Differences in Rat Dorsal Striatal NMDA and AMPA Receptors following Acute and Repeated Cocaine-Induced Locomotor Activation

Abstract

Sprague-Dawley rats can be classified as low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor activity induced by an acute low dose of cocaine. Upon repeated cocaine exposure, LCRs display greater locomotor sensitization, reward, and reinforcement than HCRs. Altered glutamate receptor expression in the brain reward pathway has been linked to locomotor sensitization and addiction. To determine if such changes contribute to the differential development of locomotor sensitization, we examined protein levels of total, phosphorylated, and cell surface glutamate N-methyl D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors (Rs) following acute or repeated cocaine (10 mg/kg, i.p.) in LCRs, HCRs and saline controls. Three areas involved in the development and expression of locomotor sensitization were investigated: the ventral tegmental area (VTA), nucleus accumbens (NAc) and dorsal striatum (dSTR). Our results revealed differences only in the dSTR, where we found that after acute cocaine, GluN2BTyr-1472 phosphorylation was significantly greater in LCRs, compared to HCRs and controls. Additionally in dSTR, after repeated cocaine, we observed significant increases in total GluA1, phosphorylated GluA1Ser-845, and cell surface GluA1 in all cocaine-treated animals vs. controls. The acute cocaine-induced increases in NMDARs in dSTR of LCRs may help to explain the more ready development of locomotor sensitization and susceptibility to addiction-like behaviors in rats that initially exhibit little or no cocaine-induced activation, whereas the AMPAR increases after repeated cocaine may relate to recruitment of more dorsal striatal circuits and maintenance of the marked cocaine-induced locomotor activation observed in all of the rats.

Extrasynaptic Targeting of NMDA Receptors Following D1 Dopamine Receptor Activation and Cocaine Self-Administration

“…Following non-contingent administration of cocaine, the majority of evidence indicates that mRNA and protein levels of NMDARs in the nucleus accumbens are not changed in early abstinence (24 hrs or less), but are increased at weeks or longer intervals of abstinence from cocaine or following extinction of cocaine-seeking (Ghasemzadeh et al, 1999; Crespo et al, 2002; Ghasemzadeh et al, 2009; Schumann and Yaka, 2009; Yamamoto and Zahniser, 2012). Some studies, however, find that non-contingent cocaine administration decreases the expression of NMDAR subunits in the nucleus accumbens (Loftis and Janowsky, 2000; Le Greves et al, 2002).…”

Cocaine-Induced Changes in NMDA Receptor Signaling

“…Cocaine-induced changes in NMDAR expression differ between brain areas, but are also highly sensitive to the choice of cocaine administration paradigm and the history of cocaine exposure. This is particularly evident in the nucleus accumbens (NAc), where short withdrawal (3 days or less) from experimenter-administered (non-contingent) cocaine is reported to decrease the NMDAR subunit levels or leave them unchanged (Yamaguchi et al, 2002; Yamamoto and Zahniser, 2012), whereas longer periods of withdrawal from non-contingent cocaine is associated with an increase in NMDAR subunit expression (Ghasemzadeh et al, 2009a, Schumann and Yaka, 2009; Zhang et al, 2007). This pattern of decreased to increased expression of NMDARs with abstinence from non-contingent cocaine is different for animals that are trained to self-administer cocaine.…”

“…1996; Lu et al, 2003) with some studies reporting no effect of cocaine on NMDAR expression (Churchill, 1999; Yamamoto and Zahniser, 2012). Although these reports suggest some common themes in regulation of NMDAR subunit expression in the NAc and the VTA, they may not reflect changes in levels of functional NMDARs.…”

“…Where some studies demonstrate an increase in the NMDAR expression, others find NMDAR levels to decrease following similar paradigms of cocaine exposure. In the striatum, after short periods of withdrawal, lack of changes and decreases in NMDAR subunit expression have been reported (Yamamoto and Zahniser, 2012; Yamaguchi et al, 2002). However, one binding study indicates an increase in binding of a competitive high affinitiy NMDAR antagonist, 3 H-CGP39653, to the NMDARs (Itzhak and Martin 2000).…”

Rats classified as low or high cocaine locomotor responders: A unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors

“…In addition to the differential locomotor response after acute cocaine, Sprague-Dawley rats that are less activated initially (LCRs) more reliably develop locomotor sensitization than HCRs in response to repeated, intermittent cocaine exposure (Allen et al, 2007; Cass et al, 1993; Mandt et al, 2008, 2009; Nelson et al, 2009, 2010; Sabeti et al, 2003; Yamamoto and Zahniser, 2012). Importantly, we have observed similar results administering 10 mg/kg i.p.…”