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.
Highlights
Initial responsiveness to cocaine and susceptibility to cocaine addiction varies among individuals [1,2]
We found acute cocaine-induced increases in phosphorylated GluN2BTyr-1472 in LCRs that are consistent with the preferential development and expression of locomotor sensitization in LCRs, as compared to HCRs
We investigated whether ionotropic glutamate receptors help to explain differential sensitivity in the locomotor-stimulant effects of low dose cocaine, with particular emphasis on the LCR/ HCR rat model
Summary
Initial responsiveness to cocaine and susceptibility to cocaine addiction varies among individuals [1,2]. Better understanding of how individuals differ in cocaine-induced glutamate neuroplasticity may help to explain why individuals vary in their susceptibility to addiction. This understanding may identify new molecular targets that block and/or reverse drug-induced changes in synaptic plasticity, which would be potentially useful for preventing relapse and/or treating drug addiction. The LCR/ HCR classification is based on the median split of the group locomotor activity in the first 30 min following an acute, relatively low dose of cocaine [(10 mg/kg., i.p.) 10,11,12]. At this dose, LCRs consistently develop locomotor sensitization in response to repeated cocaine whereas HCRs do not. With repeated cocaine, these differences disappear, in parallel with development of locomotor sensitization to cocaine in LCRs [11,16]
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