Drago J, Gerfen CR, Westphal H, Steiner H. D1 dopamine receptor-deficient mouse: cocaine-induced regulation of immediate-early gene and substance P expression in the striatum. Neuroscience 74: 813-823

Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
Neuroscience (Impact Factor: 3.36). 11/1996; 74(3):813-23. DOI: 10.1016/0306-4522(96)00145-5
Source: PubMed


Psychomotor stimulants such as cocaine alter gene expression in neurons of the striatum. Whereas many of these effects are mediated by D1 dopamine receptors, the involvement of other dopamine receptor subtypes or neurotransmitters is likely. To distinguish between these possibilities, regulation by cocaine of immediate-early genes and genes encoding neuropeptides was analysed in mice that lack functional D1 receptors. Gene expression was examined with in situ hybridization histochemistry. In these animals, cocaine failed to induce the immediate-early genes c-fos and zif 268. In contrast, substance P expression was abnormally increased by this drug. These results demonstrate that some of the effects of cocaine on gene regulation are mediated via D1 receptor-dependent mechanisms, as evidenced by the absence of immediate-early gene induction in D1-deficient mice, whereas others also involve additional, non-D1 receptor mechanisms, as shown for substance P expression.

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    • "D1 receptor null mice have been examined in the context of addictive behaviors, and initial studies revealed that D1 receptor mutant mice failed to exhibit the psychomotor stimulant effect of cocaine on motor and stereotyped behaviors compared to their wild-type littermates (Xu et al., 1994; Drago et al., 1996). However, it appears that D1 receptor KO abolishes the acute locomotor response to cocaine, but does not fully prevent locomotor sensitization to cocaine at all doses (Karlsson et al., 2008), demonstrating that genetic KO of D1 receptors is not sufficient to fully block cocaine sensitization under all conditions. "
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    ABSTRACT: Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA mesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural reward such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.
    Full-text · Article · Oct 2013 · Frontiers in Neural Circuits
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    • "The cascade of molecular events initiated in the striatum (Str) and nucleus accumbens (NAc) following acute exposure of adult animals to cocaine has been well characterized (reviewed in McGinty et al., 2008). Specifically, a wealth of experimental data identifies a rapid and robust activation of D1-like cell surface receptors activating intracellular signaling pathways to affect specific patterns of gene expression (Self et al., 1996), and alterations thereof in mice genetically engineered to be deficient in D1 mediated signal transduction in the Str (Drago et al., 1996). High throughput array-based methods have identified sets of genes activated in the Str and NAc following acute cocaine exposure that are distinguishable from those following repeated cocaine exposures (Renthal et al., 2009), emphasizing the persistent molecular adaptations, in part via recurrent D1-mediated neuronal stimulation, in contributing to the “addicted state” (Chao and Nestler, 2004). "
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    ABSTRACT: Previous work from our group and others utilizing animal models have demonstrated long lasting structural and functional alterations in the meso-cortico-striatal dopamine pathway following prenatal cocaine treatment. We have shown that prenatal cocaine treatment results in augmented D1 -induced cyclic AMP (cAMP) and cocaine-induced immediate-early gene expression in the striatum of adult mice. In this study we further examined basal as well as cocaine or D1-induced activation of a set of molecules known to be mediators of neuronal plasticity following psychostimulant treatment, with emphasis in the dorsal striatum (Str) and nucleus accumbens (NAc) of adult mice exposed to cocaine in utero. Basally, in the striatum of prenatal cocaine treated (PCOC) mice there were significantly higher levels of a number of the transcription factors studied. Following acute administration of cocaine (15 mg/kg, i.p.) or D1 agonist (SKF 82958; 1 mg/kg, i.p.) there were significantly higher levels of Ser133 P-CREB, Thr34 P-DARPP-32, and Thr202/Tyr204 P-ERK2 in the Str, that were significantly augmented in PCOC mice. In sharp contrast, in the NAc of those mice, we found increased P-CREB and P-ERK2 in PSAL mice, a response that was not evident in PCOC mice. Examination of Ser 845 P-GluA1 revealed increased levels in PSAL mice, but significantly decreased levels in PCOC mice in both the Str and NAc following acute administration of cocaine or D1 agonist. We also found significantly higher levels of the BDNF precursor, pro-BDNF and one of its receptors, TrkB in the Str of PCOC mice. These results suggest a persistent up-regulation of molecules critical to D1 and BDNF signaling in the Str of adult mice exposed to cocaine in utero. These molecular adaptations may underlie components of the behavioral deficits evident in exposed animals and a subset of exposed humans, and may represent a therapeutic target for ameliorating aspects of the prenatal cocaine-induced phenotype.
    Full-text · Article · Dec 2011 · Frontiers in Psychiatry
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    • "Studies with D 1 receptor and D 2 -receptor knockout mice provide some insight into the role of these receptors in the two MSNs. D 1 knockout mice show a blunted induction of immediate early genes (IEGs) c-Fos and Zif268 in response to cocaine, a diminished response to psychostimulant-induced locomotor activity but with no alterations in cocaine-conditioned place preference (CPP) – an indirect measure of drug reward, and diminished cocaine self-administration and ethanol consumption (Miner et al., 1995; Drago et al., 1996; Crawford et al., 1997; El- Ghundi et al., 1998; Caine et al., 2007). D 2 knockout mice display diminished rewarding effects to opiates and cocaine as well as decreased ethanol consumption but no reduction in cocaine taking (Maldonado et al., 1997; Cunningham et al., 2000; Risinger et al., 2000; Caine et al., 2002; Chausmer et al., 2002; Elmer et al., 2002; Welter et al., 2007). "
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    ABSTRACT: The striatum plays a key role in mediating the acute and chronic effects of addictive drugs, with drugs of abuse causing long-lasting molecular and cellular alterations in both dorsal striatum and nucleus accumbens (ventral striatum). Despite the wealth of research on the biological actions of abused drugs in striatum, until recently, the distinct roles of the striatum's two major subtypes of medium spiny neurons (MSNs) in drug addiction remained elusive. Recent advances in cell-type-specific technologies, including fluorescent reporter mice, transgenic, or knockout mice, and viral-mediated gene transfer, have advanced the field toward a more comprehensive understanding of the two MSN subtypes in the long-term actions of drugs of abuse. Here we review progress in defining the distinct molecular and functional contributions of the two MSN subtypes in mediating addiction.
    Full-text · Article · Jul 2011 · Frontiers in Neuroanatomy
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