Alterations in ionotropic glutamate receptor subunits during binge cocaine self-administration and withdrawal in rats - PubMed (original) (raw)

Alterations in ionotropic glutamate receptor subunits during binge cocaine self-administration and withdrawal in rats

Wenxue Tang et al. J Neurochem. 2004 May.

Abstract

Chronic cocaine use in humans and animal models is known to lead to pronounced alterations in glutamatergic function in brain regions associated with reinforcement. Previous studies have examined ionotropic glutamate receptor (iGluR) subunit protein level changes following acute and chronic experimenter-administered cocaine or after withdrawal periods from experimenter-administered cocaine. To evaluate whether alterations in expression of iGluRs are associated with cocaine reinforcement, protein levels were assessed after binge (8 h/day, 15 days; 24-h access, days 16-21) cocaine self-administration and following 2 weeks of abstinence from this binge. Western blotting was used to compare levels of iGluR protein expression (NR1-3B, GluR1-7, KA2) in the ventral tegmental area (VTA), substantia nigra (SN), nucleus accumbens (NAc), striatum and prefrontal cortex (PFC) of rats. iGluR subunits were altered in a time-dependent manner in all brain regions studied; however, selective alterations in certain iGluR subtypes appeared to be associated with binge cocaine self-administration and withdrawal in a region-specific manner. In the SN and VTA, alterations in iGluR protein levels compared with controls occurred only following binge access, whereas in the striatum and PFC, iGluR alterations occurred with binge access and following withdrawal. In the NAc, GluR2/3 levels were increased following withdrawal compared with binge access, and were the only changes observed in this region. Because subunit composition determines the functional properties of iGluRs, the observed changes may indicate alterations in the excitability of dopamine transmission underlying long-term biochemical and behavioral effects of cocaine.

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Figures

Fig. 1

Fig. 1

Mean ± SEM number of cocaine infusions and intake self-administered during limited and binge access periods for the two groups. Responding was engendered and maintained by intravenous cocaine infusions by both the binge (●) and withdrawal (○) groups. There was no significant difference in the number of infusions or intake between the two groups. The inset depicts mean ± SEM total number of infusions and intake for the experiments.

Fig. 2

Fig. 2

Regional distribution of iGluR subunits in rat brain. Aliquots of 10 μg membrane fraction combined from four control rats were subjected to sodium dodecyl sulfate–polyacrylamide gel electrophoresis and immunoblotting for NMDR1 (176 kDa), NMDR2A (170 kDa), NMDAR2B (180 kDa), NMDAR3A (130 kDa), NMDAR3B (98 kDa), GluR1 (110 kDa), GluR2/3 (110 kDaA), GluR4 (110 kDa), GluR5 (105 kDa), GluR6/7 (115 kDa), KA2 (123 kDa). STR, striatum; HIPP, hippocampus.

Fig. 3

Fig. 3

Comparisons of NMDA receptor subunit protein levels in VTA, SN, NAc, striatum and PFC following binge cocaine access (black bars) and withdrawal (grey bars). Data are mean ± SEM percentage of values for control rats in each region. Data for each subunit were statistically evaluated using one-way ANOVA. See Table 2 for significant comparisons between groups. *p < 0.05 by post-hoc analysis. Schematics of mesolimbic and nigrostriatal pathways represent graphical depiction of changes for each subunit. Green filled, increased compared with control; red filled, decreased compared with control; green diagonal bands, increased relative to binge; red diagonal bands, decreased relative to binge. N/A, not available; grey filled, no change.

Fig. 4

Fig. 4

Comparisons of AMPA receptor subunit protein levels in VTA, SN, NAc, striatum and PFC following binge cocaine access (black bars) and withdrawal (grey bars). Data are mean ± SEM percentage of values for control rats for each antibody. Data for each subunit were statistically evaluated using one-way ANOVA. See Table 2 for significant comparisons between groups. *p < 0.05 by post-hoc analysis. Schematics of mesolimbic and nigrostriatal pathways represent graphical depiction of changes for each subunit. Green filled, increased compared with control; red filled, decreased compared with control; green diagonal bands, increased relative to binge; red diagonal bands, decreased relative to binge.

Fig. 5

Fig. 5

Representative immunoblot of GluR2/3 protein levels in the striatum following binge cocaine access and withdrawal. Note the decrease in protein levels following binge access and the increase in levels following withdrawal. Data were analyzed by quantitative densiotometry and were found to be statistically different from control levels. Refer to Fig. 4(b) for graphic representation.

Fig. 6

Fig. 6

Comparisons of kainate receptor subunit protein levels in VTA, SN, NAc, striatum and PFC following binge cocaine access (black bars) and withdrawal (grey bars). Data are mean ± SEM percentage of values for control rats for each antibody. Data for each subunit were statistically evaluated using one-way ANOVA. See Table 2 for significant comparisons between groups. *p < 0.05 by post-hoc analysis. Schematics of mesolimbic and nigrostriatal pathways represent graphical depiction of changes for each subunit. Green filled, increased compared with control; red filled, decreased compared with control; green diagonal bands, increased relative to binge; red diagonal bands, decreased relative to binge.

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