Persistent drug-seeking behavior following long-term abstinence is a major challenge for treating cocaine or heroin addiction. Glutamatergic projections have been suggested to be a final common pathway for the initiation of drug seeking (Kalivas et al, 2005). In a clinical setting, neuroimaging studies have shown that cue/drug exposure increased the activity of PFC and nucleus accumbens (NAc), as well as self-reported drug craving in cocaine addicts (Goldstein and Volkow, 2002). In animal studies, a challenge of cocaine or heroin increases the synaptic release of glutamate in cocaine- or heroin-withdrawn rats as a result of the activation of corticostriatal pathways; inactivation of the corticostriatal pathway has been shown to be effective in inhibiting cocaine- or heroin-induced drug seeking (Kalivas et al, 2005).

Dendritic spines are the primary anatomical sites of excitatory synapses in NAc. It has been hypothesized that long-term structural plasticity in NAc contributes to certain long-lasting behaviors, including sensitization (Robinson and Kolb, 2004). Although there has been a paucity of experimental evidence that directly relates central structural plasticity to changes in specific behaviors, the density of spines on medium-sized spiny neurons in NAc is reportedly increased after repeated cocaine exposure (Robinson and Kolb, 2004; Pulipparacharuvil et al, 2008). By using 3D confocal image analysis of medium spiny neurons in the NAc labeled with lipophilic fluorescence dye, the spine density was found to be higher than that of spines quantified by Golgi staining (Shen et al, 2009). Withdrawal from cocaine injection was also reported to be associated with an increased density of larger diameter spines and reduced density of thinner spines. Moreover, a cocaine challenge after 3-week abstinence from daily cocaine treatment significantly increased the density of spines and the effect was found to be more pronounced in larger spines (Shen et al, 2009). These results indicate that long-lasting increases in synaptic connectivity in the NAc may provide a common ground for persistent drug seeking associated with drug addiction.

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