Locomotor sensitization to cocaine is associated with distinct pattern of glutamate receptor trafficking to the postsynaptic density in prefrontal cortex: Early versus late withdrawal effects

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Abstract

Glutamatergic neurotransmission plays an important role in the behavioral and molecular plasticity observed in cocaine mediated locomotor sensitization. Recent studies show that glutamatergic signaling is regulated by receptor trafficking, synaptic localization, and association with scaffolding proteins. The trafficking of the glutamate receptors was investigated in the dorsal and ventral prefrontal cortex at 1 and 21 days after repeated cocaine administration which produced robust locomotor sensitization. A subcellular fractionation technique was used to isolate the cellular synaptosomal fraction containing the postsynaptic density. At early withdrawal, the prefrontal cortex displayed a reduction in the synaptosomal content of the AMPA and NMDA receptor subunits. In contrast, after extended withdrawal, there was a significant increase in the trafficking of the receptors into the synaptosomal compartment. These changes were accompanied by corresponding trafficking of the postsynaptic glutamatergic scaffolding proteins. Thus, enhanced trafficking of glutamate receptors from cytosolic to synaptosomal compartment is associated with prolonged withdrawal from repeated exposure to cocaine and may have functional consequences for the synaptic and behavioral plasticity.

Introduction

Repeated cocaine administration produce enduring molecular, cellular and behavioral plasticity that resemble some addiction-related features in humans (Vanderschuren and Kalivas, 2000, Kalivas and Volkow, 2005, Everitt and Wolf, 2002, Robinson and Berridge, 2003, Everitt and Vanderschuren, 2005). In rodents, repeated intermittent exposure to cocaine leads to locomotor sensitization defined as progressive augmentation in locomotion and stereotypy in response to a dose of cocaine (Henry and White, 1995, Vanderschuren and Kalivas, 2000). Suto et al., (2004) showed that withdrawal from repeated amphetamine administration leads to an augmented cocaine self-administration and drug-seeking behavior in locomotor sensitized animals. These observations suggest that this animal model might be useful in elucidating the cellular and molecular mechanisms responsible for the enduring behavioral plasticity. Despite a wealth of information in the literature, the molecular mechanisms underlying the enduring molecular, cellular and behavioral plasticity after repeated exposure to cocaine is not clear. However, experimental data suggest that modulation of excitatory neurotransmission and signaling in a brain circuit comprising prefrontal cortex, nucleus accumbens, and ventral tegmental area plays an important role in the cocaine-mediated effects (Wolf, 1998, Vanderschuren and Kalivas, 2000, Everitt and Wolf, 2002, Li et al., 2004).

Prefrontal cortex, a component of the motive circuit of the brain, has been implicated in the behavioral and molecular changes after repeated exposure to cocaine (Steketee, 2003, McFarland and Kalivas, 2001, McFarland et al., 2004). The pyramidal projection neurons of the prefrontal cortex innervate subcortical regions, such as nucleus accumbens and ventral tegmental area, and provide glutamatergic neurotransmission (Sesack et al., 1989, Sesack and Pickel, 1992, Groenewegen et al., 1990). 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 (Heidbreder and Groenewegen, 2003). The dorsal prefrontal cortex 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 (Sesack et al., 1989, Groenewegen et al., 1990, Berendse et al., 1992). The ventral prefrontal cortex consists of the ventral portion of the prelimbic and the infralimbic cortex and preferentially innervates the nucleus accumbens shell (Sesack et al., 1989, Hurley et al., 1991, Gorelova and Yang, 1997). The mPFC is innervated by the dopaminergic afferents from the ventral tegmental area 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, prefrontal cortex innervates the ventral tegmental area with prelimbic cortex exhibiting a larger innervation than cingulate or infralimbic regions (Sesack et al., 1989, Sesack and Pickel, 1992, Hurley et al., 1991, Beckstead, 1979).

Several studies have suggested the involvement of the prefrontal cortex in the locomotor sensitization to cocaine. Lesion of the prelimbic, but not cingulate or infralimbic regions, prevented the development of locomotor sensitization to cocaine (Tzschentke and Schmidt, 1998, Tzschentke and Schmidt, 2000). Lesion of dorsal prefrontal cortex, but not ventral PFC, inhibited the expression of locomotor sensitization to cocaine (Pierce et al., 1998). Locomotor sensitization to cocaine leads to augmented glutamate release in PFC after a cocaine challenge administration at 1 and 7 days of withdrawal but not after 30 days of withdrawal (Williams and Steketee, 2004). However, the basal levels of extracellular glutamate is not changed after early (1 or 7 days) or extended (21 or 30 days) withdrawal period (Baker et al., 2003, Williams and Steketee, 2004). Further, recent studies suggest an important role for mPFC in cocaine self-administration. For example, inhibition of dPFC, but not vPFC, prevented cocaine and footshock mediated reinstatement of drug seeking (McFarland and Kalivas, 2001, McFarland et al., 2004).

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 (Malinow and Malenka, 2002, Kennedy, 2000, Kennedy and Ehlers, 2006, Derbach et al., 2007). 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 locomotor sensitization to cocaine is associated with an extensive trafficking and redistribution of glutamate receptors in the nucleus accumbens (Ghasemzadeh et al., 2008). Furthermore, neuroimaging of addicts suggest 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 reports 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 (Sun et al., 2005, Gao and Wolf, 2008). These studies suggest that plasticity in the glutamate receptors in the prefrontal cortex may contribute to the addiction-related behaviors. However, the nature and mechanisms of the glutamate receptor neuroadaptations in the prefrontal cortex after locomotor sensitization 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 the current study, in an attempt to address some of these issues, we investigated the redistribution of the glutamate receptors in the medial prefrontal cortex and anterior cingulate cortex, brain nuclei associated with addiction-related behaviors, after locomotor sensitization to cocaine and withdrawal. The glutamate receptor proteins were 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., 2003, Wyszynski et al., 1998, Dunah and Standaert, 2001, Toda et al., 2003). This study is the first to report a significant redistribution of the three subtypes of the glutamate receptors in the synaptosomal membrane fraction associated with the postsynaptic density in PFC after withdrawal from repeated exposure to cocaine. Furthermore, the time course of the receptor redistribution suggest a role for augmented glutamate receptor signaling in withdrawal-mediated increase in drug seeking and other addiction-related behaviors.

Section snippets

Animal housing

Male Sprague Dawley rats weighing 275–300 g were obtained from Harlan Laboratories (Indianapolis, IN) and housed two per cage with water and food available ad libitum. All housing and experimental procedures were conducted in AAALAC approved facilities according to guidelines established by the National Institutes of Health. A 12 h light/dark cycle was used with the lights on at 7:00 AM. Animals were acclimated to the housing facility for one week before starting experiments. Behavioral

Cocaine treatment and locomotor sensitization

Male Sprague Dawley rats (275–300 g) rats were treated with daily administration of saline (1 mg/kg, ip) or cocaine for 9 days (2 × 10 mg/kg + 7 × 30 mg/kg, ip). Four groups of 16 rats were treated with either saline (n = 8) or cocaine (n = 8) at separate times using identical procedure. The locomotor response was monitored for 120 min after the first (Day 1) and last (Day 9) administration of saline or cocaine. Two groups of animals were killed 1 day after the last saline or cocaine administration

Discussion

This study demonstrates that locomotor sensitization to cocaine is accompanied by a complex pattern of redistribution of the glutamate receptor proteins in the synaptosomal compartment associated with the postsynaptic density in the prefrontal cortex. Furthermore, the redistribution of glutamate receptor proteins was not accompanied by changes in tissue protein levels suggesting a redistribution of the existing pool of cellular proteins. The protein redistribution was dependent on the

Acknowledgement

This work was supported by United States Public Service Grant DA14328 (M.B.G.).

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