Research ReportRegional differences in the effects of withdrawal from repeated cocaine upon Homer and glutamate receptor expression: A two-species comparison
Introduction
Cocaine addiction is a chronic neuropsychiatric disorder characterized by persistent craving and a high propensity for relapse long after drug abstinence. Enduring alterations in both pre- and post-synaptic aspects of mesocorticolimbic glutamate transmission have been implicated in mediating behaviors produced by repeated cocaine treatment (Pierce et al., 1998, Reid and Berger, 1996, Szumlinski et al., 2004, Szumlinski et al., 2006a, Williams and Steketee, 2004), including cocaine self-administration (Backstrom and Hyytia, 2007, Baker et al., 2003, Cornish and Kalivas, 2001, Di Ciano and Everitt, 2001, McFarland et al., 2004, Park et al., 2002, Pulvirenti et al., 1992). A likely molecular mediator of cocaine-induced changes in mesocorticolimbic glutamate is the Homer family of postsynaptic scaffolding proteins (for reviews, Szumlinski et al., 2006b, Szumlinski et al., 2007a). Three independent genes, Homer1 (aka PSD-Zip45 or vesl-1), Homer2 (aka Cupidin or vesl-2) and Homer3 (aka vesl-3), encode this protein family (Soloviev et al., 2000), which are integral in glutamate synaptogenesis and glutamate receptor trafficking (for reviews, Bockaert et al., 2004, de Bartolomeis and Iasevoli, 2003, Duncan et al., 2005, Xiao et al., 2000). Long-form Homer proteins (Homer1b-g, Homer2a/b, and Homer3) are constitutively expressed in the brain (Klugmann et al., 2005, Shiraishi et al., 2004, Xiao et al., 1998) and share a coiled-coil (CC) structure, which allows for their multimerization (Hayashi et al., 2006), and facilitates the clustering of glutamate receptors and other proteins involved in their intracellular signaling cascades (for reviews: Bockaert et al., 2004, de Bartolomeis and Iasevoli, 2003, Duncan et al., 2005, Szumlinski et al., 2006b, Xiao et al., 2000). Additionally, Homers possess a conserved amino-terminal Ena/VASP1 homology (EVH1) domain (Brakeman et al., 1997). This domain allows Homers to bind with a proline-rich (PPXXFR; amino acid sequence) motif found in Group1 metabotropic glutamate receptors (mGluRs) (Tu et al., 1998), inositol-1,4,5-triphosphate receptors (Brakeman et al., 1997, Hwang et al., 2005, Nakamura et al., 2004, Sala et al., 2005, Shin et al., 2003, Tu et al., 1998, Yuan et al., 2003), ryanodine receptors (Feng et al., 2002, Hwang et al., 2003), transient receptor potential canonical-1 ion channels (Yuan et al., 2003), and the NMDA glutamate receptor scaffolding protein Shank (Naisbitt et al., 1999, Shiraishi et al., 2003, Tu et al., 1999). The EVH1 domain on CC-Homers compete for binding with that on the truncated transcriptional variants of Homer1 (Homer1a and ania-3), which are induced as immediate early gene (IEG) products upon synaptic activity (Brakeman et al., 1997). As Homer1a lacks both the CC-domain and the ability to multimerize (Bottai et al., 2002, Xiao et al., 1998), Homer1a acts as a natural dominant negative of CC-Homer multimers and, thus, influences the functional architecture of glutamatergic terminals and synaptic plasticity (Brakeman et al., 1997, Sala et al., 2003).
While a number of studies have examined for drug-induced changes in IEG Homer mRNA or protein expression within brain (for recent review, Szumlinski et al., 2007a), considerably less is known regarding the regulation of CC-Homer proteins by drugs of abuse (Kane et al., 2005, Swanson et al., 2001, Szumlinski et al., 2007b, Zhang et al., 2007a). With respect to stimulant drugs, the protein expression of IEG and CC-Homer1 isoforms is regulated differentially by cocaine within the dorsal or ventral aspects of the striatum of rats (Swanson et al., 2001, Zhang et al., 2007a). While behavioral genetics studies implicate a role for both Homer1 and Homer2 gene products in regulating behavioral and neurochemical sensitivity to cocaine (Lominac et al., 2005, Szumlinski et al., 2004, Szumlinski et al., 2005a, Szumlinski et al., 2006a), whether or not Homer2 protein expression is regulated within the mesocorticolimbic glutamate system by cocaine is not known. Moreover, it unknown whether or not the cocaine-induced changes in Homer2 expression relate to, or are independent of, changes in the expression of CC-Homer1 isoforms. Thus, the primary goal of the present immunoblotting study was to compare cocaine-induced changes in Homer2a/b expression with those for Homer1b/c within brain regions implicated in mediating the psychomotor-activating and rewarding effects of cocaine (incl. prefrontal cortex, NAC, striatum, and hippocampus) (Dackis and O'Brien, 2001, Everitt and Wolf, 2002, Fuchs et al., 2007, Goldstein and Volkow, 2002, Kalivas and McFarland, 2003, Kalivas et al., 2005, Koob and Le Moal, 2001, Rogers and See, 2007). As Homer2 regulates Group1 mGluR and NR2 expression in vivo (Szumlinski et al., 2004, Szumlinski et al., 2005b, Szumlinski et al., 2007b), the secondary goal of this study was to relate the cocaine-induced changes in CC-Homer expression with those of the mGluR1 and mGluR5 subtypes of Group1 mGluR and the NR2a and NR2b subunits of the NMDA receptor. To determine whether or not the cocaine-induced changes in Homer/mGluR/NMDA expression are generalizable across two mammalian species, we conducted immunoblotting in both SpragueāDawley rats and in C57BL/6J (B6) mice.
Section snippets
Results
The data summarizing the changes in CC-Homer and glutamate receptor expression within the PFC, NAC shell and the hippocampus observed at 3Ā weeks withdrawal from repeated cocaine administration (7Ā ĆĀ 30Ā mg/kg) are presented respectively in Fig. 1, Fig. 2, Fig. 3. The data for the NAC core and striatum are presented in Table 1 and all data are summarized in Table 2.
Discussion
Homer proteins are critically involved in regulating the functional architecture of glutamate synapses (e.g., Bockaert et al., 2004, de Bartolomeis and Iasevoli, 2003, Duncan et al., 2005, Xiao et al., 2000) and in regulating drug-induced neuroplasticity (for a recent review, Szumlinski et al., 2007a). With regards to cocaine, both Homer1b/c and Homer2a/b regulate the expression of cocaine-induced locomotor hyperactivity (Lominac et al., 2005, Szumlinski et al., 2004), as well as the expression
Subjects
Adult male SpragueāDawley rats (weighing 200ā225Ā g; nĀ =Ā 28) from Harlan (Indianapolis, IN) and adult male B6 mice (weighing 25ā30Ā g; nĀ =Ā 42) from Jackson Laboratories (Bar Harbor, ME) were used. All animals were pair-housed in polyethylene cages in a temperature (25Ā Ā°C) and humidity (71%) controlled vivarium under a 12Ā h day/12Ā h light cycle (lights on: 0700Ā h). Experimental protocols, as well as housing and animal care, were consistent with the guidelines provided by the National Institute of
Acknowledgments
The authors would like to thank Dr. Ilona Obara and Ms. Mimi Moras for their technical assistance and the laboratory of Dr. Paul F. Worley (The Johns Hopkins University School of Medicine) for their generous gift of the Homer1b/c and Homer2a/b primary antibodies. This project was supported by funds from the University of California at Santa Barbara to AWA and KKS and by a NARSAD Young Investigator's Award to KKS.
References (97)
- et al.
Microarray analysis of genes expressed in the frontal cortex of rats chronically treated with morphine and after naloxone precipitated withdrawal
Brain Res. Mol. Brain Res.
(2003) - et al.
Cocaine dependence: a disease of the brain's reward centers
J. Subst. Abuse Treat.
(2001) - et al.
Enhancement of hippocampal long-term potentiation induced by cocaine self-administration is maintained during the extinction of this behavior
Brain Res.
(2006) - et al.
Dissociable effects of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior
Neuropsychopharmacology
(2001) - et al.
Identification and functional roles of metabotropic glutamate receptor-interacting proteins
Semin. Cell Dev. Biol.
(2004) - et al.
Homer regulates gain of ryanodine receptor type 1 channel complex
J. Biol. Chem.
(2002) - et al.
Role of the anterior cingulate and medial orbitofrontal cortex in processing drug cues in cocaine addiction
Neuroscience
(2007) - et al.
Differential regulation of ionotropic glutamate receptor subunits following cocaine self-administration
Brain Res.
(2005) - et al.
Differential functional interaction of two Vesl/Homer protein isoforms with ryanodine receptor type 1: a novel mechanism for control of intracellular calcium signaling
Cell Calcium
(2003) - et al.
The interaction of phospholipase C-beta3 with Shank2 regulates mGluR-mediated calcium signal
J. Biol. Chem.
(2005)
Unmanageable motivation in addiction: a pathology in prefrontalāaccumbens glutamate transmission
Neuron
Novel members of the Vesl/Homer family of PDZ proteins that bind metabotropic glutamate receptors
J. Biol. Chem.
AAV-mediated hippocampal expression of short and long Homer 1 proteins differentially affect cognition and seizure activity in adult rats
Mol. Cell. Neurosci.
Drug addiction, dysregulation of reward, and allostasis
Neuropsychopharmacology
Acquisition and maintenance of intravenous cocaine self-administration in Lewis and Fischer inbred rat strains
Brain Res.
Ligand affinities at recombinant N-methyl-d-aspartate receptors depend on subunit composition
Eur. J. Pharmacol.
SAP102, a novel postsynaptic protein that interacts with NMDA receptor complexes in vivo
Neuron
Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin
Neuron
A single dose of lysergic acid diethylamide influences gene expression patterns within the mammalian brain
Neuropsychopharmacology
CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90
Neuron
NMDA receptors in the nucleus accumbens modulate intravenous cocaine but not heroin self-administration in the rat
Brain Res.
Selective inactivation of the ventral hippocampus attenuates cue-induced and cocaine-primed reinstatement of drug-seeking in rats
Neurobiol. Learn. Mem.
An analysis of cocaine effects on locomotor activities and heart rate in four inbred mouse strains
Pharmacol. Biochem. Behav.
Regulation of dendritic spine morphology and synaptic function by Shank and Homer
Neuron
Coincidence in dendritic clustering and synaptic targeting of homer proteins and NMDA receptor complex proteins NR2B and PSD95 during development of cultured hippocampal neurons
Mol. Cell. Neurosci.
Homer proteins regulate sensitivity to cocaine
Neuron
Homer proteins: implications for neuropsychiatric disorders
Curr. Opin. Neurobiol.
Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors
Neuron
Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins
Neuron
Correlation between cocaine-induced locomotion and cocaine disposition in the brain among four inbred strains of mice
Pharmacol. Biochem. Behav.
Characterization of dopamine transporter and locomotor effects of cocaine, GBR 12909, epidepride, and SCH 23390 in C57BL and DBA mice
Pharmacol. Biochem. Behav.
Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins
Neuron
Homer: a link between neural activity and glutamate receptor function
Curr. Opin. Neurobiol.
Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors
Cell
Prenatal stress alters limbo-corticostriatal Homer protein expression
Synapse
Involvement of AMPA/kainate, NMDA, and mGlu5 receptors in the nucleus accumbens core in cue-induced reinstatement of cocaine seeking in rats
Psychopharmacology (Berl.)
Neuroadaptations in cystineāglutamate exchange underlie cocaine relapse
Nat. Neurosci.
GPCR-interacting proteins (GIPs): nature and functions
Biochem. Soc. Trans.
Synaptic activity-induced conversion of intronic to exonic sequence in Homer 1 immediate early gene expression
J. Neurosci.
Homer: a protein that selectively binds metabotropic glutamate receptors
Nature
Acute and delayed effects of phencyclidine upon mRNA levels of markers of glutamatergic and GABAergic neurotransmitter function in the rat brain
Synapse
Cocaine sensitization and craving: differing roles for dopamine and glutamate in the nucleus accumbens
J. Addict. Dis.
Role of distinct NMDA receptor subtypes at central synapses
Sci. STKE
The Homer family and the signal transduction system at glutamatergic postsynaptic density: potential role in behavior and pharmacotherapy
Psychopharmacol. Bull.
Cocaine induces the expression of homer 1b/c, homer 3a/b, and hsp 27 proteins in rat cerebellum
Synapse
The glutamate receptor ion channels
Pharmacol. Rev.
Effects of Vesl/Homer proteins on intracellular signaling
Exp. Biol. Med. (Maywood)
Psychomotor stimulant addiction: a neural systems perspective
J. Neurosci.
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