Research ReportGlutamatergic plasticity in medial prefrontal cortex and ventral tegmental area following extended-access cocaine self-administration
Highlights
► We examined the glutamate receptor plasticity in extended-access cocaine self-administration (SA) animal model of addiction. ► Following cocaine self-administration, animals either stayed in home cages (abstinence) or lever pressing was extinguished. ► The postsynaptic density (PSD) NMDAR1 protein in VTA was decreased after abstinence but not extinction. ► An increase in PSD GluR1, PSD95, Actin and a decrease in mGluR5 receptor proteins were observed in the dorsomedial prefrontal cortex following extinction of SA. ► The glutamate receptor plasticity in PFC and VTA was region- and withdrawal-dependent.
Introduction
Addiction is characterized as transition from episodic drug use to compulsive use and loss of control over drug intake (Kalivas and Volkow, 2005, Leshner, 1997, O'Brien and McLellan, 1996). A major obstacle in treatment of addiction is the unpredictable relapse to drug use during abstinence, often mediated by drug-associated cues (Kreek and Koob, 1998, O'Brien, 1997). Emerging data suggest that long-lasting plasticity in glutamatergic signaling in the brain plays an important role in drug craving and relapse (Anderson et al., 2008, Conrad et al., 2008, Ghasemzadeh et al., 2009a, Ghasemzadeh et al., 2009b, Self et al., 2004). These studies have identified a brain circuit encompassing a number of loci including prefrontal cortex, nucleus accumbens and ventral tegmental area as pivotal anatomical substrates mediating addiction behaviors (Ghasemzadeh et al., 2009a, Ghasemzadeh et al., 2009b, Kalivas, 2009, Kalivas and McFarland, 2003, Thomas et al., 2008).
Prefrontal cortex, a component of the brain motive circuit has been implicated in the behavioral and molecular changes after repeated exposure to cocaine (Kalivas, 2009, McFarland et al., 2004, McFarland and Kalivas, 2001, Steketee, 2003). The pyramidal projection neurons of the prefrontal cortex innervate subcortical regions, such as nucleus accumbens, amygdala and ventral tegmental area, and provide excitatory glutamatergic neurotransmission (Brinley-Reed et al., 1995, Groenewegen et al., 1990, Sesack et al., 1989, Sesack and Pickel, 1992). The medial prefrontal cortex in the rat is a heterogeneous structure that can be subdivided into dorsal and ventral compartments based on the functional and anatomical distinctions (Berendse et al., 1992, Heidbreder and Groenewegen, 2003). The dorsomedial prefrontal cortex (dmPFC) consists of the cingulate cortex area 1 and the dorsal portion of the prelimbic cortex and preferentially innervates the dorsal striatum and nucleus accumbens core regions (Berendse et al., 1992, Groenewegen et al., 1990, Sesack et al., 1989). The ventromedial prefrontal cortex (vmPFC) consists of the ventral portion of the prelimbic and the infralimbic cortex and preferentially innervates the nucleus accumbens shell (Gorelova and Yang, 1997, Hurley et al., 1991, Sesack et al., 1989). The mPFC is innervated by the dopaminergic afferents from the ventral tegmental area (VTA) with the highest innervation received in the infralimbic and prelimbic regions (Conde et al., 1995, Lindvall et al., 1978, Thierry et al., 1973). In turn, the medial prefrontal cortex innervates the ventral tegmental area with prelimbic cortex exhibiting a larger innervation than cingulate or infralimbic regions (Beckstead, 1979, Hurley et al., 1991, Sesack et al., 1989, Sesack and Pickel, 1992).
Several studies have suggested a critical role for rat medial prefrontal cortex in drug seeking and relapse. Furthermore, the dorsal and ventral compartments of mPFC exert distinct regulation on drug-seeking behaviors suggesting a functional dichotomy between mPFC compartments. Injection of cocaine into prefrontal cortex is reinforcing and reinstates cocaine-seeking behavior (Guzman et al., 2009, Park et al., 2002). BDNF infusion into PFC reduced cocaine seeking (Berglind et al., 2007). Inhibition of dmPFC, but not vmPFC, by GABA receptor agonists prevented cocaine and footshock-mediated reinstatement of drug seeking (McFarland et al., 2004, McFarland and Kalivas, 2001). Inactivation of prelimbic cortex or dmPFC attenuates drug-taking and drug-seeking behaviors (Capriles et al., 2003, Di Pietro et al., 2006, McLaughlin and See, 2003). Cocaine self-administration increased dendritic branching and spine density of prefrontal cortex pyramidal neurons (Robinson et al., 2001). Lastly, chronic exposure to cocaine is associated with prefrontal cortex-dependent cognitive dysfunction in preclinical models (Briand et al., 2008) as well as human addicts (Bolla et al., 2003, Cunha et al., 2010).
Similar to other membrane bound receptors, postsynaptic glutamate receptor signaling is partly regulated by the presence of functional receptor on the cell membrane and receptor-mediated intracellular signaling (Derbach et al., 2007, Kennedy, 2000, Kennedy and Ehlers, 2006, Malinow and Malenka, 2002). Therefore, glutamate receptor gene activation, protein synthesis, membrane trafficking, synaptic localization, and intracellular signaling are important candidates as possible mechanisms for cocaine-mediated plasticity. In support of these observations, we have recently shown that repeated non-contingent exposure to cocaine or cocaine self-administration is associated with an extensive trafficking and redistribution of glutamate receptors in the nucleus accumbens and prefrontal cortex (Ghasemzadeh et al., 2009a, Ghasemzadeh et al., 2009b, Ghasemzadeh et al., 2009c, Ghasemzadeh et al., 2009d). Furthermore, neuroimaging of addicts suggests abnormalities in frontal cortical neuronal activity during withdrawal as well as craving and drug use (Goldstein and Volkow, 2002, Kalivas and Volkow, 2005). Two recent report, using primary prefrontal cortex neuronal cultures, have indicated that brief D1 dopamine receptor stimulation leads to augmented trafficking and membrane expression of AMPA and NMDA receptor subunits on the pyramidal neurons (Gao and Wolf, 2008, Sun et al., 2005b). These studies suggest that plasticity in the glutamate receptors in the prefrontal cortex may contribute to addiction-related behaviors. However, the nature and mechanisms of the glutamate receptor neuroadaptations in the prefrontal cortex after repeated exposure to cocaine is not clear. This information is critical since it provides a framework to enhance our understanding of the role of the glutamate signaling in addiction.
In order to identify glutamatergic plasticity associated with drug seeking, the current study investigated the redistribution of the glutamate receptors in the medial prefrontal cortex and ventral tegmental area after extended-access cocaine self-administration followed by three post self-administration withdrawal regimens differentiated according to the level of drug-seeking behavior that they produced. We have previously found that, depending on the post self-administration withdrawal regimen applied, cocaine seeking varies significantly, with high levels of cocaine seeking observed when rats remain in their home cages (Abstinence), intermediate levels observed when rats are exposed to the self-administration boxes in the absence of the previously reinforced drug lever (Box), and very low levels observed when rats undergo extinction training (Extinction) (Ghasemzadeh et al., 2009a, Ghasemzadeh et al., 2009b). Additionally, the examination of glutamatergic plasticity that is associated with these conditions may provide insight into alterations in glutamatergic neurotransmission in the medial prefrontal cortex and ventral tegmental area that may contribute to the extinction of drug-seeking behavior.
The trafficking of glutamate receptor proteins was monitored by utilizing a biochemical subcellular fractionation procedure, which isolates the cellular synaptosomal membrane fraction containing the postsynaptic density (Xiao et al., 1998, Lin et al., 1998, Wyszynski et al., 1998, Dunah and Standaert, 2001, Toda et al., 2003). This study is the first to report on redistribution of the three subtypes of the glutamate receptors in synaptosomal membrane fraction associated with the postsynaptic density after withdrawal from cocaine self-administration in prefrontal cortex and ventral tegmental area. Furthermore, our data demonstrate that receptor redistribution is both withdrawal- and region-dependent suggesting a unique role for glutamate receptor signaling in drug seeking after abstinence and extinction of drug seeking.
Section snippets
Results
The experiments in this study investigated the expression and postsynaptic density distribution of the glutamate receptor and their scaffolding proteins following withdrawal from extended-access cocaine self-administration in dmPFC, vmPFC, and VTA in male Sprague Dawley rats. In order to identify molecular plasticity in protein redistribution associated with extinction of drug-seeking behavior or forced abstinence three withdrawal conditions were examined. Following 14 days of extended-access
Discussion
In this study, we investigated the expression and postsynaptic density (PSD) distribution of glutamate receptors in mPFC and VTA following three distinct withdrawal regimens after two weeks of extended-access cocaine self-administration. Recent studies indicate that mPFC and VTA play pivotal roles in drug reinforcement and seeking and that glutamatergic neurotransmission is an integral part of their contributions to these effects (Kalivas, 2008, Rebec and Sun, 2005, Van den Oever et al., 2010,
Subjects
Seventy-five adult male Sprague–Dawley rats (Harlan Laboratories, Inc., St. Louis, MO), approximately 90 days old (325 g) were used for the study. Rats were housed individually in a temperature- and humidity-controlled, AAALAC-accredited animal facility under a 12 h/12 h reversed light/dark cycle (lights on at 18:00) and had access to food at all times, except when in the experimental chambers. Water was available at all times during the study, including in the experimental chambers. All procedures
Acknowledgments
This work was supported by NIH/NIDA Grant numbers DA14328 (MBG) and DA15758 (JRM). The generous gift of cocaine by NIH/NIDA is gratefully acknowledged.
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