Repeated exposure to cocaine can induce neuroadaptations in the brain. One mechanism by which persistent changes occur involves alterations in gene expression mediated by the dopamine receptors. Both the dopamine D1 and D3 receptors have been shown to mediate gene expression changes. Moreover, the D1 and D3 receptors are also coexpressed in the same neurons, particularly in the nucleus accumbens and also caudoputamen (CPu). Little is known however, whether these two receptors coordinately regulate gene expression after cocaine administration and the underlying mechanisms. We have used various gene mutant mice to address this issue. We show that extracellular signal-regulated kinase (ERK) activation and c-fos induction in the CPu in response to acute cocaine administration is mediated by the D1 receptor and inhibited by the D3 receptor. Moreover, ERK activation mediates acute cocaine-induced expression of Fos family genes, including c-fos, fosB and fra2. Interestingly, dynorphin, neogenin, and synaptotagmin VII, genes that possess cAMPresponse element binding protein and AP-1 transcription complex-binding consensus sequences in their promoters, are also oppositely regulated by the D1 and D3 receptors after repeated exposure to cocaine. Furthermore, such regulation depends on proper ERK activation and c-fos function. These results suggest that the D1 and D3 receptors elicit opposite regulation of target gene expression by regulating ERK activation and c-fos induction after acute and chronic cocaine treatment.

No abstract

No abstract

The development of drug addiction involves persistent cellular and molecular changes in the central nervous system. The brain dopamine and glutamate systems play key roles in mediating drug-induced neuroadaptation. Changes in dendritic morphology in medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and caudate putamen (CPu) accompany drug-induced enduring behavioral and molecular changes. We have investigated the potential involvement of dopamine D1 and D2 receptors, the N-methyl-D-aspartate (NMDA) receptor, and the extracellular signal-regulated kinase (ERK) in dendritic morphological changes induced by repeated cocaine administration. We show that either a genetic mutation or pharmacological blockade of dopamine D1 receptors attenuated cocaine-induced changes in both dendritic branching and spine density of MSNs in the shell of the NAc and CPu. In contrast, antagonism of dopamine D2 receptors had no obvious effect on changes in dendritic branching but had a partial effect on changes in spine density of MSNs in these brain regions following repeated cocaine injections. Pharmacological inhibition of either NMDA receptors or ERK attenuated cocaine-induced changes in both dendritic branching and spine density of MSNs in the shell of the NAc and CPu. These results suggest that dopamine D1 and NMDA receptors and ERK contribute significantly to neuronal morphological changes induced by repeated exposure to cocaine. Keywordsdopamine; D1 and D2 receptors; NMDA receptors; ERK; cocaine; dendrite; spine density Drug addiction is characterized by compulsive drug seeking and taking which is long-lasting (Wise, 2000;Koob et al., 2004;Hyman et al., 2006;Kauer and Malenka, 2007;Kalivas and O'Brien, 2008). Dopamine (DA) projections from the midbrain to the nucleus accumbens (NAc), caudate putamen (CPu), prefrontal cortex (PFC) and other structures play key roles in mediating the neurobiological actions of drugs of abuse (Koob, Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.© NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 June 16. Published in final edited form as:Neuroscience. 1992). Glutamatergic inputs from the PFC to the NAc also play an essential role in mediating drug actions (Kalivas, 2004;Wolf et al., 2004;. In the striatum, dopaminergic inputs terminate in the dendritic shafts whereas glutamatergic afferents form synapses at the head of dendritic spines of the medium spiny neurons (MSNs) (Sesack and Pickel, 1990). There are close interactions between these two neural systems at the cellular and molecular levels.The endu...