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The Journal of Neuroscience, June 14, 2006, 26(24):6450-6457; doi:10.1523/JNEUROSCI.0491-06.2006

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Behavioral/Systems/Cognitive
Behavioral and Molecular Effects of Dopamine D₁ Receptor Stimulation during Naloxone-Precipitated Morphine Withdrawal

Elena H. Chartoff, Stephen D. Mague, Matthew F. Barhight, Andrew M. Smith, and William A. Carlezon, Jr

Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478

Correspondence should be addressed to Elena H. Chartoff, McLean Hospital, MRC 331, 115 Mill Street, Belmont, MA 02478. Email: echartoff{at}mclean.harvard.edu

Morphine dependence is characterized by somatic and motivational signs of withdrawal that likely contribute to the maintenance of addictive behavior. The nucleus accumbens (NAc) receives extensive dopaminergic input and is an important substrate for mediating these aversive states. In the NAc, the function of the transcription factor cAMP response element binding protein (CREB) and AMPA glutamate receptor subunit, type 1 (GluR1) can be regulated by dopamine (DA) D₁ receptor-mediated phosphorylation (P-CREB, P-GluR1). However, the roles of D₁ receptors, CREB, and GluR1 in morphine dependence are not well understood. Here, we show that somatic signs of naloxone-precipitated withdrawal were associated with increased P-CREB, but not P-GluR1, in the NAc of morphine-dependent rats. The D₁ receptor agonist chloro-APB hydrobromide (SKF 82958) was rewarding in morphine-dependent rats and blocked naloxone-induced place aversions and somatic signs of withdrawal. Surprisingly, SKF 82958 increased P-GluR1, but not P-CREB, in the NAc, and naloxone reduced SKF 82958-mediated P-GluR1 induction specifically in morphine-dependent rats. Together, these results confirm that aversive treatments can increase CREB function in the NAc. Furthermore, they suggest a dependence-associated shift in the molecular mechanisms that regulate the consequences of D₁ receptor stimulation, favoring activation of GluR1 rather than CREB. These data raise the possibility that the rewarding effects of SKF 82958 in morphine-dependent rats involve increased P-GluR1 in the NAc, although the involvement of other brain regions cannot be ruled out. Regardless, these findings suggest for the first time that D₁ agonists might be useful for the treatment of withdrawal symptoms that contribute to the maintenance of opiate addiction in humans.

Key words: nucleus accumbens; CREB; GluR1; AMPA; place conditioning; SKF 82958

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Received Feb. 2, 2006; revised April 6, 2006; accepted May 4, 2006.

Correspondence should be addressed to Elena H. Chartoff, McLean Hospital, MRC 331, 115 Mill Street, Belmont, MA 02478. Email: echartoff{at}mclean.harvard.edu

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				R. H. Perlis, D. J. Holt, J. W. Smoller, A. J. Blood, S. Lee, B. W. Kim, M. J. Lee, M. Sun, N. Makris, D. K. Kennedy, et al. Association of a Polymorphism Near CREB1 With Differential Aversion Processing in the Insula of Healthy Participants Arch Gen Psychiatry, August 1, 2008; 65(8): 882 - 892. [Abstract] [Full Text] [PDF]

				B. M. Cohen and W. A. Carlezon Jr. Can't Get Enough of That Dopamine Am J Psychiatry, April 1, 2007; 164(4): 543 - 546. [Full Text] [PDF]

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