gene Therapy for Psychiatric Disorders.
R. M. Sapolsky (2003)
Am J Psychiatry 160, 208-220
   Abstract »    Full Text »    PDF »
Elevated Expression of 5-HT1B Receptors in Nucleus Accumbens Efferents Sensitizes Animals to Cocaine.
J. F. Neumaier, E. S. Vincow, A. Arvanitogiannis, R. A. Wise, and W. A. Carlezon Jr (2002)
J. Neurosci. 22, 10856-10863
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Inhibition of cAMP Response Element-Binding Protein or Dynorphin in the Nucleus Accumbens Produces an Antidepressant-Like Effect.
S. S. Newton, J. Thome, T. L. Wallace, Y. Shirayama, L. Schlesinger, N. Sakai, J. Chen, R. Neve, E. J. Nestler, and R. S. Duman (2002)
J. Neurosci. 22, 10883-10890
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Nitric Oxide Protects Neuroblastoma Cells from Apoptosis Induced by Serum Deprivation through cAMP-response Element-binding Protein (CREB) Activation.
E. Ciani, S. Guidi, G. Della Valle, G. Perini, R. Bartesaghi, and A. Contestabile (2002)
J. Biol. Chem. 277, 49896-49902
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Dopamine Induces a PI3-Kinase-Independent Activation of Akt in Striatal Neurons: A New Route to cAMP Response Element-Binding Protein Phosphorylation.
K. Brami-Cherrier, E. Valjent, M. Garcia, C. Pages, R. A. Hipskind, and J. Caboche (2002)
J. Neurosci. 22, 8911-8921
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Different Mechanisms for Loss and Recovery of Binocularity in the Visual Cortex.
D. S. Liao, A. F. Mower, R. L. Neve, C. Sato-Bigbee, and A. S. Ramoa (2002)
J. Neurosci. 22, 9015-9023
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CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli.
M. Barrot, J. D. A. Olivier, L. I. Perrotti, R. J. DiLeone, O. Berton, A. J. Eisch, S. Impey, D.